Publications by authors named "Daphne de Jong"

118 Publications

Epcoritamab induces potent anti-tumor activity against malignant B-cells from patients with DLBCL, FL and MCL, irrespective of prior CD20 monoclonal antibody treatment.

Blood Cancer J 2021 Feb 18;11(2):38. Epub 2021 Feb 18.

Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, Location VUMC, Amsterdam, Netherlands.

Epcoritamab (DuoBody-CD3xCD20, GEN3013) is a novel bispecific IgG1 antibody redirecting T-cells toward CD20 tumor cells. Here, we assessed the preclinical efficacy of epcoritamab against primary tumor cells present in the lymph node biopsies from newly diagnosed (ND) and relapsed/refractory (RR) B-NHL patients. In the presence of T-cells from a healthy donor, epcoritamab demonstrated potent activity against primary tumor cells, irrespective of prior treatments, including CD20 mAbs. Median lysis of 65, 74, and 84% were achieved in diffuse large B-cell lymphoma (n = 16), follicular lymphoma (n = 15), and mantle cell lymphoma (n = 8), respectively. Furthermore, in this allogeneic setting, we discovered that the capacity of B-cell tumors to activate T-cells was heterogeneous and showed an inverse association with their surface expression levels of the immune checkpoint molecule Herpesvirus Entry Mediator (HVEM). In the autologous setting, when lymph node (LN)-residing T-cells were the only source of effector cells, the epcoritamab-dependent cytotoxicity strongly correlated with local effector cell-to-target cell ratios. Further analyses revealed that LN-residing-derived or peripheral blood-derived T-cells of B-NHL patients, as well as heathy donor T-cells equally mediated epcoritamab-dependent cytotoxicity. These results show the promise of epcoritamab for treatment of newly-diagnosed or relapsed/refractory B-NHL patients, including those who became refractory to previous CD20-directed therapies.
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http://dx.doi.org/10.1038/s41408-021-00430-6DOI Listing
February 2021

Chromosome 20 loss is characteristic of breast implant-associated anaplastic large cell lymphoma.

Blood 2020 Dec;136(25):2927-2932

Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a very rare type of T-cell lymphoma that is uniquely caused by a single environmental stimulus. Here, we present a comprehensive genetic analysis of a relatively large series of BIA-ALCL (n = 29), for which genome-wide chromosomal copy number aberrations (CNAs) and mutational profiles for a subset (n = 7) were determined. For comparison, CNAs for anaplastic lymphoma kinase (ALK)- nodal anaplastic large cell lymphomas (ALCLs; n = 24) were obtained. CNAs were detected in 94% of BIA-ALCLs, with losses at chromosome 20q13.13 in 66% of the samples. Loss of 20q13.13 is characteristic of BIA-ALCL compared with other classes of ALCL, such as primary cutaneous ALCL and systemic type ALK+ and ALK- ALCL. Mutational patterns confirm that the interleukin-6-JAK1-STAT3 pathway is deregulated. Although this is commonly observed across various types of T-cell lymphomas, the extent of deregulation is significantly higher in BIA-ALCL, as indicated by phosphorylated STAT3 immunohistochemistry. The characteristic loss of chromosome 20 in BIA-ALCL provides further justification to recognize BIA-ALCL as a separate disease entity. Moreover, CNA analysis may serve as a parameter for future diagnostic assays for women with breast implants to distinguish seroma caused by BIA-ALCL from other causes of seroma accumulation, such as infection or trauma.
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http://dx.doi.org/10.1182/blood.2020005372DOI Listing
December 2020

Treatment of patients with MYC rearrangement positive large B-cell lymphoma with R-CHOP plus lenalidomide: results of a multicenter HOVON phase II trial.

Haematologica 2020 12 1;105(12):2805-2812. Epub 2020 Dec 1.

Dept of Hematology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, the Netherlands.

