scholarly journals The Importance of Cyclin D1, P53, Cd56 Antigen Expression in Plasma Cells and its Correlation with Serological and Clinical Parameters in Patients with Multiple Myeloma

2018 ◽  
Vol 72 (5) ◽  
pp. 259-267
Author(s):  
Jurijs Nazarovs ◽  
Regīna Kleina ◽  
Sandra Lejniece
Keyword(s):  
Multiple Myeloma ◽  
Cyclin D1 ◽  
Plasma Cells ◽  
Osteolytic Lesion ◽  
Antigen Expression ◽  
High Serum ◽  
Bone Marrow Biopsies ◽  
Low Platelet Count ◽  
Cd56 Expression ◽  
Cd56 Antigen

Abstract CD56, p53, and Cyclin D1 detection in plasma cells (PC) can help to predict prognosis of multiple myeloma (MM). Clinical and biochemical prognostic parameters were analysed in a group of 122 patients with primary diagnosed MM in the period 2011–2015. Bone marrow biopsies were analysed with Cyclin D1, p53, CD56 antibodies. Statistical analysis was performed using Microsoft Excel 2010 and Graph Pad Prism 5. Lack of CD56 expression and p53-positivity were significantly correlated with a low glomerular filtration rate (GFR), low platelet count and haemoglobin level, as well as with high serum creatinine levels. Patients with Cyclin D1 expression in PC had a significantly higher serum calcium level and more common osteolytic lesion in bones. CD56-negative as well as p53, Cyclin D1-positive groups had advanced Salmon–Durie MM stages by and significantly higher ß2-microglobulin. Expression of p53, Cyclin D1 and lack of CD56 antigen in PC are negative predictive factors in cases of MM, as these patients were diagnosed as having late Salmon–Durie stage and higher ß2-microglobulin level. Expression of p53 and lack of CD56 antigen in PC is associated with an increased creatinine level in blood and decreased GFR; therefore, these are criteria for chronic renal failure progression and poorer prognosis of MM.

Observations On Eosinophil Ifiltrates in The Bone Marrow Of Patients With Multiple Myeloma. Clinicopathological Correlates

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5338-5338
Author(s):  
Finella MC Brito-Babapulle ◽  
Tanya Cranfield ◽  
Robert B Corser ◽  
Helen Dignum ◽  
Christopher James ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Osteolytic Lesion ◽  
Inverse Correlation ◽  
Eosinophil Infiltration ◽  
Bone Marrow Biopsies ◽  
Lytic Lesions

Abstract Mouse eosinophils have been shown in 2011 to be required for the maintenance of long lasting plasma cells in the bone marrow and in maintaining the bone marrow plasma cell microenvironment. Human eosinophils have been shown by Wong et al to support multiple myeloma cell proliferation via a mechanism independent of IL6. We looked at bone marrow biopsies taken from patients who had a paraprotein and in whom a diagnosis of multiple myeloma was suspected. These samples were taken solely for the purposes of diagnosisng multiple myeloma and were retrospectively reviewed from the point of view of degree of eosinophil infiltration and its correlation with tumour load, bone lytic lesions, plasma cell morphology, whether blastic, crystalline inclusions, Mott cells, flame cells and or lymphoplasmacytoid. There were no cases of IGD or E myeloma or osteosclerotic myeloma.Nonsecretory myeloma and cases of light chain myeloma with or without amyloid were included in the series. Biopsies were not performed from osteolytic lesion unless biopsy was necessary to make a diagnosis of myeloma. Myeloma was diagnosed when plasma cell infiltrate was greater than 10% on bone marrow aspirate with a paraprotein and or lytic lesions. Eosinophil infiltration did not correlate with any of the tumour clinicopathological markers but showed an inverse correlation with degree of plasmacytosis. Eosinophils were hardly ever found in marrow aspirates that had over 70% plasma cells. They were usually found in trephine sections of bone marrow in areas where there was Grade I/II fibrosis and were often found in close proximity to focal areas of plasma cell infiltration. Whether eosinophils play a role in preventing or maintaining malignant plasma cell recurrence is currently being studied. Disclosures: No relevant conflicts of interest to declare.

