Publications by authors named "King H Lam"

37 Publications

Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.

Cell Stem Cell 2021 Apr 9;28(4):637-652.e8. Epub 2020 Dec 9.

Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands; Department of Cell Biology, Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany; Oncode Institute, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands. Electronic address:

Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.
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http://dx.doi.org/10.1016/j.stem.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024900PMC
April 2021

Case report: a fatal combination of hemophagocytic lymphohistiocytosis with extensive pulmonary microvascular damage in COVID-19 pneumonia.

J Hematop 2020 Oct 23:1-5. Epub 2020 Oct 23.

Department of Pulmonology, Erasmus MC, Rotterdam, The Netherlands.

The clinical features of COVID-19 have a considerable range from a mild illness to severe disease. Underlying pathophysiological mechanisms of the rapidly progressive, and often fatal, pulmonary disease frequently observed in COVID-19 need to be elucidated, in order to develop new treatment strategies for different disease endotypes. Fatal cases can display features of a cytokine storm, which may be related to hemophagocytic lymphohistiocytosis. Also, a spectrum of vascular changes, including microvascular damage, is known to accompany severe COVID-19. In this paper, we describe the co-occurrence of hemophagocytic lymphohistiocytosis and extensive pulmonary microvascular damage with thrombosis and its sequelae in a patient with fatal COVID-19. We believe these response patterns may be linked by common mechanisms involving hypercytokinemia and require further investigation as a fatal constellation in COVID-19, to generate appropriate treatment in patients who display these combined features.
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http://dx.doi.org/10.1007/s12308-020-00423-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581498PMC
October 2020

Stage-specific trends in primary therapy and survival in follicular lymphoma: a nationwide population-based analysis in the Netherlands, 1989-2016.

Leukemia 2020 Oct 12. Epub 2020 Oct 12.

Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands.

We assessed stage-specific trends in primary therapy and relative survival among adult follicular lymphoma (FL) patients diagnosed in the Netherlands between 1989-2016 (N = 12,372; median age, 62 years; and 21% stage I disease). Patients were stratified by disease stage and subsequently categorized into four calendar periods (1989-1995, 1996-2002, 2003-2008, and 2009-2016) and three age groups (18-60, 61-70, and >70 years). The use of radiotherapy in stage I FL remained relatively stable over time and across the three age groups (i.e., 66%, 54%, and 49% in 2009-2016, respectively). In stage II-IV FL, the start of chemotherapy within 12 months post-diagnosis decreased over time, indicating a broader application of a watch-and-wait approach. Relative survival improved considerably over time, especially since 2003 when rituximab was introduced in the Netherlands, and for stage III-IV FL patients and older age groups. Five-year relative survival for patients with stage I-II versus stage III-IV FL in the period 2009-2016 was 96% versus 90%, 93% versus 83%, and 92% versus 68% across the three age groups, respectively. Collectively, the improvement in survival since 2003 is accounted for by advances in FL management, particularly the implementation of rituximab. There remains, however, room for improvement among elderly stage III-IV FL patients.
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http://dx.doi.org/10.1038/s41375-020-01048-6DOI Listing
October 2020

Spectrum of histiocytic neoplasms associated with diverse haematological malignancies bearing the same oncogenic mutation.

J Pathol Clin Res 2021 01 27;7(1):10-26. Epub 2020 Aug 27.

Department of Paediatrics, Leiden University Medical Center, Leiden, The Netherlands.

Histiocytic disorders are a spectrum of rare diseases characterised by the accumulation of macrophage-, dendritic cell-, or monocyte-differentiated cells in various tissues and organs. The discovery of recurrent genetic alterations in many of these histiocytoses has led to their recognition as clonal neoplastic diseases. Moreover, the identification of the same somatic mutation in histiocytic lesions and peripheral blood and/or bone marrow cells from histiocytosis patients has provided evidence for systemic histiocytic neoplasms to originate from haematopoietic stem/progenitor cells (HSPCs). Here, we investigated associations between histiocytic disorders and additional haematological malignancies bearing the same genetic alteration(s) using the nationwide Dutch Pathology Registry. By searching on pathologist-assigned diagnostic terms for the various histiocytic disorders, we identified 4602 patients with a putative histopathological diagnosis of a histiocytic disorder between 1971 and 2019. Histiocytosis-affected tissue samples of 187 patients had been analysed for genetic alterations as part of routine molecular diagnostics, including from nine patients with an additional haematological malignancy. Among these patients, we discovered three cases with different histiocytic neoplasms and additional haematological malignancies bearing identical oncogenic mutations, including one patient with concomitant KRAS p.A59E mutated histiocytic sarcoma and chronic myelomonocytic leukaemia (CMML), one patient with synchronous NRAS p.G12V mutated indeterminate cell histiocytosis and CMML, and one patient with subsequent NRAS p.Q61R mutated Erdheim-Chester disease and acute myeloid leukaemia. These cases support the existence of a common haematopoietic cell-of-origin in at least a proportion of patients with a histiocytic neoplasm and additional haematological malignancy. In addition, they suggest that driver mutations in particular genes (e.g. N/KRAS) may specifically predispose to the development of an additional clonally related haematological malignancy or secondary histiocytic neoplasm. Finally, the putative existence of derailed multipotent HSPCs in these patients emphasises the importance of adequate (bone marrow) staging, molecular analysis and long-term follow-up of all histiocytosis patients.
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http://dx.doi.org/10.1002/cjp2.177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737785PMC
January 2021

Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84).

J Clin Oncol 2020 10 30;38(29):3377-3387. Epub 2020 Jul 30.

Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Purpose: Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP.

Patients And Methods: A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat.

Results: CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio [HR], 0.82; 95% CI, 0.50 to 1.36; = .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61; = .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55; = .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67; = .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections.

Conclusion: Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.
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http://dx.doi.org/10.1200/JCO.19.03418DOI Listing
October 2020

Rituximab-PECC induction followed by Y-ibritumomab tiuxetan consolidation in relapsed or refractory DLBCL patients who are ineligible for or have failed ASCT: results from a phase II HOVON study.

Br J Haematol 2019 11 10;187(3):347-355. Epub 2019 Jul 10.

Department of Haematology, University Medical Centre Groningen, Groningen, The Netherlands.

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after, or ineligible for, autologous stem cell transplantation (ASCT) have a dismal prognosis. This phase II study evaluated treatment with R-PECC (rituximab, prednisolone, etoposide, chlorambucil, lomustine), every 28 days for 4 cycles in 62 patients, followed by radio-immunotherapy consolidation with Y-ibritumomab tiuxetan in responsive patients. Primary endpoints were failure-free survival (FFS) and incidence of grade ≥3 adverse events from start of Y-ibritumomab tiuxetan. The overall response rate after R-PECC was 50%. Twenty-nine of 31 responsive patients proceeded to Y-ibritumomab tiuxetan. Five out of 15 partial remission patients converted to complete remission after Y-ibritumomab tiuxetan. One-year FFS and overall survival (OS) from start of Y-ibritumomab tiuxetan was 52% (95% confidence interval [CI], 33-68%) and 62% (95% CI, 42-77%), respectively. One-year FFS and OS from start of R-PECC was 28% (95% CI, 17-39%) and 49% (95% CI, 36-61%), respectively. Toxicities of R-PECC and Y-ibritumomab tiuxetan were mainly haematological. In conclusion, for relapsed DLBCL patients the largely oral R-PECC regimen achieves promising response rates, combined with an acceptable safety profile. Consolidation with Y-ibritumomab tiuxetan resulted in long-term response durations in approximately one third of the patients that received it.
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http://dx.doi.org/10.1111/bjh.16087DOI Listing
November 2019

Flow cytometry shows added value in diagnosing lymphoma in brain biopsies.

Cytometry B Clin Cytom 2018 11 3;94(6):928-934. Epub 2018 Sep 3.

Department of Immunology, Laboratory Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Background: To assess the sensitivity, specificity and turnaround time of flow cytometric analysis on brain biopsies compared to histology plus immunohistochemistry analysis in tumors with clinical suspicion of lymphoma.

Methods: All brain biopsies performed between 2010 and 2015 at our institution and analyzed by both immunohistochemistry and flow cytometry were included in this retrospective study. Immunohistochemistry was considered the gold standard.

Results: In a total of 77 biopsies from 71 patients, 49 lymphomas were diagnosed by immunohistochemistry, flow cytometry results were concordant in 71 biopsies (92.2%). We found a specificity and sensitivity of flow cytometry of 100% and 87.8%, respectively. The time between the biopsy and reporting the result (turnaround time) was significantly shorter for flow cytometry, compared to immunohistochemistry (median: 1 vs. 5 days).

Conclusions: Flow cytometry has a high specificity and can confirm the diagnosis of a lymphoma significantly faster than immunohistochemistry. This allows for rapid initiation of treatment in this highly aggressive tumor. However, since its sensitivity is less than 100%, we recommend to perform histology plus immunohistochemistry in parallel to flow cytometry. © 2018 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cyto.b.21641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585701PMC
November 2018

Reinforcement of the colon anastomosis with cyanoacrylate glue: a porcine model.

J Surg Res 2017 09 10;217:84-91. Epub 2017 May 10.

Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Previous experimental studies on cyanoacrylate (CA) glue for the prevention of colorectal anastomotic leakage (AL) have shown promising results. The aim of this study was to investigate the effect of CA in prevention of leakage in a porcine model of ischemic colorectal AL.

Methods: Twenty-four animals were divided into four groups of six: (1)ischemic anastomosis with sufficient suture (ISCH), (2)ischemic anastomosis with sufficient suture and CA reinforcement (CA-ISCH), (3)ischemic anastomosis with insufficient suture (ISCH-AI), and (4)ischemic anastomosis with insufficient suture and CA reinforcement (CA-ISCH-AI). In CA groups, N-butyl-2-cyanoacrylate was applied between the colon ends. Anastomotic bursting pressure, abscess formation, and adhesion formation were evaluated on postoperative day 7. Tissue samples were obtained for histologic evaluation of foreign body reaction.

Results: The AL rate was 4 of 6 (67%) in the ISCH-AI group compared with none in the other three groups. The ISCH and ISCH-AI groups had significantly higher AL scores compared with the CA groups. The mean anastomotic bursting pressure was 167 ± 54 mm Hg in the ISCH-group versus 213 ± 43 mm Hg in the CA-ISCH-group (P = nonsignificant) and 145 ± 102 mm Hg in the ISCH-AI group versus 187 ± 19 mm Hg in the CA-ISCH-AI group (P = nonsignificant). The average adhesion score was significantly higher in the ISCH group than in the CA-ISCH group (4.2 ± 1.3 versus 1.7 ± 0.82; P = 0.019). Stricture of the anastomosis occurred only in the non-CA groups (3/12, 25%).

Conclusions: Anastomotic reinforcement with CA is effective and safe to prevent leakage in a high-risk colorectal anastomosis in a porcine model.
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http://dx.doi.org/10.1016/j.jss.2017.05.001DOI Listing
September 2017

Chronic signs of memory B cell activation in patients with Behçet's disease are partially restored by anti-tumour necrosis factor treatment.

