Molecular basis of multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a heterogeneous hematological malignancy characterized by clonal expansion of malignant plasma cells in the bone marrow. The disease is accompanied by various clinical manifestations, such as bone lesions, anemia, hypercalcemia, and renal insufficiency. However, despite significant advances in treatment over the last two decades, the disease remains challenging to treat, and most patients relapse. Although its pathogenesis has not yet been elucidated, it is clear that genomic instability plays a key role in its develop-ment or resistance to treatment. In some instances, the cause of this instability is chromothripsis, a form of complex genomic rearrangement that involves shattering and subsequent haphazard reassembly of chromosomes within a single catastrophic event. The resulting rearrangements involve a variety of structural changes, including deletions, duplications, inversions, and translocations, that lead to genome disruption. Specifically, these changes may result in alteration or inactivation of tumor suppressor genes (TP53 and CDKN2C), activation of oncogenes (MAF, FGFR3, and CCND1) or genes involved in key cellular processes. Unraveling the mechanisms that result in chromothripsis provides opportunities to identify critical genes and pathways involved in MM pathogenesis. These findings may serve as a basis for improved dia-gnostic approaches. PURPOSE: The goal of this review is to summarize the common primary and secondary chromosomal aberrations in MM with a particular focus on introducing complex chromosomal aberrations, especially chromothripsis in MM.

Monoclonal gammopathy of clinical signifi cance with osteosclerotic lesions - a case report and a literature review.

INTRODUCTION: Multiple myeloma is a common plasma cell neoplasia usually accompanied by the formation of osteolytic foci, whereas osteosclerotic myeloma is a very rare form of plasma cell dyscrasia. When osteosclerotic myeloma is detected, osteosclerotic foci are usually part of the POEMS syndrome. Osteosclerotic myeloma without other manifestations of the POEMS syndrome is an unusual finding. CASE DESCRIPTION: In a 46-year-old woman, osteosclerotic changes of the temporoparietal region caused soft tissue induration over this lesion, which initiated further investigation. Imaging studies subsequently showed multiple osteosclerotic foci in the skull. Examination of blood proteins revealed 8 g/L of IgG-lambda monoclonal immunoglobulin, subclass IgG1. In search of the cause of the osteosclerotic changes, FDG-PET/CT was performed, which revealed no FDG accumulation, i.e., no other tumor (breast or stomach cancer). Low-dose CT showed irregular bone structure, but not significant osteolytic or osteosclerotic foci. To map the extent of osteosclerotic changes, NaF-PET/CT imagination followed, which revealed multiple spots with high fluoride accumulation. A parietal bone biopsy showed osteosclerosis with minor clonal plasma cell infiltration. Trepanobioptic bone marrow sampling revealed an infiltration of bone marrow with atypical plasma cells in 8%. Flow-cytometric examination of bone marrow showed 0,37% of plasma cells, however predominantly (91%) clonal with lambda expression. MRI of the brain identified asymptomatic meningeal thickening. There was no evidence of POEMS syndrome in the patient; thus, we concluded the diagnosis as monoclonal gammopathy of clinical significance with osteosclerosis which was previously termed osteosclerotic multiple myeloma. CONCLUSION: Monoclonal gammopathy of clinical significance (MGCS) with osteosclerotic skeletal changes, documented on CT and multiple foci with intensive osteoneogenesis, documented on NaF-PET/CT without evidence of POEMS syndrome, is an extremely rare form of plasma cell dyscrasia. This publication documents the unique clinical manifestations of IgG-lambda type plasma cell proliferation without signs of POEMS syndrome and the role of NaF-PET/CT imaging. Classification of this disease as MGSC with osteosclerotic manifestations is more consistent with the indolent nature of the disease with a significantly better prognosis, compared with multiple myeloma.

Overview of histiocytic and dendritic disorders by the 5th version of WHO Classifi cation of Hematolymphoid Tumours from 2022.

BACKGROUND: Histiocytoses are rare disorders characterized by the accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs of children and adults, with a wide range of clinical manifestations, presentations, and histology. The histiocytoses are classified according to the WHO Classification, the last version of which was published in 2022, or according to the Histiocyte Society Classification, with the last version published in 2016. PURPOSE: This text provides an overview of histiocytoses as described in the WHO Classification 2022.

The endoplasmic reticulum and its signaling pathways - a novel target for multiple myeloma treatment.