Automated digital enumeration of plasma cells in bone marrow trephine biopsies of multiple myeloma

2020 ◽  
pp. jclinpath-2020-207066
Author(s):  
Jacques A J Malherbe ◽  
Kathryn A Fuller ◽  
Bob Mirzai ◽  
Bradley M Augustson ◽  
Wendy N Erber
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Intraclass Correlation ◽  
Antigen Expression ◽  
Bone Marrow Biopsies ◽  
Bone Marrow Trephine ◽  
Bone Marrow Trephine Biopsy ◽  
Plasma Cell Neoplasms

AimsDetermination of the number of plasma cells in bone marrow biopsies is required for the diagnosis and ongoing evaluation of plasma cell neoplasms. We developed an automated digital enumeration platform to assess plasma cells identified by antigen expression in whole bone marrow sections in multiple myeloma, and compared it with manual assessments.MethodsBone marrow trephine biopsy specimens from 91 patients with multiple myeloma at diagnosis, remission and relapse were stained for CD138 and multiple myeloma oncogene 1 (MUM1). Manual assessment and digital quantification were performed for plasma cells in the entire trephine section. Concordance rates between manual and digital methods were evaluated for each antigen by intraclass correlation analyses (ICC) with associated Spearman’s correlations.ResultsThe digital platform counted 16 484–1 118 868 cells and the per cent CD138 and MUM1-positive plasma cells ranged from 0.05% to 93.5%. Overall concordance between digital and manual methods was 0.63 for CD138 and 0.89 for MUM1. Concordance was highest with diffuse plasma cell infiltrates (MUM1: ICC=0.90) and lowest when in microaggregates (CD138: ICC=0.13). Manual counts exceeded digital quantifications for both antigens (CD138: mean=26.4%; MUM1: mean=9.7%). Diagnostic or relapse threshold counts, as determined by CD138 manual assessments, were not reached with digital counting for 16 cases (18%).ConclusionsAutomated digital enumeration of the entire, immunohistochemically stained bone marrow biopsy section can accurately determine plasma cell burden, irrespective of pattern and extent of disease (as low as 0.05%). This increases precision over manual visual assessments which tend to overestimate plasma burden, especially for CD138, and when plasma cells are in clusters.

scholarly journals Plasma cells in multiple myeloma express a natural killer cell- associated antigen: CD56 (NKH-1; Leu-19)

Blood ◽  
1990 ◽  
Vol 76 (2) ◽  
pp. 377-382 ◽  
Author(s):  
B Van Camp ◽  
BG Durie ◽  
C Spier ◽  
M De Waele ◽  
I Van Riet ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Plasma Cells ◽  
Killer Cell ◽  
Neoplastic Tissue ◽  
Aggressive Disease ◽  
Reactive Plasma ◽  
Gut Mucosa ◽  
Cd56 Expression

Abstract Bone marrow samples from 55 patients with multiple myeloma (MM) and 23 patients with monoclonal gammopathy of undertermined significance (MGUS) were evaluated with a broad panel of monoclonal antibodies. Plasma cells from 78% (43/55) of patients with MM strongly expressed the natural killer cell antigen CD56 (NKH-1, Leu-19). Of the 23 patients with MGUS, none showed strong CD56 reactivity, although three had weak reactivity in less than 20% of plasma cells. Myeloma cells expressing CD56 did not coexpress the CD57 or CD16 antigens. Patients with CD56-positive plasma cells had both indolent and aggressive disease. However, the 12 CD56-negative patients had predominantly aggressive disease with an unexpected preponderance of kappa Bence Jones only myeloma (5/10[50%] evaluable patients). Polyclonal plasma cells from non-neoplastic tissue sites (normal bone marrows, lymph nodes, tonsillar biopsies, and gut-mucosa biopsies) showed a near absence of CD56. We conclude that isolated, strong CD56 expression is common in MM, but not in MGUS or reactive plasma cells. The potential biologic importance of CD56 positivity in myeloma is reviewed.