Rheumatology (Oxford) 2017 01 15;56(1):134-144. Epub 2016 Oct 15.

Department of Internal Medicine

Objectives: Behçet's disease (BD), an auto-inflammatory vasculitis with oro-genital ulcerations, skin lesions and uveitis, is regarded as T cell mediated. A successful trial with rituximab suggests an additive role for B cells in the pathogenesis. Therefore, we studied B cell abnormalities in BD patients and the effect of TNF-blocking therapy.

Methods: B cells in blood (n = 36) and tissue (n = 6) of BD patients were analysed with flow cytometry and/or immunohistochemistry and compared with healthy controls (n = 22). BD current activity form (BDCAF) in relation to B cell somatic hypermutations (SHMs) and immunoglobulin class-switching were studied.

Results: Thirty-six patients (17 males) were included, mean age 44 years, average disease duration 10 years and mean BDCAF 2.7. Blood B cell numbers were significantly lower in patients than in controls (P = 0.0061), mostly due to decreased CD27 memory B cells expressing IgM (P = 0.0001), IgG (P = 0.0002) and IgA (P = 0.0038) B cell subsets. CD27 IgA B cells showed the highest magnitude of decrease in active disease, measured with BDCAF (P = 0.02). CD27 IgM IgD B cells were impaired in replication history (P = 0.0133) and selection of SHM, whereas IgA B cells carried elevated SHM levels (P = 0.04) and lower IgA2 subclass usage (P = 0.0004) than controls. Immunohistochemistry revealed B cells in tissue of active mucosal ulcers. In adalimumab-treated patients, blood B cells were similar to controls.

Conclusion: We show significant deviations in the memory B cell compartment, related to disease activity and therapeutic efficacy. Pronounced molecular impairments were seen in the fast-responding IgM-memory and the mucosal IgA-memory B cells. Because of the demonstrated abundance of B cells in affected tissue, we hypothesize relocation of memory B cells to the site of inflammation could account for the deviations found in blood of BD patients. These peripheral B cells are easily accessible as a marker to monitor therapeutic efficacy.
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http://dx.doi.org/10.1093/rheumatology/kew366DOI Listing
January 2017

Sutureless closure of colonic defects with tissue adhesives: an in vivo study in the rat.

Am J Surg 2017 Jan 16;213(1):151-158. Epub 2016 Jun 16.

Department of Surgery, Erasmus University Medical Center, Room Ee-173, Postbus 2040, 3000 CA Rotterdam, The Netherlands.

Background: Tissue adhesives (TAs) in gastrointestinal surgery are gradually gaining acceptance. Before implementation as colonic sealants, an evaluation of the sealing capability of a TA when in contact with fecal matter, as in a leaking anastomosis, is needed. In this study, we used clinically available TAs for the sutureless closure of colonic defects evaluating mechanical strength and tissue healing.

Methods: A total of 160 rats were divided into 8 groups. Two .5-cm incisions were created, one in the proximal and another in the distal colon. Incisions were sealed with a TA: Histoacryl Flex, Bioglue, Dermabond, Tissucol, Duraseal Xact, gelatin-resorcinol-formaldehyde or Glubran 2. A control group was included in which the colonic defects were not sealed. Follow-up time was 3 or 10 days. Clinical complication rate, bursting pressure, and histopathologic analysis was included.

Results: Leakage rates in the TA groups were highest for Duraseal Xact, Bioglue, and gelatin-resorcinol-formaldehyde at 3 and 10 days. The cyanoacrylates Glubran 2, Histoacryl Flex, and Omnex, and the fibrin glue Tissucol showed the lowest overall clinical complication rates while maintaining the highest bursting pressure at day 10. Histoacryl Flex exhibited significantly higher collagen formation at day 10 than the other TAs.

Conclusions: This experimental model evaluates the protective effect of a TA seal on a leaking colonic defect. We found large differences in leakage rates and inertness of the tested TAs. The cyanoacrylates Histoacryl Flex, Omnex, and Glubran 2 as well as the fibrin glue Tissucol demonstrated the lowest leakage rates and the most inert histopathologic profile while maintaining high mechanical strength.
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http://dx.doi.org/10.1016/j.amjsurg.2016.05.009DOI Listing
January 2017

B-Cell Dysregulation in Crohn's Disease Is Partially Restored with Infliximab Therapy.

PLoS One 2016 28;11(7):e0160103. Epub 2016 Jul 28.

Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.

Background: B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn's disease.

Objective: To elucidate the involvement of B cells in Crohn's disease, we here performed an 'in depth' analysis of intestinal and blood B-cells in this chronic inflammatory disease.

Methods: Patients with Crohn's disease were recruited to study B-cell infiltrates in intestinal biopsies (n = 5), serum immunoglobulin levels and the phenotype and molecular characteristics of blood B-cell subsets (n = 21). The effects of infliximab treatment were studied in 9 patients.

Results: Granulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21low B cells were elevated. IgM memory B cells were reduced and natural effector cells showed decreased replication histories and somatic hypermutation (SHM) levels. In contrast, IgG and IgA memory B cells were normally present and their Ig gene transcripts carried increased SHM levels. The numbers of transitional and natural effector cells were normal in patients who responded clinically well to infliximab.