BACKGROUND: The endoplasmic reticulum (ER), an organelle composed of a system of cisternae and tubules, is essential for many cellular processes, including protein synthesis and transport. When misfolded proteins accumulate in the ER lumen, ER stress is induced, and the subsequent response to the disruption of homeostasis is the activation of the unfolded protein response (UPR). The purpose of this process is to restore homeostasis by increasing the capacity of the ER and its ability to fold proteins. Activation of the homeostatic UPR occurs via one of three transmembrane proteins, inositol-requiring enzyme 1a (IRE1a), protein kinase R-like ER kinase (PERK) and activating transcription factor 6 (ATF6). Failure of the attempt to restore homeostasis, on the other hand, leads to the development of terminal UPR and apoptosis via hyperactivation of the same proteins. Activation of UPR has been described in many malignancies, including multiple myeloma (MM), which is characterized by malignant transformation of plasma cells and increased monoclonal immunoglobulin synthesis, where the role of the ER is of particular importance. Despite advances in the treatment of MM, the disease remains difficult to treat and targeting signaling pathways associated with the UPR could, for example, enhance the effect of proteasome inhibitors. PURPOSE: This review intends to present the molecular response to ER stress under physiological circumstances and in the context of cancer, particularly with regard to potential therapeutic targets in MM.

Erdheim-Chester disease.

Erdheim-Chester disease is a rare inflammatory myeloid clonal disease which is classified into histiocytoses. It is characterized by excessive production and accumulation of foamy histiocytes and Touton giant cells in various tissues and organs. Foamy histiocytes and Touton giant cells produce proinflammatory cytokines and chemokines and contain somatic mutations in genes activating the MAPK/ERK signaling pathway, but also in genes activating the PI3K/AKT signaling pathway. BRAFV600E is the most common somatic mutation. Furthermore, somatic mutations in the MAP2K1, KRAS, NRAS, ARAF or PIK3CA genes are abundant. Erdheim-Chester dis-ease is a multisystemic disease in which any organ can be affected, especially the long bones of the lower extremities, but also the cardiovascular system, retroperitoneum, endocrine system, central nervous system, lungs, skin or orbit. The dia-gnosis is difficult because of the various manifestations of this disease. The disease occurs mainly in adults and is more common in men than in women. Targeted treatment by kinase inhibitors, interferon a, cytokine blockers or cladribine is used for the treatment.

Waldenström macroglobulinemia.

BACKGROUND: Waldenström macroglobulinemia (WM) is a hematological malignancy; it is a monoclonal gammopathy, a disease characterized by presence of a monoclonal immunoglobulin in serum and/or urine. The median age at dia-gnosis is 71 years. WM is not an aggres-sive disease and patients with this dia-gnosis can live for several years. Infiltration of the bone marrow with lymphoplasmacytoid cells causes anemia, leading to various problems, mainly fatigue. Hepatomegaly, splenomegaly and lymphadenopathy can also occur. Hyperviscosity syndrome can appear and is caused by excessive production of immunoglobulin M. A mutation in MYD88 gene is detected in almost every WM patient, and in almost one third of them, a mutation in CXCR4 gene is detected. The detection of MYD88 mutation is important for a correct therapeutic strategy, since a Brutons tyrosine kinase inhibitor, ibrutinib, is most effective in patients with mutated MYD88 and wt CXCR4. The therapy is started when first symptoms occur. PURPOSE: The aim of this study is to summarize current knowledge about this disease, its dia-g-nostics, molecular basis and treatment.

Role of exosomes in malignancies.

BACKGROUND: Extracellular vesicles are closed structured surrounded by a lipid membrane that are secreted by almost all types of cells; their function is information delivery during cell-to-cell communication. They are most commonly divided into three categories - exosomes, microvesicles and apoptotic bodies. Exosomes are small vesicles with the size of 30-100 nm, and they are found in almost all body fluids, including peripheral blood, urine, breast milk, saliva and others. They are able to deliver their content to target cells and change their behavior. Cancer cells are able to secrete more exosomes and also contain different proteins and RNA species than the exosomes from healthy cells. Due to their specific composition that is connected to the cell of origin, exosomes could be used as bio-markers of various diseases in the future. PURPOSE: The aim of this work is to summarize current knowledge about exosomes and their role in various processes connected to resistance in tumors. This work was supported by grant of the Ministry of Health of the Czech Republic AZV 17-29343A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Diagnostic relevance of 18F-FDG PET/CT in newly diagnosed patients with monoclonal gammopathy of undetermined significance (MGUS): Single-center experience.

Monoclonal gammopathy of undetermined significance (MGUS) is a known precursor of more serious cancers, such as multiple myeloma (MM), Waldenström macroglobulinemia (MW) and other lymphoproliferative disorders. Using 18F-FDG PET/CT, we aimed to evaluate its benefit in early detection of various accompanying disorders and illnesses in MGUS patients. We prospectively analyzed the diagnostic relevance of 18F-FDG PET/CT in 390 newly diagnosed MGUS patients. On 18F-FDG PET/CT scans, the presence of focal or diffuse areas of detectable increased tracer uptake was recorded in 37 (9.5%) MGUS patients. The most frequent pathology was lymphadenopathy (3.8%), followed by thyroid diseases (2.1%), rheumatic diseases (1.8%), and other solid malignancies (1.5%). These results have major implications for confirmed associations of MGUS with numerous malignant and non-malignant disorders. We believe that 18F-FDG PET/CT imaging in newly diagnosed MGUS patients may be useful in early detection of other serious pathologies, not only in predicting progression of MGUS to active MM, and should be strongly recommended if available.

Bortezomib retreatment is effective in relapsed multiple myeloma patients - real-life clinical practice data.

Nowadays, bortezomib, a proteasome inhibitor, is widely used in treatment of newly diagnosed or relapsed multiple myeloma. The aim of this study was to analyze efficiency of bortezomib retreatment in patients with relapsed or refractory multiple myeloma. From 2004 to 2016, 283 patients were retrospectively evaluated at all hematological centers in the Czech Republic. Bortezomib was administered at the standard dosing and in combined therapy with corticosteroids, chemotherapy or thalidomide. Before bortezomib retreatment, 61% of patients received previous lenalidomide treatment, 40.6% autologous transplantation, and median number of prior lines of therapy was three. In total, 21% of patients were refractory to the first bortezomib treatment. In bortezomib retreatment, overall response rate was 34.5%, median progression-free survival was 7.8 months (95% CI: 6.7-8.9), median duration of response was 10.5 months (95% CI: 8.0-13.0) and median overall survival was 20.3 months (95% CI: 17.9-22.7). Grade 3-4 adverse events included thrombocytopenia, neutropenia, anemia and infection. Neuropathy grade 2 or higher occurred in 19.4% of patients. We conclude that bortezomib retreatment is an effective and safe therapeutic alternative for relapsed or refractory multiple myeloma patients.

Bortezomib and Thalidomide Treatment Results in Newly Diagnosed Transplant-Ineligible Multiple Myeloma Patients are Comparable in Long-Term Follow-Up.

BACKGROUND: Thalidomide-and bortezomib-containing regimens are widely used for transplant-ineligible newly diagnosed multiple myeloma patients. The aim of this study was to analyse the efficiency of thalidomide-or bortezomib-based regimens in long-term follow-up. MATERIALS AND METHODS: From 2008 to 2012, 142 transplant-ineligible newly diagnosed multiple myeloma patients were analysed retrospectively. Bortezomib was administered at the standard dosing of 1.3mg/m2 weekly, and thalidomide was administered at a daily dose of 100mg. Both drugs were combined with cyclophosphamide and dexamethasone. A total of 95 patients were treated with thalidomide and 47 with bortezomib. A median four cycles of treatment were administered in both groups. RESULTS: In the thalidomide group, the overall response rate was 60.6%, the median progression-free survival (PFS) was 10.3 months (95% CI 7.4-13.2) and the median overall survival (OS) was 35.1 months (95% CI 23.9-46.3). In the bortezomib group, the overall response rate was 51.1%, the median PFS was 11.9 months (95% CI 8.8-15) and the median OS was 25.4 months (95% CI 9.3-41.6). There was a statistically significant difference in OS (p = 0.027), favouring the cyclophosphamide/thalidomide/dexamethasone group, but the response rates and PFS intervals were not significantly different between both groups. The median follow-up in the thalidomide group was 35.1 months (95% CI 0.2-95.9) compared to 25.1 months (95% CI 0.4-60.6) in the bortezomib group (p = 0.004). The incidence of serious adverse events was comparable in both groups. CONCLUSION: In conclusion, the results of bortezomib treatment are comparable to thalidomide treatment under conditions of short administration. According to other clinical trials, long-term bortezomib treatment provides an additional advantage for PFS and OS.

Plasma Cell Leukemia ­â€Š the Forgotten Dis­ease

BACKGROUND: Plasma cell leukemia (PCL) is a rare dis-ease and possibly the most aggressive form of monoclonal gammopathy. It is classified into two forms -  primary PCL that occurs without a previously identifiable multiple myeloma stage, and secondary PCL that develops from previously dia-gnosed multiple myeloma. These two forms have different cytogenetic and molecular profiles, but both forms have an aggressive clinical course. Combinations of different therapeutic approaches includ-ing autologous stem cell transplantation and currently proteasome inhibitors and immunomodulatory drugs are used to treat PCL. Current dia-gnostic criteria, developed in the 1970s, may underestimate PCL prevalence; thus, prospective re-evaluation is be-ing considered. PURPOSE: The aim of this study is to review all available information about PCL with an emphasis on dia-gnostics, treatment, and circulat-ing plasma cells features. CONCLUSION: Although PCL is rare, it is quite a severe dis-ease. Current treatments us-ing the latest therapeutics have prolonged patient survival. However, due to the low incidence of PCL, information about the dis-ease is very limited and comes mostly from small retrospective studies. Further studies of PCL are needed, because new information could increase in patient survival and our understand-ing of its pathogenesis. Key words plasma cell leukemia -  multiple myeloma -  plasma cells -  cytogenetics -  treatment This work was supported by grant NV18-03-00203. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submited: 2. 11. 2018 Accepted: 18. 11. 2018.

Levels of CEACAM6 in Peripheral Blood Are Elevated in Patients with Plasma Cell Disorders: A Potential New Diagnostic Marker and a New Therapeutic Target?

INTRODUCTION: The prognosis of multiple myeloma is still unfavorable due to inherent characteristics of the disease and the often-delayed diagnosis due to widespread and unspecific symptoms such as back pain and fatigue. Therefore, a simple diagnostic blood test would be helpful to speed up the diagnostic procedure in such patients (pts.). Here, we evaluated the diagnostic value of plasma levels of carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) in the peripheral blood and bone marrow of pts. with plasma cell disorders and in healthy controls. MATERIALS AND METHODS: Immunoreactive CEACAM6 was determined in the peripheral blood and bone marrow (n = 95/100) of pts. with monoclonal gammopathy of unknown significance (MGUS: 28/37), newly diagnosed multiple myeloma (NDMM: 42/40), and relapsed/refractory multiple myeloma (RRMM: 25/23) by sandwich ELISA. RESULTS: Median CEACAM6 levels in the peripheral blood of pts. with plasma cell disorders were significantly higher than those of healthy controls (healthy controls: 15.2 pg/ml (12.1-17.1); MGUS: 19.0 pg/ml (16.4-22.5); NDMM: 18.0 pg/ml (13.4-21.2); and RRMM: 18.9 pg/ml (15.2-21.5); p < 0.001). Plasma levels of CEACAM6 discriminated healthy subjects from MGUS/NDMM pts. (AUC = 0.71, 95% CI: 0.6-0.8); i.e., a CEACAM6 level > 17.3 pg/ml has an 82% (95% CI: 70-90) predictive probability for the identification of MGUS or NDMM. Moreover, CEACAM6 levels in the bone marrow were significantly higher in RRMM pts. than in NDMM pts. (p = 0.04), suggesting a role of this molecule in disease progression. CONCLUSION: CEACAM6 plasma levels can noninvasively identify pts. with a plasma cell disorder and should be evaluated prospectively as a potential diagnostic marker. Moreover, due to high CEACAM6 levels in the bone marrow in RRMM pts., this adhesion molecule might be a therapeutic target in multiple myeloma pts.

Retreatment with lenalidomide is an effective option in heavily pretreated refractory multiple myeloma patients.

The combination of lenalidomide and dexamethasone is the current gold standard for treatment of relapsed multiple myeloma. This study analyzes the efficiency of repeated lenalidomide treatment in patients with relapsed and refractory multiple myeloma. A total of 41 patients were prospectively evaluated at the University Hospital Brno. Lenalidomide was administered at standard dosing and in combination with corticosteroids and/or chemotherapy. The maximum cumulative dose of lenalidomide was limited to 4,200 mg because of Czech health insurance rules. Before the second lenalidomide treatment, all patients were refractory to the last treatment; previously, 95% of patients had bortezomib treatment, 48% had autologous transplantation and the median number of prior therapy lines was three. A partial 14.2% or better response was achieved with the second lenalidomide treatment. The median progression-free survival was 4.8 months, and median overall survival was 11.9 months. Unfortunately, predicting risk factors in lenalidomide retreatment proved unsuccessful. Although our treatment results were significantly affected by limited Czech health care system coverage for lenalidomide, we established that its repeated treatment is an effective therapeutic alternative for heavily pretreated patients with relapsed and refractory multiple myeloma.

[MicroRNA Analysis for Extramedullary Multiple Myeloma Relapse]. / Analýza mikroRNA u extramedulárního relapsu mnohocetného myelomu.

INTRODUCTION AND AIMS: Multiple myeloma (MM) is the second most common hematooncological disease. Patient survival has been greatly improved by the introduction of new drugs into clinical practice, but survival is negatively affected by the so-called extramedullary relapse (EM), caused by the loss of plasma cell dependence on the bone marrow microenvironment and their migration out of the bone marrow. The nature and causes of this process are currently unclear. MicroRNAs (miRNAs) are short, non-coding RNA molecules involved in many physiological and pathological processes. Their significance in the pathogenesis of MM has been demonstrated by several studies. We assume that they are also involved in the development of the EM. The aim of this study was to analyze different miRNA expression between MM and EM patients. MATERIAL AND METHODS: Using next generation sequencing, we analyzed 39 samples of bone marrow cells from MM patients at diagnosis and 9 bone marrow plasma samples of EM patients. RESULTS: In total, 2,278 miRNA were sequenced, but only 658 miRNAs were analyzed as they were expressed in all samples and had at least 20 reads. Expression data were generated using the Chimira tool from fastq data. All sequences were mapped using miRBase v20. Further analyses were performed using the R/Bioconductor package. The Bayesian procedure was used for normalization of expression. P values were adjusted using the Benjamini-Hochberg method. Analysis found 10 miRNA (p < 0.0005) that are statistically significantly expressed in EM vs. MM patients - these are miR-26a-5p, miR-26b-5p, miR-30e-5p, miR-424-3p, miR-503-5p, miR-767-5p, miR-105-5p, miR-5695-5p, miR-450b-5p and miR-92b-3p. These miRNAs will be further verified by qPCR method on a larger set of MM and EM patients. CONCLUSION: Our pilot study has shown that there are differentially expressed miRNAs between MM and EM patients.Key words: multiple myeloma - microRNA - carcinogenesis - next generation sequencing The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papersThis work was supported by grant MZ CR AZV 17- 29343A. Submitted: 17. 3. 2018Accepted: 20. 3. 2018.

Biobanking - the First Step to Successful Liquid Biopsy Experiments.

BACKGROUND: Archiving of biological materials in biobanks is considered to be the initial crucial part of research activities. Most often, biobanks are founded for research purposes since they allow collection of sufficient material for analysis of new or testing of previously identified biomarkers. Biobanking needs to quickly react to current needs of researchers as well as clinicians, it is not a rigid system. Laboratory analyses of monoclonal gammopathies are based on separation of plasma cells from bone marrow of patients. A specific problem is usually a lack of tumor cell fraction, which is due to location of tumor cell in bone marrow in combination with low infiltration. One of the challenges in clinical research is the necessity of changes in biobanking for samples allowing detection of minimal residual disease in the bone marrow but also from peripheral blood by the so-called liquid biopsies. AIM: The aim of this review is to show the importance of archiving biological material in the Czech Republic and to show concrete examples of its usage in hematooncology. CONCLUSION: A general problem in solving many research questions is the availability of a critical amount of specimens for statistical analysis. Obtaining critical amount of specimens of biological material can be quickly archived by cooperation of biobanks sharing both methodological standards and informations about the availability of samples for research projects.Key words: archiving - biological material - informed consent - multiple myeloma - plasma cells.

Liquid Biopsies - the Clinics and the Molecules.

Unlike bone marrow biopsies, liquid biopsies represent a gentler, more accessible, less painful, repeatable and more comprehensive approach to get biologically relevant information about the entire tumor but also about treatment response and level of minimal residual disease. This is all possible since peripheral blood contains not only circulating tumor cells but also many circulating molecules of nucleic acids (microRNA, cell-free DNA, long non-coding RNA etc.). Multiple myeloma is a genetically heterogeneous disease characterized by multifocal tumor deposits in the bone marrow but also focal lesions elsewhere. Single-site biopsy of the bone marrow creates a sampling bias that provides a limited molecular profile as the biopsy cannot capture all subclones. Moreover, during disease progression and treatment, molecular profile is changed and subclones of multiple myeloma cells resistant to treatment are formed. Likewise, various clones found in extramedullary sites that are not present in the bone marrow respond differently to treatment directly influencing survival of patients. Thus, liquid biopsies seem to be a relevant and necessary next step for diseases such as multiple myeloma.Key words: multiple myeloma - minimal residual disease - prognosis - liquid biopsies - cell-free DNA - non-coding RNA.