Patients with MYC-rearrangement positive large B-cell lymphoma (MYC+ LBCL) have an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as compared to patients without MYC rearrangement. Although intensive chemotherapy regimens yield higher remission rates, toxicity remains a concern. Lenalidomide is an oral immunomodulatory drug which downregulates MYC and its target genes thereby providing support using lenalidomide as additional therapeutic option for MYC+ LBCL. A phase II trial was conducted evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients identified through a nationwide MYC-FISH screening program. The primary endpoint was complete metabolic response (CMR) on centrally reviewed 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computer tomography (CT)-scan at end-of-treatment. Secondary endpoints were overall survival (OS), disease-free survival (DFS) and event-free survival (EFS). Eighty-two patients with stage II-IV MYC+ LBCL were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 25.4 months, 2-year estimates (95% CI) for OS, DFS, EFS were 73% (62-82%), 75% (63-84%) and 63% (52-73%) respectively. In this prospective trial for newly diagnosed MYC+ LBCL patients, we found that administering R2CHOP was safe, and yields comparable CMR and survival rates as in studies applying more intensive chemotherapy regimens. Hence, these findings offer new prospects for MYC+ LBCL patients and warrant comparison in prospective randomized clinical trials. This trial was registered at www.clinicaltrialsregister.eu (#2014-002654-39).
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http://dx.doi.org/10.3324/haematol.2019.238162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716355PMC
December 2020

Bayesian adaptive decision-theoretic designs for multi-arm multi-stage clinical trials.

Stat Methods Med Res 2020 Nov 26:962280220973697. Epub 2020 Nov 26.

Department of Epidemiology and Data Science, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Multi-arm multi-stage clinical trials in which more than two drugs are simultaneously investigated provide gains over separate single- or two-arm trials. In this paper we propose a generic Bayesian adaptive decision-theoretic design for multi-arm multi-stage clinical trials with () arms. The basic idea is that after each stage a decision about continuation of the trial and accrual of patients for an additional stage is made on the basis of the expected reduction in loss. For this purpose, we define a loss function that incorporates the patient accrual costs as well as costs associated with an incorrect decision at the end of the trial. An attractive feature of our loss function is that its estimation is computationally undemanding, also when >2. We evaluate the frequentist operating characteristics for settings with a binary outcome and multiple experimental arms. We consider both the situation with and without a control arm. In a simulation study, we show that our design increases the probability of making a correct decision at the end of the trial as compared to nonadaptive designs and adaptive two-stage designs.
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http://dx.doi.org/10.1177/0962280220973697DOI Listing
November 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

Chromosome 20 loss is characteristic for Breast implant-Associated Anaplastic Large Cell Lymphoma.

Blood 2020 Sep 8. Epub 2020 Sep 8.

VU University Medical Center, Amsterdam, Netherlands.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a very rare type of T-cell lymphoma, uniquely caused by a single environmental stimulus. Here we present a comprehensive genetic analysis of a relatively large series of BIA-ALCL (n=29), for which genome-wide chromosomal copy number aberrations (CNA) and mutational profiles for a subset (n=7) were determined. For comparison, CNAs for ALK-negative nodal-ALCLs (n=24) were obtained. CNAs were detected in 94% of BIA-ALCLs with losses at chromosome 20q13.13 in 66% of the samples. Loss of 20q13.13 is characteristic for BIA-ALCL as compared to other classes of ALCL, such as primary cutaneous ALCL, systemic type ALK-positive and -negative ALCL. Mutational patterns confirm that the IL6-JAK1-STAT3 pathway is deregulated. Although this is commonly observed across various types of T-cell lymphomas, the extent of deregulation however is significantly higher in BIA-ALCL as indicated by pSTAT3 immunohistochemistry. The characteristic loss of chromosome 20 in BIA-ALCL provides further justification to recognize BIA-ALCL as a separate disease entity. Moreover, CNA analysis may serve as a parameter for future diagnostic assays for women with breast implants to distinguish seroma caused by BIA-ALCL from other causes of seroma accumulation such as infection or trauma.
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http://dx.doi.org/10.1182/blood.2020005372DOI Listing
September 2020

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

Combining brentuximab vedotin with dexamethasone, high-dose cytarabine and cisplatin as salvage treatment in relapsed or refractory Hodgkin lymphoma: the phase II HOVON/LLPC Transplant BRaVE study.

Haematologica 2020 04 9. Epub 2020 Apr 9.

Dept of Hematology, Amsterdam UMC, University of Amsterdam, and LYMMCARE, Amsterdam, The Netherlands.

