Long non-coding RNA plasmacytoma variant translocation 1 and growth arrest specific 5 regulate each other in osteoarthritis to regulate the apoptosis of chondrocytes.

Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) and growth arrest specific 5 (GAS5) have opposite functions in the apoptosis of chondrocytes, which are involved in the pathogenesis of osteoarthritis (OA). The opposite roles of PVT1 and GAS5 in OA may indicate the existence of crosstalk between them in OA. This study aimed to explore the possible interaction between PVT1 and GAS5 in OA. Accumulation of PVT1 and GAS5 in OA and control synovial fluid samples was measured by RT-qPCR. The interaction between PVT1 and GAS5 in chondrocytes was explored by overexpression experiments. Dual-luciferase reporter assay was performed to analyze the binding of PVT1 and GAS5 to each other's promoter regions. Regulatory roles of PVT1 and GAS5 in the apoptosis of chondrocytes were studied with cell apoptosis assay. PVT1 was upregulated in OA, and GAS5 was downregulated in OA. An inverse correlation between PVT1 and GAS5 was observed across OA samples. Under lipopolysaccharides (LPS) treatment, PVT1 was upregulated and GAS5 was downregulated. Interestingly, PVT1 and GAS5 overexpression downregulated each other in chondrocytes. Cell apoptosis analysis showed that PVT1 overexpression promoted cell apoptosis, while GAS5 overexpression suppressed cell apoptosis induced by LPS. Co-transfection of PVT1 and GAS5 failed to significantly affect cell apoptosis. PVT1 and GAS5 directly bound to each other's promoter regions. Our study characterized the interaction between PVT1 and GAS5 in OA. Their interaction regulated the apoptosis of chondrocytes, which play a critical role in OA. PVT1 and GAS5 may form a negative feedback loop in OA.

Decrease of CD38 expression is linked to increase of solitary plasmacytoma pathological grade: a single institution experience from China.

INTRODUCTION: Solitary plasmacytoma (SP) is a rare plasma cell disorder characterized by localized neoplastic proliferation of monoclonal plasma cell. Due to its rarity, further understanding of the spectrum of its clinicopathologic features is needed. METHODS: A retrospective analysis of cases from a single institution was conducted. Clinical characteristics of the patients were collected; histopathological and semi-quantitative immunohistochemical analyses were performed. RESULTS: Thirteen cases were identified from our pathology archives, including 4 cases of solitary plasmacytoma of bone (SPB) (30.8%) and 9 extraosseous plasmacytoma (EP) (69.2%). The mean age of EP is a decade older than SPB. There is no gender disparity. The most common sites involved are the vertebrae and nasopharynx. Histologically, the tumors can be classified into two grades based on degree of differentiation. Immunohistochemically the tumor cells express CD38, CD138, MUM-1, and exhibit light chain restriction. Ki-67 proliferation index is 30%. In situ hybridization for Epstein-Barr virus-encoded small RNAs (EBER) is negative in six cases tested. Semi-quantitative immunohistochemical analysis showed decreased integrated optical density (IOD) of CD38 in neoplastic cells. IgH gene rearrangement was identified in two cases. CONCLUSION: SP is a rare plasmacytoid neoplasm that occurs more frequently in older patients. Diagnosis requires a systematic clinical approach combined with the pathological characteristics of plasmacytoid morphology, immunophenotype and light chain restriction. There are more cases of EP than SPB in our series, which is in contrast to that reported in literature. Results from this study suggest that CD38 is a potential immunohistochemical marker associated with prognosis of SP. Further studies with more cases and longer term follow-up may provide more definitive information on risk of progression from SP to multiple myeloma (MM).

Solitary Bone Plasmacytoma of Humerus Presenting as a Nonhealing Fracture in a Child: A Rare Entity.

Solitary bone plasmacytoma is an extremely rare entity and is characterized by localized proliferation of monoclonal plasma cells. Plasmacytomas are extremely rare in the pediatric population. The median age at diagnosis is usually the fifth or sixth decade, with axial skeleton being more commonly involved than appendicular. We hereby, report the case of a 13-year-old boy with solitary bone plasmacytoma of the right humerus. Though extremely rare in the pediatric age group, plasmacytomas may be considered as one of the remote differentials in children presenting with solitary bone tumors.