Conclusions: B cells in patients with Crohn's disease showed signs of chronic stimulation with localization to granulomatous tissue and increased molecular maturation of IgA and IgG. Therapy with TNFα-blockers restored the defect in IgM memory B-cell generation and normalized transitional B-cell levels, making these subsets candidate markers for treatment monitoring. Together, these results suggest a chronic, aberrant B-cell response in patients with Crohn's disease, which could be targeted with new therapeutics that specifically regulate B-cell function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160103PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965034PMC
August 2017

[Leukocytosis and skin lesions: consider malignancy; adult T-cell leukaemia/lymphoma].

Ned Tijdschr Geneeskd 2016 ;160:A9866

Erasmus Medisch Centrum, Rotterdam.

Background: Adult T-cell leukaemia/lymphoma (ATLL) is a rare mature T-cell malignancy that occurs in patients infected with human T-cell leukaemia virus type 1 (HTLV-1). Only a minority of HTLV-1 carriers develop neoplastic transformation to ATLL after a 40- to 60-year latency period.

Case Description: A 49-year-old Columbian male presented to the Emergency Department with abdominal pain, weight loss, generalized cutaneous papules and epistaxis. Extensive cytomorphological, histopathological, immunophenotypical, serological, and molecular (cyto)genetic analysis all contributed to reach the diagnosis of acute HTLV-1 associated ATLL. The patient was treated with multiagent cytotoxic chemotherapy, consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

Conclusion: Acute ATLL is a clinically aggressive disease and carries a poor prognosis. Treatment options include antiviral regimens, chemotherapy, monoclonal antibody-targeted therapy, and allogeneic stem-cell transplantation. The incidence of ATLL in non-endemic areas, such as the Netherlands, is increasing due to emigration of HTLV-1 carriers from endemic areas.
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May 2017

Clinical, mechanical, and immunohistopathological effects of tissue adhesives on the colon: An in-vivo study.

J Biomed Mater Res B Appl Biomater 2017 05 24;105(4):846-854. Epub 2016 Jan 24.

Department of Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands.

Background: Tissue adhesives may be useful for sealing bowel anastomoses by preventing anastomotic leakage. Prior to clinical implementation, an in-depth analysis of the clinical and immunohistopathological effects of tissue adhesives on the target tissue and of the mechanical strength of the adhesive bond in an in vivo model is needed.

Materials And Methods: In 84 rats, two bowel segments were glued using one of the following tissue adhesive: Bioglue, Gelatin-resorcinol-formaldehyde (GRF), Glubran 2, Histoacryl Flex, Omnex, Duraseal Xact, or Tissucol. Rats were followed for 7 or 28 days. Endpoints were clinical complication rate, mechanical strength, and immunohistopathological reactions.

Results: Of the seven tissue adhesives, GRF and Bioglue showed the highest rates of bowel wall destruction and ileus and the most severe immunohistopathological tissue reactions at 7 and 28 days. Cyanoacrylates (Histoacryl Flex, Omnex, Glubran 2) showed high mechanical strength and mild immunohistopathological reactions at 7 and 28 days. Duraseal Xact and Tissucol were the most inert tissue adhesives, but exhibited low mechanical strength. At 28 days, mechanical strength was significantly correlated to CD8, CD68, and Ki67 cell counts.

Conclusion: Based on the clinical and immunohistopathological outcomes, GRF and Bioglue were found to be the least suitable tissue adhesives for colonic use. Duraseal Xact and Tissucol were inert but also showed low mechanical strength. Cyanoacrylates exhibited mild clinical and immunohistopathological effects while maintaining high strength, which makes them promising as colonic sealants. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 846-854, 2017.
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http://dx.doi.org/10.1002/jbm.b.33621DOI Listing
May 2017

Cytokine and viral load kinetics in human herpesvirus 8-associated multicentric Castleman's disease complicated by hemophagocytic lymphohistiocytosis.

Int J Hematol 2016 Apr 21;103(4):469-72. Epub 2015 Dec 21.

Section of Clinical Immunology, Department of Internal Medicine, Erasmus University MC, University Medical Center, Room D-419, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Human herpes virus 8 (HHV-8)-associated secondary hemophagocytic lymphohistiocytosis is a rare but critical immuno-hematological entity in immunocompetent patients. Establishing a diagnosis is challenging as is the monitoring of disease activity and therapeutic effects. We report a case of a HHV-8-associated hemophagocytic lymphohistiocytosis in a HIV-negative adult patient with multicentric Castleman's disease. As a novel finding, we report the use of certain inflammatory parameters, primarily interleukin-10 combined with viral load monitoring of the causative infectious agent in this case HHV-8 to monitor the clinical course of the hemophagocytic lymphohistiocytosis in the setting of bacterial septic complications.
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http://dx.doi.org/10.1007/s12185-015-1928-4DOI Listing
April 2016

Reducing colorectal anastomotic leakage with tissue adhesive in experimental inflammatory bowel disease.

Inflamm Bowel Dis 2015 May;21(5):1038-46

Departments of *Surgery, †Orthopaedics, ‡Pathology, §Neuroscience, and ‖Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Background: Anastomotic leakage after gastrointestinal surgery remains a challenging clinical problem. This study aimed to investigate the effectiveness of TissuCol (fibrin glue), Histoacryl Flex (n-butyl-2-cyanoacrylate), and Duraseal (polyethylene glycol) on colorectal anastomotic healing during experimental colitis.

Methods: We first performed colectomy 7 days after 10 mg trinitrobenzene sulfonic acid (TNBS)-induced colitis to validate a rat TNBS-colitis-colectomy model. Subsequently, this TNBS-colitis-colectomy model was used in 73 Wistar rats that were stratified into a colitis group (CG, no adhesive), a TissuCol group (TG), a Histoacryl group (HG), and a Duraseal group (DG). Anastomotic sealant was applied with one adhesive after constructing an end-to-end hand-sewn anastomosis. Clinical manifestations, anastomotic bursting pressure, and immunohistochemistry of macrophage type-one (M1) and type-two (M2) was performed on postoperative day (POD)3 or POD7.