Achieving a metabolic complete response (mCR) before high-dose chemotherapy (HDC) and autologous peripheral blood stem-cell transplant (auto-PBSCT) predicts progression free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL). We added brentuximab vedotin (BV) to DHAP to improve the mCR rate. In a Phase I dose-escalation part in 12 patients, we showed that BV-DHAP is feasible. This Phase II study included 55 R/R cHL patients (23 primary refractory). Treatment consisted of three 21-day cycles of BV 1.8 mg/kg on day 1, and DHAP (dexamethasone 40mg days 1-4, cisplatin 100mg/m2; day 1 and cytarabine 2x2g/m2; day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central FDG-PET-CT review, 42 of 52 evaluable patients (81% [95% CI: 67-90]) achieved an mCR before HDC/auto-PBSCT, five had an mPR and five had progressive disease (three were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. The 2-year PFS was 74% [95% CI: 63-86], and the overall survival 95% [95% CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematological toxicity, fever, nephrotoxicity, ototoxicity (grade 1/2) and transiently elevated liver enzymes during BV-DHAP. Eighteen patients developed new onset peripheral neuropathy (maximum grade 1/2) and all recovered. In conclusion, BV-DHAP is a very effective salvage regimen in R/R cHL patients, but patients should be monitored closely for toxicity. ClinicalTrials.gov identifier: NCT02280993.
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http://dx.doi.org/10.3324/haematol.2019.243238DOI Listing
April 2020

Bortezomib maintenance after R-CHOP, cytarabine and autologous stem cell transplantation in newly diagnosed patients with mantle cell lymphoma, results of a randomised phase II HOVON trial.

Br J Haematol 2020 08 9;190(3):385-393. Epub 2020 Mar 9.

Haematology, University Medical Center Groningen, Groningen, Netherlands.

Rituximab-containing induction followed by autologous stem cell transplantation (ASCT) is the standard first-line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo-immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high-dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow-up of 77·5 months for patients still alive, 5-year event-free survival (EFS) was 51% (95% CI 42-59%); 5-year overall survival (OS) was 73% (95% CI 65-80%). The median follow-up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5-year EFS of 63% (95% CI 44-78%) and 5-year OS of 90% (95% CI 72-97%). The patients randomised to observation had 5-year PFS of 60% (95% CI, 40-75%) and OS of 90% (95% CI 72-97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.
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http://dx.doi.org/10.1111/bjh.16567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496560PMC
August 2020

Prognostic Significance of Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium.

J Clin Oncol 2019 12 9;37(35):3359-3368. Epub 2019 Sep 9.

Hospices Civils de Lyon and Université de Lyon, Lyon, France.

Purpose: rearrangement (-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of R on prognosis may be influenced by the partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of (single-, double-, and triple-hit status) in DLBCL within the context of the partner gene.

Methods: The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the , , , and IG heavy and light chain loci was used, and results were correlated with clinical outcomes.

Results: A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for -R. -R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of R was only evident in patients with a concurrent rearrangement of and/or and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; < .001).

Conclusion: The negative prognostic impact of -R in DLBCL is largely observed in patients with double hit/triple-hit disease in which is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.
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http://dx.doi.org/10.1200/JCO.19.00743DOI Listing
December 2019

High frequency of inactivating tetraspanin mutations in diffuse large B-cell lymphoma at immune-privileged sites.

Blood 2019 09 31;134(12):946-950. Epub 2019 Jul 31.

Department of Tumor Immunology and.

Tetraspanin CD37 is predominantly expressed on the cell surface of mature B lymphocytes and is currently being studied as novel therapeutic target for B-cell lymphoma. Recently, we demonstrated that loss of CD37 induces spontaneous B-cell lymphoma in -knockout mice and correlates with inferior survival in patients with diffuse large B-cell lymphoma (DLBCL). Here, mutation analysis was performed in a cohort of 137 primary DLBCL samples, including 44 primary immune-privileged site-associated DLBCL (IP-DLBCL) samples originating in the testis or central nervous system. mutations were exclusively identified in IP-DLBCL cases (10/44, 23%) but absent in non-IP-DLBCL cases. The aberrations included 10 missense mutations, 1 deletion, and 3 splice-site mutations. Modeling and functional analysis of missense mutations revealed loss of function by impaired CD37 protein expression at the plasma membrane of human lymphoma B cells. This study provides novel insight into the molecular pathogenesis of IP-DLBCL and indicates that anti-CD37 therapies will be more beneficial for DLBCL patients without mutations.
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http://dx.doi.org/10.1182/blood.2019001185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789512PMC
September 2019

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

Breast Implant Prevalence in the Dutch Female Population Assessed by Chest Radiographs.