A case of solitary plasmacytoma of bone showing co-expression of both immunoglobulin light chains.

BACKGROUND: Solitary plasmacytoma of bone (SPB) is a rare plasma cell neoplasm. It arises in bone as a single locus in the absence of any plasma cell myeloma lesions. Plasma cell neoplasms intrinsically express only one immunoglobulin light chain (IgL)-kappa or lambda-and using this fact, kappa/lambda deviation is the decisive factor for diagnosis. Co-expression of both IgLs in a single tumor cell is extremely rare. CASE PRESENTATION: We report a case of SPB that arose in the vertebra of a 52-year-old Japanese woman. Histologically, the resected mass showed diffuse plasma cell proliferation. Dual IgL expression was detected by flow cytometry, immunohistochemistry, and in situ hybridization (ISH) targeting IgL mRNA. CONCLUSION: We have presented an extremely rare case of SPB showing dual expression of kappa and lambda IgLs. This unusual case of plasma cell neoplasia might represent a possible exceptional example of failure of "IgL isotypic exclusion."

Salvianolic Acid A Protects H9C2 Cardiomyocytes from Doxorubicin-Induced Damage by Inhibiting NFKB1 Expression Thereby Downregulating Long-Noncoding RNA (lncRNA) Plasmacytoma Variant Translocation 1 (PVT1).

BACKGROUND A cardioprotective effect of salvianolic acid A (SalA) has been described, but it is unknown whether SalA can protect cardiomyocytes against doxorubicin (Dox)-induced cardiotoxicity. This study aimed to investigate whether SalA could inhibit Dox-induced apoptosis in H9C2 cells and to uncover the potential mechanism. MATERIAL AND METHODS H9C2 cardiomyocytes exposed to Dox were treated with SalA or not, and then cell viability, apoptosis, and the expression of nuclear factor-kappaB (NF-kappaB) signaling were detected by Cell Counting Kit-8, TUNEL staining, and western blot assays, respectively. Nuclear factor kappa B subunit 1 (NFKB1) was overexpressed in H9C2 cells, and then alterations in cell viability and apoptosis in H9C2 cells co-treated with Dox and SalA were investigated. RESULTS SalA (2, 10, and 50 µM) had no effect on H9C2 cell viability, while Dox reduced cell viability in a concentration-dependent manner. In addition, SalA rescued Dox-decreased cell viability. Dox also triggered apoptosis as evidenced by an increased ratio of TUNEL-positive cells, enhanced expression of pro-apoptotic proteins, and reduced expression of anti-apoptotic protein BCL-2, which were all partially blocked by SalA co-treatment. The proteins involved in NF-kappaB signaling including IkappaBalpha, IKKalpha, IKKß, and p65 were activated by Dox but inactivated by SalA co-treatment. Moreover, Dox increased NFKB1 mRNA and nuclear expression, which was blocked by SalA. NFKB1 could bind to plasmacytoma variant translocation 1 (PVT1) and upregulate PVT1 expression. Mechanistically, the overexpression of NFKB1 blocked the inhibitory effect of SalA on Dox-induced cell viability impairment and apoptosis. CONCLUSIONS We demonstrated that SalA may exert a protective effect against Dox-induced H9C2 injury and apoptosis via inhibition of NFKB1 expression, thereby downregulating lncRNA PVT1.

Pathology and Proteomics-Based Diagnosis of Localized Light-Chain Amyloidosis in Dogs and Cats.