Results: TNBS-caused mucosal and submucosal colon damage and compromised anastomotic healing (i.e., abscess formation and low anastomotic bursting pressure). On POD3, higher severity of abscesses was seen in CG. Average anastomotic bursting pressure was 53.2 ± 35.5 mm Hg in CG, which was significantly lower than HG (134.4 ± 27.5 mm Hg) and DG (95.1 ± 54.3 mm Hg) but not TG (83.4 ± 46.7 mm Hg). Furthermore, a significantly higher M2/M1 index was found in HG. On POD7, abscesses were only seen in CG (6/9) but not in other groups; HG had the lowest severity of adhesion.

Conclusions: We describe the first surgical IBD model by performing colectomy in rats with TNBS-induced colitis, which causes intra-abdominal abscess formation and compromises anastomotic healing. Anastomotic sealing with Histoacryl Flex prevents these complications in this model. Alternative activation of macrophages seems to be involved in its influence on anastomotic healing.
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http://dx.doi.org/10.1097/MIB.0000000000000336DOI Listing
May 2015

Paediatric nodal marginal zone B-cell lymphadenopathy of the neck: a Haemophilus influenzae-driven immune disorder?

J Pathol 2015 Jul 8;236(3):302-14. Epub 2015 Apr 8.

Microbiology and Infection Control, Zorggroep Twente, Hengelo, The Netherlands.

Many hyperplasias and lymphomas of marginal zone B-cells are associated with infection. We identified six children and one adolescent with cervical lymphadenopathy showing prominent polyclonal nodal marginal zone hyperplasia (pNMZH) and four adolescents with monoclonal paediatric nodal marginal zone lymphoma (pNMZL). The clonality status was assessed using BIOMED-2-IG PCR analysis. Haemophilus influenzae was identified in all six cases of pNMZH that could be tested by direct culture (N = 3) or a very sensitive PCR for the H. influenzae gyrase gene in frozen materials (N = 5). H. influenzae was not detected in three pNMZLs and 28 non-specific reactive cervical lymph nodes of age-matched controls, except for a single control node that was obtained during oropharyngeal surgery for a cleft palate showing very low copy numbers of H. influenzae. pNMZH patients were younger than pNMZL patients (median age 12 versus 21 years). pNMZH showed a prominent nodular appearance with variable fibrosis without acute inflammation. Within the nodules, the expanded germinal centres and variably sized marginal zones were colonized by activated B-cells with weak expression of IgD and lack of CD10 and/or BCL6 expression. Some areas showed skewed light chain expression in plasma cells (4/5 cases lambda). In four cases tested, this was confirmed by flow cytometry for surface Ig (3/4 cases lambda). In contrast, pNMZL showed more extensive expansion of marginal zones by centrocytoid cells and often expression of BCL2 protein. Several H. influenzae strains are known to interact with the constant part of IgD on human B-cells, leading to their polyclonal proliferation and activation. We speculate that in vivo stimulation of IgD+ marginal zone B-cells by this bacterium may be implicated in this particular lymphadenopathy that should be distinguished from monoclonal pNMZL.
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http://dx.doi.org/10.1002/path.4524DOI Listing
July 2015

A reference image-based method for optimization of clinical immunohistochemistry.

Histopathology 2015 Aug 19;67(2):193-205. Epub 2015 Feb 19.

Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.

Aims: Cold ischaemic and formalin fixation time (CIT and FFT) are considered to be crucial parameters for intralaboratory variation in immunohistochemistry (IHC). Here we describe a new method to optimize IHC, by using control tissue blocks with known pre-analytical history and comparing the IHC outcome with digitized reference slides.

Methods And Results: Tissue specimens (two per tissue type) were divided into eight samples, which were subjected to different CIT and FFT. Immunohistochemistry was performed with 34 routinely used antibodies, following standard operating procedures. Relative staining intensity of four sections per slide was scored. Of the antibodies studied, seven were influenced by CIT, 13 by FFT and five by both parameters. IHC protocols were adapted until most sections on the slide showed the same intensity. Changing the antibody dilution for 10 protocols and the antigen retrieval method for six protocols improved the consistency of the IHC staining. Nine protocols could not be optimized. The optimized staining results were compared to reference slides and were found to be of adequate quality.

Conclusions: It was possible to optimize most IHC protocols by adapting the analytical, rather than the pre-analytical, phase. If global references can be established, this method could decrease interlaboratory variation, preceding standardization of the pre-analytical workflow.
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http://dx.doi.org/10.1111/his.12646DOI Listing
August 2015

Colorectal anastomotic leakage caused by insufficient suturing after partial colectomy: a new experimental model.

Surg Infect (Larchmt) 2014 Dec;15(6):733-8

1 Department of Surgery, Erasmus University Medical Center , Rotterdam, The Netherlands .

Background: Colorectal anastomotic leakage (CAL) is the most important complication of colorectal surgery, accounting for one third of post-operative deaths. To prevent it, many interventions have been tested in animal models, mostly rats. However, few of these models have been validated. We aimed to develop a reproducible rat CAL model by creating an anastomosis with insufficient suturing after partial colectomy.