scholarly journals Increased expression of cyclin-D1 on trephine bone marrow biopsies independently predicts for shorter overall survival in patients with multiple myeloma treated with novel agents

2012 ◽  
Vol 87 (7) ◽  
pp. 734-736 ◽  
Author(s):  
Anna Tasidou ◽  
Maria Roussou ◽  
Evangelos Terpos ◽  
Efstathios Kastritis ◽  
Maria Gkotzamanidou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Cyclin D1 ◽  
Novel Agents ◽  
Bone Marrow Biopsies

scholarly journals Different CD44 splicing patterns define prognostic subgroups in multiple myeloma

Blood ◽  
1996 ◽  
Vol 88 (8) ◽  
pp. 3101-3108 ◽  
Author(s):  
R Stauder ◽  
M Van Driel ◽  
C Schwarzler ◽  
J Thaler ◽  
HM Lokhorst ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Bone Marrow Biopsies ◽  
Cd44 Variant ◽  
Rna Transcripts ◽  
Variant Isoforms ◽  
Extracellular Region ◽  
Additional Protein ◽  
Splicing Patterns

CD44 variant isoforms (CD44v) are generated by alternative splicing of the nuclear RNA resulting in the expression of additional protein domains in the extracellular region of the CD44 standard molecule (CD44s). In multiple myeloma (MM), CD44 mediates binding of tumor cells to stroma and regulates interleukin-6 production. To evaluate the role of CD44v isoforms in MM, CD44v expression was analyzed by immunohistochemical staining of 64 bone marrow biopsies from 38 MM patients. Expression of variant isoforms containing the 9v domain was observed in 36% of cases and was associated with an advanced stage (P ‼ .02; n = 61), a progressive disease (P ‼ .001; n = 61), and a shorter overall survival (P ‼ .02; n = 36). In contrast, 3v, 4v, 6v, or 10v isoforms were detected only in a small percentage of the patients. To analyze the exon composition in RNA-transcripts, reverse transcriptase polymerase chain reaction analyses followed by Southern hybridization with exon-specific probes were performed in fluorescence-activated cell sorted myeloma plasma cells. Tumors expressing the 9v domain showed complex, 9v-containing transcripts in combinations with the 3v, 7v, 8v, and 10v exons. Identical transcripts were detected in several myeloma cell lines and in a Ki-1 B-immunoblastic lymphoma. Similar to high-grade non-Hodgkin's lymphoma and gastric and renal cell carcinoma, overexpression of 9v-containing isoforms in MM is related to an unfavorable clinical presentation and represents a new prognostic parameter.

CD28-Mediated Regulation of Multiple Myeloma Cell Proliferation and Survival.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 355-355
Author(s):  
Kelvin P. Lee ◽  
Nizar J. Bahlis ◽  
Anne M. King ◽  
Despina Kolonias ◽  
Louise M. Carlson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
T Cells ◽  
Cell Survival ◽  
Plasma Cells ◽  
Survival Function ◽  
Myeloma Cell ◽  
Serum Starvation ◽  
Bone Marrow Biopsies

Abstract Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown due to the complexity of the bone marrow microenvironment. The CD28 receptor, which costimulates survival signals in T cells, is also expressed on normal plasma cells and myeloma cells. In MM, CD28 expression correlates significantly with disease progression, also suggesting a pro-survival function. In contrast to T cells however, activation and function of CD28 in myeloma and plasma cells is almost entirely undefined. We found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induced activation of NFkappaB, suppressed MM cell proliferation and protected against serum starvation and dexamethasone-induced cell death. We hypothesized that the specific CD80/CD86 expressing stromal cell partner of this interaction is a professional antigen presenting cells, in particular dendritic cells. Histological studies demonstrated DC were extensively interdigitated throughout the myeloma infiltrates in patient bone marrow biopsies. In vitro coculture with DC also elicited CD28-mediated effects on MM survival and proliferation, and could be blocked by CD28Ig. Our findings suggest a previously undescribed myeloma:DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also suggest that CD28 may represent a therapeutic target in the treatment of multiple myeloma.