Amyloidosis is classified according to the amyloid precursor protein, and accurate diagnosis of the amyloidosis type may guide appropriate treatment. Immunohistochemistry and Congo red staining are the most frequently used methods used to distinguish types of amyloidosis, but problems with specificity and sensitivity indicate the need for an alternative diagnostic method. In this study, we evaluated laser microdissection-liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS) for the diagnosis of amyloid light-chain (AL) amyloidosis in animals. Plasmacytomas with amyloid deposits from 15 dogs and 2 cats were subjected to Congo red staining with or without potassium permanganate pretreatment, immunohistochemistry for kappa and lambda light chains, and LMD-LC-MS/MS. Congo red staining was diagnostic in 12 of 17 cases based on resistance to potassium permanganate pretreatment, but in 5 of 17 cases the pretreatment unexpectedly reduced Congo red staining or abrogated the birefringence and a definitive diagnosis could not be reached. Immunohistochemistry detected kappa or lambda light chains in 6 of 17 cases. With LMD-LC-MS/MS, immunoglobulin lambda light chain was detected in all 17 cases. The amyloid signature proteins ApoA-I, ApoA-IV, and ApoE were detected in 9, 1, and 3 of the 15 canine cases by LMD-LC-MS/MS, but not in the feline cases. In conclusion, LMD-LC-MS/MS consistently determined the amyloid type in all examined specimens, while Congo red staining after potassium permanganate treatment and immunohistochemistry were less sensitive tests.

18F-FDG PET or PET/CT role in plasmacytoma: A systematic review. / Papel de la 18F-FDG PET o PET/TC en el plasmocitoma: una revisión sistemática.

BACKGROUND: The metabolic behavior of plasmacytoma at 18F-FDG PET/CT is not yet clear. OBJECTIVE: The aim of this systematic review was to analyze published data about the role of 18F-FDG PET or PET/CT in patients affected by plasmacytoma. METHODS: Acomprehensive computer literature search of the Scopus, PubMed/MEDLINE, Embase and Cochrane Library databases was conducted including articles up to July 2019 to find relevant published papers about the performance of 18F-FDG PET and PET/CT in plasmacytoma. RESULTS: The comprehensive computer literature search revealed 371 articles. On reviewing the titles and abstracts, 363 articles were excluded because the reported data were not within the field of interest of this review. Eight articles were selected and retrieved in full-text version. From the analyses of the selected studies, the following main findings have been founded: 1) plasmacytoma generally is a 18F-FDG-avid tumor and PET/CT had good diagnostic performance with high sensitivity; 2) 18F-FDG PET/CT influenced patient management in most cases avoiding useless therapies and choosing the best therapeutic approach; 3) prognostic value of PET/CT qualitative and semiquantitative parameters is only suggested with controversial reports. CONCLUSION: Despite several limitations affect this analysis, especially related to the low number of articles and patients studied, plasmacytoma looks to be an 18F-FDG-avid tumor in most of the cases; 18F-FDG PET or PET/CT had good diagnostic performance and had a significant clinical impact in change of therapeutic approach. Moreover, a possible prognostic role of PET/CT features is described.

Current and potential applications of positron emission tomography for multiple myeloma and plasma cell disorders.

Fluorine-18 (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET) allows evaluation of elevated glucose metabolism in malignancies. There has been increasing interest in FDG PET/CT for plasma cell disorders since the International Myeloma Working Group outlined multiple applications of this imaging modality, including distinguishing smoldering myeloma from active multiple myeloma, confirmation of solitary plasmacytoma, and multiple indications in patients with known multiple myeloma, including determining extent of initial disease, monitoring therapy response, and detection of residual disease following therapy. The field of molecular imaging is now shifting focus from evaluation of metabolism to targeted evaluation of specific tumor markers. Targeted PET imaging targeted of CXCR4 and CD38 has advanced into translational clinical trials, bringing us closer to powerful imaging options for myeloma. In this review we discuss the current applications of FDG PET/CT in plasma cell disorders, as well as advances in targeted PET imaging.