Aesthet Surg J 2020 01;40(2):156-164

Division of Epidemiology of the Netherlands Cancer Institute, Amsterdam, Netherlands.

Background: Breast implant-related health problems are a subject of fierce debate. Reliable population-based estimates of implant prevalence rates are not available, however, due to a lack of historical registries and incomplete sales data, precluding absolute risk assessments.

Objectives: This study aimed to describe the methodology of a novel procedure to determine Dutch breast implant prevalence based on the evaluation of routine chest radiographs.

Methods: The validity of the new method was first examined in a separate study. Eight reviewers examined a series of 180 chest radiographs with (n = 60) or without (n = 120) a breast implant confirmed by a computed tomography or magnetic resonance imaging scan. After a consensus meeting with best-performing expert reviewers, we reviewed 3000 chest radiographs of women aged 20 to 70 years in 2 large regional hospitals in the Netherlands in 2015. To calculate the national breast implant prevalence, regional prevalence variations were corrected utilizing the National Breast Cancer Screening Program.

Results: Eight reviewers scored with a median sensitivity of 71.7% (range, 41.7%-85.0%) and a median specificity of 94.6% (range, 73.4%-97.5%). After a consensus meeting and a reevaluation by best-performing expert reviewers, sensitivity was 79.9% and specificity was 99.2%. The estimated national prevalence of breast implants among women between 20 and 70 years was 3.0%, ranging from 1.7% at 21 to 30 years to 3.9% between 51 and 60 years.

Conclusions: The novel method in this study was validated with a high sensitivity and specificity, resulting in accurate prevalence estimates and providing the opportunity to conduct absolute risk assessment studies on the health consequences of breast implants.

Level Of Evidence: 2:
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http://dx.doi.org/10.1093/asj/sjz136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006872PMC
January 2020

The Dutch Breast Implant Registry: Registration of Breast Implant-Associated Anaplastic Large Cell Lymphoma-A Proof of Concept.

Plast Reconstr Surg 2019 05;143(5):1298-1306

From the Department of Plastic and Reconstructive Surgery, Erasmus MC Cancer Institute University Medical Center Rotterdam; the Dutch Institute for Clinical Auditing, Dutch Breast Implant Registry; the Department of Plastic, Reconstructive, and Hand Surgery, Maastricht University Medical Centre; the Dutch Nationwide Network and Registry of Histo- and Cytopathology; the Departments of Medical Oncology and Epidemiology and Biostatistics, Netherlands Cancer Institute; the Department of Pathology, Amsterdam University Medical Center, VU University Medical Centre; and the Department of Plastic, Reconstructive, and Hand Surgery, Ziekenhuis Groep Twente/Medisch Spectrum Twente.

Background: The Dutch Breast Implant Registry (DBIR) was established in April of 2015 and currently contains information on 38,000 implants in 18,000 women. As a clinical registry, it evaluates the quality of breast implant surgery, including adverse events such as breast implant-associated (BIA) anaplastic large cell lymphoma (ALCL). To examine the efficacy of the DBIR, the capture rate of BIA-ALCL was compared to the registration of BIA-ALCL in the Dutch Nationwide Network and Registry of Histo- and Cytopathology (PALGA) as a gold standard, in combination with matching these databases to obtain complementary information.

Methods: All BIA-ALCL patients diagnosed and registered in The Netherlands in 2016 and 2017 were identified separately in the PALGA and DBIR databases. In addition, both databases were matched using indirect key identifiers. Pathologic information from the PALGA and clinical and device characteristics from the DBIR were obtained for all patients.

Results: Matching of both databases gave a capture rate of BIA-ALCL in the DBIR of 100 percent (n = 6) in 2016 and 70 percent (n = 7) in 2017. In total, 17 patients were identified in the PALGA, of which 14 patients were also identified in the DBIR; three patients were not registered; and 10 patients were registered false-positive. Of all confirmed patients, symptoms, staging results, treatment, and implant information were registered.

Conclusions: Currently, the DBIR contains 2 full registration years and captures most of the BIA-ALCL patients despite overestimation. Therefore, pathology confirmation remains essential. By matching these databases, complementary clinical and implant information could be retrieved, establishing the DBIR as an essential postmarketing surveillance system for health risk assessments.
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http://dx.doi.org/10.1097/PRS.0000000000005501DOI Listing
May 2019

Pioneers of Breast Implant-Associated Anaplastic Large Cell Lymphoma: History from Case Report to Global Recognition.

Plast Reconstr Surg 2019 03;143(3S A Review of Breast Implant-Associated Anaplastic Large Cell Lymphoma):7S-14S

From the Department of Hematopathology, The University of Texas MD Anderson Cancer Center; Universidad Peruana de Ciencias Aplicadas; Department of Hematopathology, The University of Texas MD Anderson Cancer Center; MultiCare Regional Cancer Center, MultiCare Health Systems; Department of Plastic Surgery, Keck School of Medicine, University of Southern California; Department of Pathology, VU University Medical Center; Department of Pathology, Memorial Sloan Kettering Cancer Center; and Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center.

The first case of breast implant-associated anaplastic large cell lymphoma (breast implant ALCL) was described by John Keech and the late Brevator Creech in 1997. In the following 2 decades, much research has led to acceptance of breast implant ALCL as a specific clinicopathologic entity, a process that we bring up to life through the memories of 6 persons who were involved in this progress, although we acknowledge that many others also have contributed to the current state of the art of this disease. Dr. Keech recalls the events that led him and Creech to first report the disease. Ahmet Dogan and colleagues at the Mayo Clinic described a series of 4 patients with breast implant ALCL, and led to increased awareness of breast implant ALCL in the pathology community. Daphne de Jong and colleagues in the Netherlands were the first to provide epidemiologic evidence to support the association between breast implants and ALCL. Garry Brody was one of the first investigators to collect a large number of patients with the disease, present the spectrum of clinical findings, and alert the community of plastic surgeons. Roberto Miranda and L. Jeffrey Medeiros and colleagues studied the pathologic findings of a large number of cases of breast implant ALCL, and published the findings in 2 impactful studies in the medical oncology literature. The recognition and acceptance of this disease by surgeons, epidemiologists, and medical oncologists, working together, has led to subsequent studies on the pathogenesis and optimal therapy of this disease.
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http://dx.doi.org/10.1097/PRS.0000000000005564DOI Listing
March 2019

Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study.

Lancet Oncol 2019 02 7;20(2):216-228. Epub 2019 Jan 7.

Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.

Background: The prognosis for primary CNS lymphoma has improved with the use of high-dose methotrexate-based chemotherapy, but patient outcomes remain poor. Rituximab, a chimeric monoclonal antibody that targets the CD20 cell surface protein, has substantial activity in systemic CD20-positive diffuse large B-cell lymphoma, but its efficacy in primary CNS lymphoma is unknown and low penetration of the large rituximab molecule through the blood-brain barrier could limit its effect. We aimed to investigate the addition of rituximab to a high-dose methotrexate-based chemotherapy regimen in patients with newly diagnosed primary CNS lymphoma.

Methods: This intergroup, multicentre, open-label, randomised phase 3 study was done at 23 hospitals in the Netherlands, Australia, and New Zealand. Non-immunocompromised patients aged 18-70 years with newly diagnosed primary CNS lymphoma were randomly assigned (1:1) to receive methotrexate-based chemotherapy with or without intravenous rituximab. We used a web-based randomisation system with stratification by centre, age, and Eastern Cooperative Oncology Group-WHO performance status, and a minimisation procedure. All group assignment was open label and neither investigators nor patients were masked to allocation. All patients were treated with two 28-day cycles of induction chemotherapy, consisting of intravenous methotrexate 3 g per m on days 1 and 15, intravenous carmustine 100 mg per m on day 4, intravenous teniposide 100 mg per m on days 2 and 3, and oral prednisone 60 mg per m on days 1-5, with (R-MBVP) or without (MBVP) intravenous rituximab 375 mg per m on days 0, 7, 14, and 21 in cycle one and days 0 and 14 in cycle two. Patients with response at the end of induction subsequently received high-dose cytarabine and, in patients aged 60 years or younger, low-dose whole-brain radiotherapy. The primary endpoint was event-free survival, with events defined as not reaching complete response or complete response unconfirmed at the end of treatment, or progression or death after response; analysis was adjusted for age and performance score. Patients were analysed on a modified intention-to-treat basis. This trial is registered with the Nederlands Trial Register, number NTR2427, and the Australian New Zealand Clinical Trials Registry, number ACTRN12610000908033. The trial was closed on May 27, 2016, after achieving complete accrual, and follow-up is ongoing.

Findings: Between Aug 3, 2010, and May 27, 2016, we recruited 200 patients (109 men and 91 women; median age was 61 years [IQR 55-67]). We randomly assigned 100 patients to MBVP and 99 patients to R-MBVP. One patient was randomly assigned to the R-MBVP group but found to be ineligible because of an incorrect diagnosis and was excluded from all analyses. After a median follow-up of 32·9 months (IQR 23·9-51·5), 98 patients had had an event (51 in the MBVP group and 47 in the R-MBVP group), of whom 79 had died (41 in the MBVP group and 38 in the R-MBVP group). Event-free survival at 1 year was 49% (95% CI 39-58) in the MBVP group (no rituximab) and 52% (42-61) in the R-MBVP group (with rituximab; hazard ratio 1·00, 95% CI 0·70-1·43, p=0·99). Grade 3 or 4 adverse events occurred in 58 (58%) patients in the MBVP group and 63 (64%) patients in the R-MBVP group, with infections (24 [24%] patients receiving MBVP vs 21 [21%] patients receiving R-MBVP), haematological toxicity (15 [15%] vs 12 [12%]), and nervous system disorders (ten [10%] vs 15 [15%]) being the most common. Life-threatening or fatal serious adverse events occurred in 12 (12%) patients in the MBVP group and ten (10%) patients in the R-MBVP group, and five (5%) patients in the MBVP group and three (3%) in the R-MBVP group died from treatment-related causes.

Interpretation: We found no clear benefit of addition of rituximab to methotrexate, carmustine, teniposide, and prednisone chemotherapy in primary CNS lymphoma. Therefore, the results of this study do not support the use of rituximab as a component of standard treatment in primary CNS lymphoma.

Funding: Roche, the Dutch Cancer Society, and Stichting STOPhersentumoren.
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http://dx.doi.org/10.1016/S1470-2045(18)30747-2DOI Listing
February 2019

A practical cytological approach to the diagnosis of breast-implant associated anaplastic large cell lymphoma.

Cytopathology 2019 07 14;30(4):363-369. Epub 2019 Feb 14.

Department of Pathology, VU University Medical Center, Amsterdam UMC, Amsterdam, The Netherlands.

The role of cytopathology in malignant lymphoma is largely restricted to primary screening in patients with lymphadenopathy of unknown causes and evaluation of relapse and transformation during follow-up of patients with known and fully classified malignant lymphoma. Few lymphoma diagnoses fully rely on cytology, although breast-implant associated anaplastic large cell lymphoma is currently the centre of clinical attention. Due to the major attention both in the medical and lay media for the recently substantiated high lymphoma risk in women with breast implants, cytopathology departments now frequently receive seroma fluid aspirates with this specific differential diagnostic consideration. In this review, we discuss clinico-pathological aspects of breast-implant associated anaplastic large cell lymphoma from a cytological point of view and provide guidelines for the processing of aspirates in daily practice and strategies for diagnostic work-up of seroma fluids.
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http://dx.doi.org/10.1111/cyt.12678DOI Listing
July 2019

Risks for lymphoma and gastrointestinal carcinoma in patients with newly diagnosed adult-onset celiac disease: Consequences for follow-up: Celiac disease, lymphoma and GI carcinoma.

United European Gastroenterol J 2018 Dec 12;6(10):1485-1495. Epub 2018 Sep 12.

Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.

Background: The association between celiac disease (CD) and the development of lymphoid and gastrointestinal (GI) malignancies have been reported. However, data are scarce yet needed to develop evidence-based follow-up programs.

Objective: The objective of this article is to assess relative (RR) and absolute risks of lymphoma and GI carcinoma for newly diagnosed patients.

Methods: A case-control design to determine RR was performed with cases (lymphoma or GI carcinoma) and controls (melanoma or basal cell carcinoma) diagnosed 1994-2014, retrieved from the Dutch nationwide population-based pathology database (PALGA). Within this population, individuals with histologically proven CD before or simultaneously diagnosed with the malignancy were identified.

Results: A total of 349/301,425 cases (0.1%) and 282/576,971 (0.05%) controls were diagnosed with CD. Risk of T-cell lymphoma, predominantly enteropathy-associated T-cell lymphoma (EATL), was strongly associated with CD diagnosis (RR = 35.8 (95% CI 27.1-47.4)). Although most often synchronously diagnosed, T-cell lymphoma RR ≥ 1 year after CD diagnosis was still elevated (RR = 12.7 (95% CI 7.6-21.3)). Other CD-associated malignancies were small bowel adenocarcinoma (RR = 11.9 (95% CI 8.2-17.2)) and esophageal squamous cell carcinoma (RR = 3.5 (95% CI 2.1-5.8)). Absolute risks were relatively low. Other types of lymphomas and GI carcinomas were not associated with CD.

Conclusion: Increased risk for specific malignancies in CD should alert physicians for EATL (both intestinal and extraintestinal) and small bowel adenocarcinoma in patients with CD diagnosed at age ≥ 50 years.
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http://dx.doi.org/10.1177/2050640618800540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297918PMC
December 2018

and hijack immunoglobulin light-chain enhancers in cyclin D1 mantle cell lymphoma.

Blood 2019 02 11;133(9):940-951. Epub 2018 Dec 11.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1 MCL has been recognized, and approximately one-half of them harbor translocations while the primary event in cyclin D1/D2 MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1/SOX11 MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified rearrangements in 39 cases (70%) but not rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to (6 cases) and (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1 MCL cases lacked cyclin D rearrangements and showed upregulation of and These cases had blastoid morphology, high genomic complexity, and and deletions. Both genomic and gene-expression profiles of cyclin D1 MCL cases were indistinguishable from cyclin D1 MCL. In conclusion, virtually all cyclin D1 MCLs carry rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1/D2/D3 MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1 MCL.
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http://dx.doi.org/10.1182/blood-2018-07-862151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396173PMC
February 2019

Immunodeficiency-associated lymphoproliferative disorders: time for reappraisal?

Blood 2018 11 6;132(18):1871-1878. Epub 2018 Aug 6.

VU University Medical Center, Amsterdam, The Netherlands.

Immunodeficiency-associated lymphoproliferative disorders (IA-LPDs) are pathologically and clinically heterogeneous. In many instances, similar features are shared by a spectrum of IA-LPDs in clinically diverse settings. However, the World Health Organization (WHO) classifies IA-LPDs by their immunodeficiency setting largely according to the paradigm of posttransplant lymphoproliferative disorders but with inconsistent terminology and disease definitions. The field currently lacks standardization and would greatly benefit from thinking across immunodeficiency categories by adopting a common working vocabulary to better understand these disorders and guide clinical management. We propose a 3-part unifying nomenclature that includes the name of the lesion, associated virus, and the specific immunodeficiency setting for all IA-LPDs. B-cell lymphoproliferative disorders (LPDs) are usually Epstein-Barr virus (EBV) and show a spectrum of lesions, including hyperplasias, polymorphic LPDs, aggressive lymphomas, and, rarely, indolent lymphomas. Human herpes virus 8-associated LPDs also include polyclonal and monoclonal proliferations. EBV B-cell LPDs and T- and NK-cell LPDs are rare and less well characterized. Recognition of any immunodeficiency is important because it impacts the choice of treatment options. There is an urgent need for reappraisal of IA-LPDs because a common framework will facilitate meaningful biological insights and pave the way for future work in the field.
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http://dx.doi.org/10.1182/blood-2018-04-842559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213318PMC
November 2018

Risk of Breast Implant-Associated Anaplastic Large Cell Lymphoma-Reply.

JAMA Oncol 2018 10;4(10):1435

Epidemiology, Netherlands Cancer Institute, Amsterdam, Noord-Holland, the Netherlands.

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http://dx.doi.org/10.1001/jamaoncol.2018.2624DOI Listing
October 2018

Macrotextured Breast Implants with Defined Steps to Minimize Bacterial Contamination around the Device: Experience in 42,000 Implants.

Plast Reconstr Surg 2018 10;142(4):590e-591e

Department of Plastic, Reconstructive and Hand-Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands.

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http://dx.doi.org/10.1097/PRS.0000000000004783DOI Listing
October 2018

Intracerebral lymphoproliferative disorder in an MS patient treated with fingolimod.

Neurol Neuroimmunol Neuroinflamm 2018 Sep 10;5(5):e483. Epub 2018 Jul 10.

Department of Neurology (B.A.d.J., Z.L.E.v.K.), Amsterdam Neuroscience, VUmc MS Center Amsterdam, VU University Medical Center; Department of Radiology & Nuclear Medicine (M.P.W.), VUmc MS Center, Amsterdam, The Netherlands; Department of Diagnostic and Interventional Neuroradiology (M.P.W.), Hannover Medical School, Hannover, Germany; and Departments of Hematology (P.M.S., M.E.D.C.), and Pathology (L.P., D.B., D.d.J.), VU University Medical Center, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1212/NXI.0000000000000483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047430PMC
September 2018

Interobserver variation in CD30 immunohistochemistry interpretation; consequences for patient selection for targeted treatment.

Histopathology 2018 Sep 26;73(3):473-482. Epub 2018 Jun 26.

Department of Pathology, VU Medical Center, Amsterdam, the Netherlands.

Aims: CD30 immunohistochemistry (IHC) in malignant lymphoma is used for selection of patients in clinical trials using brentuximab vedotin, an antibody drug-conjugate targeting the CD30 molecule. For reliable implementation in daily practice and meaningful selection of patients for clinical trials, information on technical variation and interobserver reproducibility of CD30 immunohistochemistry (IHC) staining is required.

Methods And Results: We conducted a three-round reproducibility assessment of CD30 scoring for categorised frequency and intensity, including a technical validation, a 'live polling' pre- and post-instruction scoring round and a web-based round including individual scoring with additional IHC information to mimic daily diagnostic practice. Agreement in all three scoring rounds was poor to fair (κ = 0.12-0.35 for CD30-positive tumour cell percentage and κ = 0.16-0.41 for staining intensity), even when allowing for one category of freedom in percentage of tumour cell positivity (κ = 0.30-0.61). The first round with CD30 staining performed in five independent laboratories showed objective differences in staining intensity. In the second round, approximately half the pathologists changed their opinion on CD30 frequency after a discussion on potential pitfalls, highlighting hesitancy in decision-making. Using fictional cut-off points for percentage of tumour cell positivity, agreement was still suboptimal (κ = 0.35-0.60).

Conclusions: Lack of agreement in cases with heterogeneous expression is shown to influence patient eligibility for treatment with brentuximab vedotin, both in clinical practice and within the context of clinical trials, and limits the potential predictive value of the relative frequency of CD30-positive neoplastic cells for clinical response.
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http://dx.doi.org/10.1111/his.13647DOI Listing
September 2018

Benign and malignant tumors in Rubinstein-Taybi syndrome.

Am J Med Genet A 2018 03 23;176(3):597-608. Epub 2018 Jan 23.

Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands.

Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomalies syndrome associated with mutations in CREBBP (70%) and EP300 (5-10%). Previous reports have suggested an increased incidence of specific benign and possibly also malignant tumors. We identified all known individuals diagnosed with RSTS in the Netherlands until 2015 (n = 87) and studied the incidence and character of neoplastic tumors in relation to their CREBBP/EP300 alterations. The population-based Dutch RSTS data are compared to similar data of the Dutch general population and to an overview of case reports and series of all RSTS individuals with tumors reported in the literature to date. Using the Nationwide Network and Registry of Histopathology and Cytopathology in the Netherlands (PALGA Foundation), 35 benign and malignant tumors were observed in 26/87 individuals. Meningiomas and pilomatricomas were the most frequent benign tumors and their incidence was significantly elevated in comparison to the general Dutch population. Five malignant tumors were observed in four persons with RSTS (medulloblastoma; diffuse large-cell B-cell lymphoma; breast cancer; non-small cell lung carcinoma; colon carcinoma). No clear genotype-phenotype correlation became evident. The Dutch population-based data and reported case studies underscore the increased incidence of meningiomas and pilomatricomas in individuals with RSTS. There is no supporting evidence for an increased risk for malignant tumors in individuals with RSTS, however, due to the small numbers this risk may not be fully dismissed.
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http://dx.doi.org/10.1002/ajmg.a.38603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838508PMC
March 2018