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.To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease.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.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.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.
We hypothesized that ultrasound-guided selective nerve root block could play a role in the prediction of clinical outcomes in patients with multilevel cervical disease following selective anterior cervical discectomy and fusion.
Residual biospecimens that are stored in hospitals' diagnostic specimen archives can be used for scientific research under strict legal and ethical regulations. In the Netherlands, a Code of Conduct governs responsible secondary use of residual biospecimens. However, implementation of this Code seems to be challenging. This study aims to explore the most important factors that facilitate or hinder the implementation of the Code. In addition, it investigates what is needed to further foster the responsible use of residual biospecimens. A mixed-methods design was used. Questionnaires were sent out to pathologists, patient information centers, physicians, researchers, data protection officers (DPOs), members of research ethics committees, and members of the boards of directors of all hospitals in the Netherlands (81 hospitals). To further investigate the barriers and facilitators, interviews were conducted with pathologists, patient information centers, physician-researchers, DPOs, review boards, research coordinators, and quality managers of pathology departments. In total, 246 respondents filled out the questionnaire and 36 interviews were conducted. Major barriers for implementing were a lack of resources (time, money), a lack of attention for responsible use, and a lack of practical knowledge (knowing what to do, where to go with questions). In contrast, the perception that implementing the Code was necessary, either by the respondent or by colleagues, was considered "a driver" for implementation. Practical instruments such as checklists and roadmaps were considered necessary to foster implementation; however, the creation of such instruments was hindered by a lack of clear-cut answers regarding legal aspects. Therefore, more clarity and harmonization on how to interpret both the Code and legislation regarding secondary use were considered necessary.
Patients with multiple myeloma (MM) demonstrate variable outcomes with treatment. With increasing treatment options, predictive factors for response and outcome are relevant to inform treatment choices. Immunomodulating agents (IMiDs) represent the cornerstone of MM treatment and act through binding to Cereblon (CRBN), affecting downstream targets of this E3 ubiquitin ligase. We hypothesized differential expression of effector or target proteins from the CRBN pathway to predict outcome in patients treated with IMiDs. Bone marrow (BM) biopsies were obtained from 148 newly diagnosed, transplant non-eligible patients with MM. Per HOVON-87/NMSG-18 trial protocol, these patients were treated with thalidomide or lenalidomide combined with melphalan and prednisone followed by thalidomide/lenalidomide maintenance (i.e. MPT-T or MPR-R). Immunohistochemistry was performed for CRBN, its neosubstrates Ikaros and Aiolos and the downstream targets interferon regulatory factor 4 (IRF-4) and cellular myelocytomatosis oncogene (c-MYC). Patients with response of VGPR or better have higher nuclear CRBN expression compared to patients with PR or worse (≥VGPR: median CRBN H-score=185 (interquartile range (IQR), 147-211) vs ≤PR median CRBN H-score=159 (IQR 129-193); p=0.02). Higher nuclear CRBN expression was associated with a longer progression-free survival (PFS) and overall survival (OS). For PFS a hazard ratio (HR) of 0.53 was found (95% confidence interval (CI) =0.37-0.77; p<0.001); for OS: HR = 0.59 (95% CI=0.38-0.90; p=0.02). The association between CRBN and OS varied with IRF-4 levels. In patients with IRF-4 levels above the median, a hazard ratio of 0.22 was found (95% CI=0.10-0.49; p=0.0002); in contrast, patients with IRF-4 levels below the median, had a hazard ratio of 0.82 (95% CI=0.44-1.53; p=0.5). For Ikaros, Aiolos and c-MYC no correlation with survival was found, either alone or in combination with CRBN. In conclusion, higher expression of nuclear CRBN was associated with a superior PFS and OS upon MPT or MPR treatment. Levels of nuclear CRBN protein, possibly in combination with IRF-4, may represent a biomarker for predicting treatment outcome in patients treated with IMiDs.
Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a rare variant of Hodgkin's lymphoma (HL) in children. Since specific immunohistochemical staining has become available, NLPHL can be separated from classical Hodgkin's lymphoma (cHL) more accurately. Scarce information is available about pediatric NLPHL treated with chemotherapy only. Therefore, clinical characteristics, treatment, response and outcome of seven pediatric NLPHL patients, median age 9.2 years (range 7.5 - 14.2 years), diagnosed between 1986 - 2003 among 58 HL patients, uniformly treated in a single center with chemotherapy only, were evaluated. The median follow-up time was 4.2 years (range 2.1 - 10.2 years). NLPHL patients were stage I (n = 5), II (n = 2), whereas cHL, median age 11.4 years (range 3.3 - 15.9 years), were stage I (n = 8), II (n = 17), III (n = 9), IV (n = 1). Upfront treatment of NLPHL patients consisted of six courses of epirubicin, bleomycin, vinblastine and dacarbazine (EBVD) without radiotherapy, whereas cHL patients received six courses of EBVD (n = 14) or 4 - 6 courses of EBVD/MOPP (mitoxin, oncovin, procarbazine, prednison; n = 21). Chemotherapy was used as primary treatment thereby aiming to avoid radiotherapy with potential serious side effects to growing jaws and thyroid. All seven patients reached complete remission (CR). Four patients relapsed, of which three locally. These three were salvaged with second-line chemotherapy without radiation therapy (RT) and are in second CR. One patient relapsing with stage III disease was salvaged by EBVD/MOPP followed by autologous BMT and is also in second CR for 36 months. The event-free survival (EFS) is 43% and overall survival (OS) 100%. This study shows that apart from histology, immunohistochemistry (ICH) is required for diagnosing NLPHL. Moreover, it illustrates that although cure of pediatric NLPHL is feasible with chemotherapy only, high dosages of cytotoxic drugs are necessary as salvage treatment in a relatively high proportion of patients after relapse.
Hydroxyethyl starch (HES) solutions have largely replaced conventional plasma expanders such as human albumin and colloidal fluids. Only a few side effects have been reported and mainly concern pruritus or blood coagulation disorders. Excessive HES exposure can result in diffuse tissue storage and accumulation with foamy appearing macrophages which produce the enzyme chitotriosidase (CT). In case of massive tissue storage, this enzyme activity can reach levels comparable to those of Gaucher disease.In this single-center retrospective analysis of 11 consecutive patients receiving large amounts of HES for chronic plasmapheresis, plasma CT activity was investigated. Five patients receiving chronic intermittent plasmapheresis with conventional plasma expanders served as controls. Plasma CT activity was measured and plotted against creatinine clearance. Where available, marrow aspirate was analyzed with light microscopy to detect foamy macrophages. One patient developed a lysosomal storage disease and was examined extensively.Conventional plasma expanders did not alter plasma CT activity. In patients with impaired renal function, frequent plasma replacement with HES resulted in an increase in plasma CT activity. In the patient with the acquired lysosomal storage disease, massive tissue infiltration with activated foamy macrophages was observed. The phagocytic capacity in this patient, however, did not seem to be altered.Patients with impaired renal function receiving large amounts of HES exhibit an increase in plasma CT activity. Because excessive HES exposure can result in an acquired lysosomal storage disease, this should be avoided in chronic plasmapheresis procedures.