Methods: To establish the number of sutures that would create an appropriate leakage rate for research (20%-50%), partial colectomy was performed in 60 Wistar rats using a 12-suture anastomosis in the control group and an anastomosis with insufficient suturing in the experimental group, starting with five sutures. Seven days later, the rats were examined for the occurrence and severity of CAL, the presence of adhesions, and anastomotic bursting pressure. When an acceptable leakage rate was achieved, the experimental and control studies were repeated twice to confirm the adequacy of the chosen technique.

Results: On day 7, five-suture and 12-suture anastomoses had leakage rates of 50% vs. 30%, 44.4% vs. 20%, and 50% vs. 20%, respectively, in the various series. Overall, the five-suture group had a significantly higher CAL rate than did the 12-suture group (48.3% vs. 23.3%; p=0.045). It also had higher CAL severity and more adhesions (p for both<0.05). The bursting pressure of these anastomoses was significantly lower than that in the 12-suture group (116.8±58.9 mm Hg vs. 150.4±50.3 mm Hg; p=0.041).

Conclusion: Anastomosis with five sutures after partial colectomy provides a suitable rat CAL model. Its future applications may help to improve the consistency of CAL studies.
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http://dx.doi.org/10.1089/sur.2013.197DOI Listing
December 2014

The prevention of colorectal anastomotic leakage with tissue adhesives in a contaminated environment is associated with the presence of anti-inflammatory macrophages.

Int J Colorectal Dis 2014 Dec 26;29(12):1507-16. Epub 2014 Sep 26.

Department of Surgery, Erasmus University Medical Center, Postbus 2040, 3000 CA, Rotterdam, The Netherlands,

Background: Colorectal anastomoses created in a contaminated environment result in a high leakage rate. This study investigated whether using anastomotic sealants (TissuCol(®), Histoacryl(®) Flex, and Duraseal(®)) prevents leakage in a rat peritonitis model.

Study Design: Sixty-seven Wistar rats were divided into control and experimental groups (TissuCol, Histoacryl, and Duraseal groups). Peritonitis was induced 1 day before surgery with the cecal ligation puncture model. On day 0, colonic anastomosis was constructed with sutures and then sealed with no adhesive (control group) or one select adhesive (experimental groups). Bursting pressure, abscess formation, and adhesion severity were evaluated on day 3 or day 14. Hematoxylin and eosin staining and immunohistochemical staining for CD4, CD8, CD206, and iNOS were performed.

Results: On day 3, bursting pressures of the TissuCol group (120.1 ± 25.3 mmHg), Histoacryl group (117.3 ± 20.2 mmHg), and Duraseal group (123.6 ± 35.4 mmHg) were significantly higher than the that of the control group (24.4 ± 31.7 mmHg, p < 0.001). Abscesses around the anastomosis were found in the control group (6/7) and Duraseal group (2/9) but not in the TissuCol group or Histoacryl group. A higher number of CD206+ cells (M2 macrophages), a lower number of iNOS+ cells (M1 macrophages), a higher M2/M1 index, and a higher CD4+/CD8+ index were seen at the anastomotic site in all experimental groups compared with the control group on day 3. On day 14, abscesses were only found in the control group. Adhesion severity in the Duraseal group was significantly lower than that in the control group (p = 0.001).

Conclusions: Anastomotic sealing using TissuCol(®), Histoacryl(®) Flex, or Duraseal(®) seems to be an effective and safe option to prevent leakage in contaminated colorectal surgery. The presence of large numbers of anti-inflammatory macrophages seems to be involved in preventing the leakage.
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http://dx.doi.org/10.1007/s00384-014-2012-xDOI Listing
December 2014

Aspirin-responsive, migraine-like transient cerebral and ocular ischemic attacks and erythromelalgia in JAK2-positive essential thrombocythemia and polycythemia vera.

Acta Haematol 2015 7;133(1):56-63. Epub 2014 Aug 7.

Department of Hematology, University Hospital Antwerp, Antwerp, Belgium.

Migraine-like cerebral transient ischemic attacks (MIAs) and ocular ischemic manifestations were the main presenting features in 10 JAK2(V617F)-positive patients studied, with essential thrombocythemia (ET) in 6 and polycythemia vera (PV) in 4. Symptoms varied and included cerebral ischemic attacks, mental concentration disturbances followed by throbbing headaches, nausea, vomiting, syncope or even seizures. MIAs were frequently preceded or followed by ocular ischemic events of blurred vision, scotomas, transient flashing of the eyes, and sudden transient partial blindness preceded or followed erythromelalgia in the toes or fingers. The time lapse between the first symptoms of aspirin-responsive MIAs and the diagnosis of ET in 5 patients ranged from 4 to 12 years. At the time of erythromelalgia and MIAs, shortened platelet survival, an increase in the levels of the platelet activation markers β-thromboglobulin and platelet factor 4 and also in urinary thromboxane B2 were clearly indicative of the spontaneous in vivo platelet activation of constitutively JAK2(V617F)-activated thrombocythemic platelets. Aspirin relieves the peripheral, cerebral and ocular ischemic disturbances by irreversible inhibition of platelet cyclo-oxygenase (COX-1) activity and aggregation ex vivo. Vitamin K antagonist, dipyridamole, ticlopidine, sulfinpyrazone and sodium salicylate have no effect on platelet COX-1 activity and are ineffective in the treatment of thrombocythemia-specific manifestations of erythromelalgia and atypical MIAs. If not treated with aspirin, ET and PV patients are at a high risk of major arterial thrombosis including stroke, myocardial infarction and digital gangrene.
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http://dx.doi.org/10.1159/000360388DOI Listing
February 2015

A comparison between ultrasonographic, surgical and histological assessment of tenosynovits in a cohort of idiopathic carpal tunnel syndrome patients.