Evaluation of NCAM and DKK1 Expression in Multiple Myeloma and MGUS by Gene and Tissue Microarrays: Expression Accompanies Progression.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3399-3399
Author(s):  
Sushil Gupta ◽  
Yongsheng Huang ◽  
James Stewart ◽  
Fenghuang Zhan ◽  
Bart Barlogie ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Plasma Cells ◽  
Molecular Classification ◽  
Tissue Microarrays ◽  
Bone Lesions ◽  
Bone Marrow Biopsies ◽  
Dkk1 Expression ◽  
Significant Difference ◽  
Expression Microarrays

Abstract Introduction: Expression NCAM1, a cell adhesion molecule involved in neuron-neuron adhesion, is also expressed by multiple myeloma (MM PC). Osteolytic bone lesions are a hallmark of MM and elevated expression of NCAM in MM PC has been correlated with this process (Ely and Knowles, 2003). We have previously reported that MM PC express DKK1 and MM blocks osteoblast differentiation in a DKK1-specific manner, suggesting that secretion of the Wnt signaling inhibitor plays a role in MM bone disease. Herein we used gene expression microarrays and tissue microarrays (TMAs) to investigate the simultaneous expression of DKK1 and NCAM in MM and MGUS. Methods: The study population consisted of 198 newly diagnosed MM and 44 MGUS. RNA from CD138-selected plasma cells was hybridized to Affymetrix U133Plus microarrays and data processed with Affymetrix Microarray Suite GCOS1.1 software. TMAs were constructed from formalin-fixed, paraffin embedded bone marrow biopsies. Serial sections of TMA were immunostained for CD138, NCAM and DKK1. TMAs were scanned using ScanScope using 20x lens, assessed using TMA lab software (Aperio Technologies) and scored as an average number of cells in the context of CD138 staining. Results: When put in context of a recently described molecular classification (Zhan et al., 2006), NCAM and DKK1 were found significantly co-over-expressed (DKK1+/NCAM+) in HYPERDIPLOID MM (P < 0.01); NCAM+/DKK1− was typical for MMSET-spike MM (P<0.001); NCAM−/DKK1+ DKK1 was characteristic of MM in MAF-spike disease (P < 0.001), CCND1 spikes with co-expression of CD20 (P<0.01), and the so-called MYELOID subgroup (P<0.001). In contrast, virtually all cases of MGUS were DKK1−/NCAM-. On TMAs, DKK1 expression varied in CD138-positive cells in MM, and in osteocytes and megakaryocytes in MM and MGUS, but was clearly negative in osteoblasts/lining cells. NCAM expression, was also variably expressed in PC of MM cases and in virtually 100% of osteoblasts/lining cells in both MM and MGUS. Osteocytes were distinctly negative for NCAM in both diseases. Of 195 analyzable MM biopsies, PC were DKK1+ in 1% to > 90% of PC in 191 (98%); of these, 94 were also NCAM+ in 5% to > 90% of PC; 1 case was positive for NCAM+/DKK− and 3 were NCAM−/DKK−. There was no significant difference in clinical parameters and survival in a comparison of NCAM+/DKK+ and NCAM−/DKK+ groups. DKK1 gene expression was higher in DKK1+/NCAM+ than in DKK1+/NCAM− MM (P=0.006); NCAM gene expression was higher in DKK1+/NCAM+ than in DKK+/NCAM− MM (P<0.0001) and NCAM was the number one SAM-defined gene over-expressed in DKK1+/NCAM+ relative to DKK1+/NCAM− disease. Consistent with GEP data, DKK1+/NCAM+ MM was over-represented in HYPERDIPLOID MM (32% v. 10%; P<0.001), while DKK1+/NCAM− disease was overrepresented in MAF-spike (15% v. 2%; P=0.003) and MYELOID subgroups (32% v. 18%; P=0.03). DKK1+/NCAM+ MM was completely absent in CCND1-spike /CD20-negative disease, with only 4% of DKK1+/NCAM− cases in this subgroup. No difference was observed for the other subtypes. Conclusion: DKK1 is expressed in all cases of MM with half also expressing NCAM. Neither gene is expressed in MGUS PC. These data suggests that expression of these genes in plasma cells accompanies disease progression.

Relationship Between CD56 Antigen Expression and Quantification of MDR1 Gene Expression in Patients with De Novo Acute Myeloid Leukemia(AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4677-4677
Author(s):  
Bing Xu ◽  
Xiaoyan Song ◽  
Pengcheng Shi ◽  
Pengnan Xiao ◽  
Zhengshan Yu ◽  
...  
Keyword(s):  
Gene Expression ◽  
De Novo ◽  
Antigen Expression ◽  
Expression Level ◽  
Mdr1 Gene ◽  
Mdr1 Gene Expression ◽  
Mdr1 Expression ◽  
Cd56 Expression ◽  
Cd56 Antigen ◽  
De Novo Aml

Abstract Abstract 4677 Introdution The expression of CD56 antigen and over-expression of the multidrug resistance gene 1 (MDR1) seems to confer the poor therapeutic outcome to AML. The aim of this study is to investigate the relationship between CD56 antigen expression and MDR1 gene expression in patients with de novo AML and explore the indicating effect of these two factors on clinical drug resistance. Patients and methods A real-time quantitative reverse transcriptase polymerase chain reaction method was established for detecting MDR1 expression levels and a three-color flow cytometry analysis with CD45/SSC gating was used to examine CD56 antigen expression in 79 patients with de novo AML. Results CD56 antigen was recorded in 19 out of 79 cases (24.1%) and particularly in those with M5 subtype and t(8;21) AML. Moreover, CD56 expression was significantly associated with unfavorable cytogenetic abnormalities (P< 0.05). Significantly higher percentage (57.1%, 4/7) of patients with t(8;21) demonstrated CD56 expression than those with favorable cytogenetic abnormalities (P< 0.05). CD56+ AML patients had higher incidence of splenohepatomegalia and level of lactate dehydrogenase than CD56- patients (P< 0.05). The median expression level of MDR1 was statistically higher in CD56+ AML patients than that in CD56- cases (P< 0.001) and 89.5% (17/19) CD56+ AML patients were found with high MDR1 expression. The CR rate in high MDR1 / CD56+ AML patients was significantly lower than that in low MDR1/ CD56- cases. (58.8% vs 89.2%, P< 0.01). Conclusions There is a linear correlation between MDR1 and CD56 expression in AML. This relationship may explain why CD56 expression is related to a poor prognosis in AML. Therefore both with high MDR1 expression level and CD56 antigen expression can identify AML patients with unfavorable outcome. Disclosures: No relevant conflicts of interest to declare.

Increased Expression of Cyclin-D1 on Trephine Bone Marrow Biopsies Independently Predicts for Shorter Overall Survival In Patients with Multiple Myeloma Treated with Novel Agents

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2965-2965
Author(s):  
Evangelos Terpos ◽  
Maria Roussou ◽  
Anna Tasidou ◽  
Magdalini Migkou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Cyclin D1 ◽  
Plasma Cells ◽  
Univariate Analysis ◽  
Novel Agents ◽  
Positive Staining ◽  
Newly Diagnosed ◽  
Immunohistochemical Expression

Abstract Abstract 2965 The cyclin-D1 proto-oncogene is an important cell regulator of G1 to S phase progression. The overexpression of cyclin-D1 has been linked to the development and progression of several malignancies. The aim of our study was to evaluate the impact of the immunohistochemical expression of cyclin-D1on the plasma cells of trephine biopsies on survival of newly-diagnosed patients with multiple myeloma (MM) who were treated with novel agents. We evaluated formalin-fixed, paraffin-embedded, bone marrow sections of 130 consecutive patients with newly-diagnosed MM (67M/63F; median age 68 years) before any kind of therapy administration. One hundred and fifteen patients had symptomatic disease that required therapy: 29 (25%) received bortezomib-based regimens and 31 (26%) received thalidomide-based regimens as first line therapy, while all patients received regimens containing bortezomib or an IMiD at some point during the course of their disease. Immunohistochemistry was performed in all trephine biopsies using monoclonal antibodies against cyclin-D1 (Cell Marque Corp., Rocklin, CA, USA), but also against CD56 (Cell Marque Corp., Rocklin, CA, USA), CD27 (Novocastra, Newcastle upon Tyne, UK), CD117 and MUM-1 (DAKO A/S, Glostrup, Denmark), as recommended by the manufacturers. A case was considered positive if there was unequivocal positive staining of at least 20% of the plasma cells for cyclin-D1, CD56 and MUM-1 and a positive staining of at least 10% of the plasma cells for CD117 and CD27. Among patients with symptomatic myeloma (N=115), positive staining for cyclin-D1 was found in 35 (30%) patients, for CD56 in 45 (39%), for CD117 in 94 (81%) and for CD27 in 72 (62%) patients. In patients with asymptomatic myeloma, positive staining for Cyclin-D1 was found only in 1 (7%) patient, for CD56 in 9 (64%), and for CD117 in 6 (43%) (p<0.01 for all comparisons compared to symptomatic patients). There were significant positive correlations between positivity for CD27 and CD56 (p<0.001), between positivity for cyclin-D1 and CD117 (p=0.045) and a negative correlation between positivity for CD117 and CD56 (p=0.001). We also observed significant correlations between CD56 positivity and ISS-1 or ISS-2 (p=0.01) and between CD117 positivity and ISS-3 disease (p=0.002). The median overall survival (OS) for patients with symptomatic MM was 57 months (range 22–120 months). In the univariate analysis, positivity for cyclin-D1 (41 vs. 62 months, p=0.03) and for CD117 (50 vs. 75 months p=0.018) were associated with inferior survival, while positivity for CD56 (47 vs. 62 months, p=0.286), MUM-1 (52.7 vs. 63.8 months, p=0.528) and CD27 (57 vs. 50 months, p=0.445) were not. Other factors associated with inferior OS, in the univariate analysis, included ISS-3 (median OS 37 months, vs. 57 months for ISS-2 and 73 months for ISS-1, p=0.005), Hb <10 g/dl (56 vs. 73 months, p=0.044), corrected serum calcium >11.5 g/dl (29 vs. 62 months, p=0.02), serum LDH above upper normal limit (31 vs. 61 months, p=0.05), serum creatinine >2 mg/dl (26 vs. 64 months, p=0.007), low platelet counts (<100,000/ml) (22 vs. 62 months, p=0.031) and age >65 years (45 months vs. not reached for younger patients, p=0.002). In the multivariate analysis, positivity for cyclin-D1 (HR: 2.6; p=0.001), ISS stage (HR: 1.8; p=0.001) and age >65 (HR 2.7, p=0.003) were independently associated with inferior survival. Immunohistochemistry for cyclin-D1 identified subgroups of patients in ISS-2 and in ISS-3 who had extremely poor outcome. Patients with cyclin-D1 positivity had a median survival of 22 months in ISS-2 (vs. 64 months for the rest of ISS-2 patients, p=0.01) and of 13 months in ISS-3 (vs. 47 months for the rest of ISS-3, p=0.012). Our findings underline that the immunohistochemical expression of cyclin-D1 in the bone marrow trephine biopsies has independent prognostic value in MM patients, even in the era of novel agents. This marker can easily be assessed in patients who undergo a trephine biopsy as part of their initial evaluation and offers significant prognostic information. Furthermore, novel agents targeting cyclin-D1 may be of therapeutic value in MM. Disclosures: No relevant conflicts of interest to declare.

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