[Potential of Long Non- coding RNA Molecules in Diagnosis of Tumors]. / Potenciál dlouhých nekódujících molekul RNA v diagnostice nádorových onemocnení.

Long non-coding RNA molecules (lncRNA) are defined as molecules over 200 nucleotides long that are localized in the nucleus and cytoplasm of cells. Although function of most lnRNA is not known, it is obvious that they are involved in various biological processes. LncRNA play a key role in transcriptional as well as posttranscriptional regulatory pathways and are involved in important cell processes, such as proliferation, differentiation, apoptosis but also pathogenesis of various diseases. Their dysregulation is important in steps of tumor transformation. In this review, we will describe the nature, function and molecular basis of these molecules as well as their diagnostic potential. The main focus of this review is the usage of these molecules in the most often diagnosed tumors in the Czech population--colorectal carcinoma, breast and prostate carcinomas.

[Potential of Cell-free Circulating DNA in Diagnosis of Cancer]. / Potenciál volné cirkulující DNA v diagnostice nádorových onemocnení.

Circulating cell-free DNA (cf-DNA) is characterized as extracellular DNA that may be present in the blood of healthy individuals in low concentrations. Cf-DNA is released by apoptosis or necrosis into the bloodstream. Increased levels are found in pathological conditions, such as inflammation, autoimmune diseases, or stress. Significant increase of cf-DNA is particularly evident in patients with malignancies, especially in the advanced stages of the disease. In this case, the tumor specific cf-DNA is released by necrosis from the cells of primary tumor and metastases. Recently, many studies concentrate on the so-called 'liquid biopsies' that allow detection of circulating tumor cells and circulating nucleic acids from peripheral blood for tumor diagnostics. Quantitative methods and detection of genetic and epigenetic alternations of cf-DNA in patients with different malignancies have potential applications in molecular diagnosis, prognosis, monitoring of disease progression and response to treatment. This review focuses on potential utility of cf-DNA as a blood biomarker in selected solid tumors and hematologic malignancies.

[Cereblon -  a new target of therapy in the treatment of multiple myeloma]. / Cereblon -  nový terapeutický ciel v liecbe mnohopocetného myelómu.

Treatment of multiple myeloma (MM), currently an incurable disease, aims to achieve complete remission. Immunomodulatory drugs (IMiDs), represented by thalidomide, are one class of very effective drugs. However, the mechanism of IMiDs action is not yet completely understood. Recent research suggests that cereblon (CRBN) plays an important role in mediating anti-tumor effects of IMiDs; therefore, our review focuses on this protein. CRBN is a substrate receptor of Cul4- E3 ubiquitin ligase complex, and thus recognizes proteins destined for degradation. Bind-ing of CRBN and IMiDs inhibits function of the entire ubiquitin proteasome complex which partly explains their anti-tumor effects. In addition, a correlation between CRBN gene expression and effectiveness of treatment in MM patients treated with IMiDs was confirmed. These findings suggest that CRBN expression could possibly serve as a bio-marker to predict response to IMiD in MM patients.

Impact of anakinra treatment on cytokine and lymphocytes/ monocytes profile of an Erdheim-Chester patient.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare non-Langerhans cells histiocytosis associated with intense immune activation. In our clinical center, an ECD patient was treated with anakinra, IL1RA (interleukin1 receptor antagonist), resulting in clinical improvement and major decrease of pathological fatigue. The aim of the study was to evaluate changes in cytokine profile and shift of immune cells estimated by flow cytometric analysis of ECD patient before, during initial stages of anakinra treatment as well as after treatment ceased in comparison to healthy donors. METHODS: Singleplex reactions of 19 individual cytokines from serum of ECD patient were measured by FACS array. Flow cytometric analyses were performed on peripheral blood cells. RESULTS: The most striking result is substantial decrease of IL6 immediately after anakinra treatment started suggesting a major role of IL1 pathway in ECD pathophysiology. As for flow cytometric analysis, increased number of CD16+ monocytes before treatment is a new finding. CONCLUSION: Our results suggest that IL6 may be a marker of early treatment response of ECD patients treated with anakinra.