Clin Rheumatol 2016 Mar 24;35(3):775-80. Epub 2014 Jun 24.

HandsOnCare, Medical Center Zuiderzee, Lelystad, The Netherlands.

Carpal tunnel syndrome (CTS) may be caused by subclinical tenosynovitis which may be detected by ultrasonography (US). The objective of this study is to investigate whether ultrasonography has a place in the workup of idiopathic CTS patients. Therefore, we investigated the prevalence of tenosynovitis and its association with the clinical outcome of surgery. A cohort of 31 consecutive idiopathic CTS patients (33 wrists) who were a candidate for carpal tunnel release (CTR) surgery was assessed using greyscale ultrasonography (GSUS) and power Doppler ultrasonography (PDUS). Peroperatively, tenosynovitis was evaluated macroscopically by the surgeon. Tissue samples from areas macroscopically suspected for tenosynovitis were taken for histological evaluation. The clinical outcome of the operation was assessed after 6 months and if applicable alternative diagnoses for the CTS were proposed. US tenosynovitis (OMERACT) was detected preoperatively in 58 % of the wrists. Peroperatively, macroscopic tenosynovitis was detected visually in 88 % of the wrists. Histological evaluation demonstrated a limited influx of lymphocytes indicative of a mild chronic inflammatory response in 19 %. Non-specific reactive changes were observed in 78 % of the cases. Ultrasonographically defined tenosynovitis was associated with an OR of 2.81 (95 % CI 0.61-13) for responding well to surgery. Most cases of ultrasonographic and peroperatively defined tenosynovitis were classified by histology as reactive changes. The presence of ultrasonographic tenosynovitis might be associated with a better clinical outcome of surgery.
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http://dx.doi.org/10.1007/s10067-014-2720-1DOI Listing
March 2016

Blastic plasmacytoid dendritic cell neoplasm.

Br J Haematol 2014 Mar 25;164(6):757. Epub 2013 Nov 25.

Department of Dermatology, Erasmus Medical Centre, Rotterdam, The Netherlands.

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http://dx.doi.org/10.1111/bjh.12666DOI Listing
March 2014

Successive B-cell lymphomas mostly reflect recurrences rather than unrelated primary lymphomas.

Am J Clin Pathol 2013 Jul;140(1):114-26

Dept. of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.

Objectives: To address whether successive B-cell lymphomas, diagnosed within a 5- to 15-year interval, are recurrences or unrelated primary lymphomas.

Methods: Immunoglobulin heavy and κ light chain gene rearrangements were studied using multiplex polymerase chain reaction fragment assays and sequence analysis in 61 patients.

Results: Clonal patterns of the multiple lymphomas from 36 patients were determined and classified accordingly: 30 recurrences, 2 possible recurrences, 2 different clones with a common origin, and 2 unrelated primary lymphomas.

Conclusions: Regardless of subtype, 89% to 94% of late B-cell lymphoma relapses were recurrences of the primary tumor. Therefore, routinely investigating the possible clonal relationship between successive lymphomas may not be warranted except for specific lymphoma subtypes such as diffuse large B-cell lymphomas.
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http://dx.doi.org/10.1309/AJCPI14GXNWASVUZDOI Listing
July 2013

Perigranuloma localization and abnormal maturation of B cells: emerging key players in sarcoidosis?

Am J Respir Crit Care Med 2013 Feb 13;187(4):406-16. Epub 2012 Dec 13.

Department of Immunology, University Medical Center, Rotterdam, The Netherlands.

Rationale: Recent observations of abnormal immunoglobulin responses and case reports describing successful B-cell ablative therapy suggest involvement of B cells in the pathogenesis of sarcoidosis.

Objectives: To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease.

Methods: Patients with sarcoidosis (n = 32) were included for detailed analysis by immunohistochemistry of tissue, flow cytometry of blood B-cell subsets, and serum immunoglobulin levels. Vaccination responses in patients with sarcoidosis to influenza virus and encapsulated bacteria and molecular analysis of immunoglobulin heavy chain transcripts were studied for functional analysis of immunoglobulin responses.

Measurements And Main Results: Perigranuloma localization of IgA-producing plasma cells and numerous B cells were found in affected tissues. Total blood B-cell numbers were normal, CD27(+) memory B cells were significantly reduced, and CD27(-)IgA(+) B cells were significantly increased; the results are normalized in patients treated with TNF-α blockers. Despite this, patients had normal serum immunoglobulin levels and normal antigen-specific immunoglobulin responses. IgA and IgG transcripts, however, showed high frequencies of somatic hypermutations and increased usage of downstream IgG subclasses, suggestive for prolonged or repetitive responses.

Conclusions: The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD27(-)IgA(+) B cells could be a marker for treatment with TNF-α blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis.
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http://dx.doi.org/10.1164/rccm.201206-1024OCDOI Listing
February 2013

Reproducibility of histologic classification in nonfibrotic myeloproliferative neoplasia.

Am J Clin Pathol 2011 Oct;136(4):618-24

Dept. of Pathology, University Hospital Maastricht, Maastricht, the Netherlands.

Early phases of polycythemia vera, essential thrombocythemia, and primary myelofibrosis (PMF) can be difficult to distinguish by morphologic studies alone because they share many morphologic characteristics. Histologic criteria according to the 2008 World Health Organization (WHO) classification are part of the myeloproliferative neoplasia (MPN) diagnosis. Our aim was to assess the reproducibility of morphologic characteristics and determine their relative importance for histologic diagnoses on selected trephine biopsy sections. For the study, 56 prefibrotic MPN trephine specimens were blindly reviewed by 4 hematopathologists using a scoring list of 16 histologic characteristics mentioned in the WHO classification. Consensus was defined as agreement by 3 of 4 hematopathologists. High degrees of consensus were reached for individual major morphologic features used in the WHO classification, especially for the nuclear features of megakaryocytes (83%). Some of the features correlated positively or negatively with the histologic diagnosis of PMF. Consensus for the histologic classification of MPN was reached in 39 (70%) of 56 cases without knowledge of clinical data. This finding indicates a difference in the relative importance assigned to individual histologic characteristics by different hematopathologists.
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http://dx.doi.org/10.1309/AJCP2UG9SGGWAHUADOI Listing
October 2011

The expression of the peripheral cannabinoid receptor CB2 has no effect on clinical outcome in diffuse large B-cell lymphomas.

Eur J Haematol 2011 Jun 1;86(6):466-76. Epub 2011 Apr 1.

Departments of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: The peripheral cannabinoid receptor (CB2) is mainly detected on B cells in the germinal centers (GCs) of the immune system, using an antibody directed against the extra cellular N-terminal domain of the receptor. We retrospectively investigated the CB2 receptor expression in diffuse large B-cell lymphomas (DLBCL) and its clinical relevance for treatment outcome.

Patients And Methods: We have constructed a tissue micro-array (TMA) using lymphoma tissue of a large cohort of patients with DLBCL (N = 104) who were treated with CHOP.

Results:   Forty-five out of 79 evaluable cases (57%) were CB2 positive. The expression of CB2 receptors was variably present in both the germinal center B cell (GCB) (n = 31) and the non-GCB/activated B-cell (ABC) (n = 43) DLBCL subtypes. CB2 positivity was not associated with a different outcome in this patient cohort (CR; P = 0.87, EFS; P = 0.32, DFS; P = 0.06 and OS; P = 0.18). Implementation of CB2 expression in the Hans algorithm using the markers CD10, BCL6, and MUM1 did not result in added prognostic value (all P-values >0.1).

Conclusions: We hypothesize that although CB2 is normally expressed in GCs, the expression in one of the malignant counterparts such as DLBCL is aberrant. This may be an explanation for the absence of prognostic relevance for the expression of this protein.
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http://dx.doi.org/10.1111/j.1600-0609.2011.01596.xDOI Listing
June 2011

Prognostic relevance of immunohistochemical subclassification of diffuse large B-cell lymphoma in two prospective phase III clinical trials.

Clin Lymphoma Myeloma Leuk 2011 Feb;11(1):23-32

Department of Hematology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.

Purpose: Until now molecular biologic techniques have not been easily used in daily clinical practice to stratify patients for therapeutic purposes. Therefore, we have investigated the prognostic relevance of the immunohistochemical (IHC) germinal center B-cell (GCB) versus non-GCB diffuse large B-cell lymphoma (DLBCL) subtypes.

Patients And Methods: We have analyzed tumor samples from patients treated in 2 prospective multicenter phase III trials, ie HOVON 25 (patients≥65 years, n=153) and HOVON 26 (patients<65 years, n=144) using whole sections (WS) or tissue microarray (TMA). CD10, BCL6, and MUM1 were applied in a specific IHC algorithm. The effect on clinical outcome using WS or TMA and variations in cut-off levels of these markers was also investigated.

Results: The GCB subtype was not associated with a better OS in either trial. Small differences were observed in the HOVON 25 trial between techniques, with TMA showing a better outcome for GCB than did WS. Variation of cut-off levels in the specific algorithm did not improve the prediction of clinical outcome.

Conclusion: We did not observe a consistent predictive power of the GCB and non-GCB classification by IHC in this large series of DLBCL patients treated with CHOP. This underscores the need to determine the biologic variation and the standardization of the protein expression levels and to further study the relevance of prognostic IHC classifications, preferably in phase III clinical trials.
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http://dx.doi.org/10.3816/CLML.2011.n.003DOI Listing
February 2011

The expression of the peripheral cannabinoid receptor on cells of the immune system and non-Hodgkin's lymphomas.

Leuk Lymphoma 2007 Jul;48(7):1389-99

Department of Hematology, Erasmus Medical Centre, Rotterdam, The Netherlands.

The peripheral cannabinoid receptor CB2 is expressed highly on normal human B-lymphocytes. C-terminal specific anti-CB2 antibody recognises a non-phosphorylated inactive receptor on naïve and resting B-lymphocytes. Another, N-terminal specific CB2 antibody, primarily recognises B-cells present in the germinal centres of secondary follicles in lymph nodes. We hypothesise that N-terminal specific CB2 antibody recognises activated CB2 receptors. In this study, we showed using these antibodies, that expression of CB2 is generally absent on T-lymphocytes in reactive, non-malignant human lymphoid tissues. Applying single and dual immunohistochemistry, CD23(+) follicular dendritic cells and a small but significant subpopulation of CD68(+) macrophages showed positive staining with the N-terminal specific CB2 antibody but not with the C-terminal specific CB2 antibody. This may indicate the presence of an active CB2 receptor on these cells with possible involvement in immunomodulation. In contrast to the low expression on normal T-cells, abundant levels of CB2 protein were present on T-non-Hodgkin's lymphomas (NHL). Moreover, in many B-NHL, high CB2 protein expression was found as well. In contrast to the distinct expression patterns in normal immune tissues using the two different CB2 antibodies, NHL specimens in general stained positively with both. We conclude that CB2 receptor expression pattern may be abnormal in NHL.
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http://dx.doi.org/10.1080/10428190701377030DOI Listing
July 2007