Whole-genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy with a poorly understood pathobiology and no effective therapeutic options. Despite a few recurrent genetic defects (eg, single nucleotide changes, indels, large chromosomal aberrations) have been identified in BPDCN, none are disease-specific, and more importantly, none explain its genesis or clinical behavior. In this study, we performed the first high resolution whole-genome analysis of BPDCN with a special focus on structural genomic alterations by using whole-genome sequencing and RNA sequencing. Our study, the first to characterize the landscape of genomic rearrangements and copy number alterations of BPDCN at nucleotide-level resolution, revealed that IKZF1, a gene encoding a transcription factor required for the differentiation of plasmacytoid dendritic cell precursors, is focally inactivated through recurrent structural alterations in this neoplasm. In concordance with the genomic data, transcriptome analysis revealed that conserved IKZF1 target genes display a loss-of-IKZF1 expression pattern. Furthermore, up-regulation of cellular processes responsible for cell-cell and cell-ECM interactions, which is a hallmark of IKZF1 deficiency, was prominent in BPDCN. Our findings suggest that IKZF1 inactivation plays a central role in the pathobiology of the disease, and consequently, therapeutic approaches directed at reestablishing the function of this gene might be beneficial for patients.

IRF4 Activity Is Required in Established Plasma Cells to Regulate Gene Transcription and Mitochondrial Homeostasis.

The transcription factor interferon regulatory factor 4 (IRF4) is critical for the development, maintenance, and function of plasma cells. The mechanism by which IRF4 exerts its action in mature plasma cells has been elusive due to the death of all such cells upon IRF4 loss. While we identify apoptosis as a critical pathway for the death of plasma cells caused by IRF4 loss, we also determine that IRF4 did not regulate the intrinsic apoptotic pathway directly. By using an inducible IRF4 deletion system in the presence of the overexpression of anti-apoptotic BCL2, we identify genes whose expression is coordinated by IRF4 and that in turn specify plasma cell identity and mitochondrial homeostasis.

Adenopathy and extensive skin patch overlying a plasmacytoma with unusual histologic findings in a patient with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes syndrome and Castleman disease.

A 56-year-old previously healthy man presented to the dermatology clinic with a 2-year history of an expanding, violaceous, infiltrated plaque on the right flank. Biopsy revealed a diffuse dermal vascular proliferation of bland, capillary-sized vessels admixed with conspicuous fibrohistiocytic cells including scattered multinucleated floret cells. Further workup revealed a monoclonal gammopathy, an osteolytic chest wall plasmacytoma underlying the plaque, and regional lymphadenopathy leading to a diagnosis of adenopathy and extensive skin patch overlying a plasmacytoma (AESOP). Biopsy of an enlarged lymph node revealed Castleman disease. The patient subsequently developed polyneuropathy and peripheral edema, which supported an additional diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome. Herein, we discuss the unique findings of our patient, the potential pathogenesis of AESOP, and the link between these three rare paraneoplastic entities along with review of the literature.

Primary pulmonary plasmacytoma presenting with rare IgG lambda monoclonal gammopathy.

Extramedullaryplasmacytoma (EMP) represents a peculiar and typically progressive malignancy that can originate outside the bone marrow. Primary pulmonary plasmacytoma (PPP) is a rare subset of EMP, confined to the lung. A 55-year-old man, diabetic, non-smoker presented to our clinic with a right chest wall swelling. A routine chest radiograph showed a well-circumscribed opacity in the right upper lung zone. A CT of the chest revealed a large right upper lobe mass with extensive local infiltration. Biopsy and immunohistochemical evaluation led to a diagnosis of PPP. Screening for multiple myeloma was negative. Serum immunofixation showed an IgG lambda monoclonal gammopathy, found in a minority of PPP patients. In view of disease extent, treatment with chemotherapy and radiotherapy was initiated. The patient is currently in out patient follow-up and has shown a favourable response to the treatment with a considerable decrease in serum IgG levels.

Mast Cells and Angiogenesis in Human Plasma Cell Malignancies.

Bone marrow angiogenesis plays an important role in the pathogenesis and progression of hematological malignancies. It is well known that tumor microenvironment promotes tumor angiogenesis, proliferation, invasion, and metastasis, and also mediates mechanisms of therapeutic resistance. An increased number of mast cells has been demonstrated in angiogenesis associated with hematological tumors. In this review we focused on the role of mast cells in angiogenesis in human plasma cell malignancies. In this context, mast cells might act as a new target for the adjuvant treatment of these tumors through the selective inhibition of angiogenesis, tissue remodeling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression.