Polyclonal Gamma Globulin Suppression and Risk Of MGUS Progression Into Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1875-1875 ◽  
Author(s):  
Jawad Z. Sheqwara ◽  
Mohammad Alhyari ◽  
Shannon Keating ◽  
Philip Kuriakose
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Plasma Cell ◽  
Total Protein ◽  
Gamma Globulin ◽  
Conflicts Of Interest ◽  
Significant Risk ◽  
M Protein ◽  
Plasma Cell Dyscrasia ◽  
Female Ratio

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is the most common form of plasma cell dyscrasia, with a prevalence of 3% in the general population above age of fifty. MGUS has a malignant evolution rate of 1% per year. Large longitudinal studies have suggested that virtually all patients diagnosed with multiple myeloma (MM) had a preceding MGUS, with 75 % having detectible Monoclonal (M) protein ≥8 years prior to diagnosis. It is important to identify the features at diagnosis that can predict neoplastic transformation to MM. Purpose We identified 239 patients at our institute in whom MGUS was diagnosed between 2000 and 2010. The presenting clinico-hematologic features were correlated with the frequency of evolution into MM to identify early predictors of evolution. The primary end point was progression to MM. Results The patients' mean age was 70.7 years. The Male/Female ratio was 0.7. The mean concentration of the M component (MC) was 0.7 g/dL. IgG was the most frequent MC (77%), followed by IgA (13%). The median ratio of MC protein to total protein was 0.5. Single or multiple background polyclonal (PC) suppression was noted in 36% of patients. PC suppression of 50% or more was noted in 20.1% of patients, 49.8% had < 50% and 30.1% had no suppression. Mean bone marrow plasma cell percentage was 4.5 percent and mean hemoglobin was 12.4 g/dL. Eighteen of the 239 patients with MGUS progressed into MM over ten years of follow up. Univariate comparisons of all variables between those who progressed and those who did not, showed that the initial concentration of the serum M protein, ratio of M protein to the total protein, number of PC gamma globulins suppressed, degree of PC suppression and IgM gamma globulin suppression were statistically significant risk factors that correlated with progression into MM. Fourteen out of eighteen patients with progressive disease had either PC suppression or background IgM suppression. Conclusions Monoclonal protein concentration, ratio of M protein to the total protein and abnormal serum free light chain ratio are simple variables that have been shown in multiple previous studies to predict the progression of MGUS into MM. In our study, we additionally found that number of PC suppressed, degree of suppression and IgM suppression are also key risk factors that can predict progression. We believe that these variables can be potentially applied into an approach that uses a detailed risk stratification system to predict which cases of MGUS will progress into MM and to provide more intensive monitoring for patients more likely to progress. Disclosures: No relevant conflicts of interest to declare.

Retrospective Study Of Incidence Of Thromboses In Chinese Versus African Americans With Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1121-1121
Author(s):  
Radha Raghupathy ◽  
Sabarish Ayyappan ◽  
Dhivya Prabhakar ◽  
Frankie KF Mo ◽  
Erica L. Campagnaro ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Retrospective Study ◽  
Lower Risk ◽  
Conflicts Of Interest ◽  
Significant Risk ◽  
Chinese Patients ◽  
Asian Patients ◽  
Venous Thromboembolic Events ◽  
The Difference

Abstract Background Risk of arterial (ATE) and venous thromboembolic events (VTE) is increased in multiple myeloma (MM). Immunomodulator therapy (Imid) concurrent with steroids further increases this risk. Retrospective single arm studies suggest that Asian patients with MM may have a lower risk of TE than in other ethnicities. We performed a retrospective study comparing Chinese (C) and African American (AA) patients in two centers, the Department of Clinical Oncology, Prince of Wales Hospital, the Chinese University of Hong Kong (PWH) and the University hospitals, Case Medical Center, Cleveland, Ohio (CMC), for ethnic differences in incidence of TE in MM. Methods 120 Chinese patients from PWH and 100 AA patients from CMC fulfilling IMWG consensus criteria for MM diagnosis between Jan 1st 2000 and Dec 31st 2011 were identified and selected for analysis. Data regarding demographics, comorbidities, myeloma characteristics, therapy and thrombotic complications were collected by electronic and paper chart review. Data collection was censored as of Dec 31st 2012. Results The Chinese cohort comprised more men, lower baseline incidence of diabetes (DM), hypertension (HTN) and non-myeloma related renal failure (CRF), advanced myeloma at diagnosis and more IgA subtype than AA. Over 90% of patients of both groups received chemotherapy. 72% of Chinese and 80% of AA received Imid based treatment. Lenalidomide with steroids was used more often in AA (36.8% AA vs 3.6%C, p<0.0001), Chinese received more thalidomide with steroids. (62.2% C vs 42.1%, p:0.004) Use of thromboprophylaxis (TP) is not routine in PWH, less Chinese were on TP during the disease course (11.7% vs 68%, p<0.0001) or during Imid based treatment. (16% vs 85%, p: 0.0001) Relative rates of aspirin, low molecular weight heparin and warfarin usage for TP were similar across both groups. Despite lower TP rates, a significantly lower rate of symptomatic VTE was observed in the Chinese. (3.3% vs 22%, p:0.001) The difference in VTE detection persisted on correction for number of imaging studies performed, 24 imaging tests in Chinese and 145 in AA. (16.7% vs 48.3%, p:0.004). Amongst the Chinese, all 4 events (100%) occurred on thalidomide dexamethasone (TD), 3 events (75%) in the absence of TP. In the AA, 21 of 26 events (81%) occurred on Imid based treatment. 12 events (46%) occurred in the absence of TP. On binary logistic regression using race, gender, prior venous thrombosis, any TP, TD and lenalidomide dexamethasone therapy as covariates, AA race (OR: 5.022, 95% CI:1.3- 19.4) and TD therapy (OR: 4.07, 1.26- 3.13) emerged as significant risk factors for VTE. Overall incidence of VTE on TD treatment was 4.5% in Chinese versus 22% in AA. (p:0.002) An increased number of arterial events were seen in the Chinese (9.2% vs 3% in AA) but the difference did not reach statistical significance. Of the 11 arterial events in Chinese, 5 (46%) occurred on Imid based therapy, 9 events (82%) were in the absence of TP. 7 were cardiac and 4 cerebrovascular. Of the 3 arterial events in AA, 1 (33.3%) occurred on Imids and all patients were receiving TP. 1 was cardiac, 1 abdominal and 1 upper limb. Conclusion Our study suggests that the Chinese have a lower risk of VTE than AA in the setting of MM. However , despite lower prevalence of most vascular risk factors in Chinese, ATE rates in Chinese were higher than AA, while not statistically significant. Larger studies are necessary to further elucidate these differences in thrombosis risk and to develop specific guidelines for TP in Asian patients with MM Disclosures: No relevant conflicts of interest to declare.

Plasma Circulating Proteasomes As Biomarkers Along Natural History Of Asymptomatic Monoclonal Gammopathies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3133-3133 ◽  
Author(s):  
Carlos Fernández de Larrea ◽  
Adriana Zingone ◽  
Elisabet E. Manasanch ◽  
Neha Korde ◽  
Peter Wu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Mayo Clinic ◽  
M Protein ◽  
Current Time ◽  
Monoclonal Gammopathies ◽  
Chymotrypsin Activity ◽  
Healthy Donors

Abstract Background Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic plasma cell dyscrasias with a heterogeneous probability to progress to symptomatic multiple myeloma (MM). Reliable markers for progression to MM are vital to advance the understanding of myeloma precursor disease and for the development of intervention trials designed to delay/prevent MM. The Mayo Clinic and Spanish PETHEMA have proposed models to stratify patient risk based on clinical parameters. At the current time, no molecular biomarkers have been established to determine risk of transformation. Based on the fact that MM tumor cells are highly sensitive to proteasome inhibition and that circulating proteasomes (cProt) have been detected in the blood of MM patients, we conducted a prospective clinical study designed to characterize patterns of cProt in peripheral blood from MGUS, SMM and MM patients. Patients and Methods Ninety two patients diagnosed with asymptomatic monoclonal gammopathies (39 MGUS and 53 SMM; median age 63 years; 46M/47F) were studied. This group was compared to normal sera from healthy donors (n=6) and untreated patients with recent diagnosed MM (n=38). Initial baseline demographics, clinical and laboratory data were collected. MGUS patients were classified according to Mayo Clinic risk score (M-protein, monoclonal isotype and serum FLC), while SMM could be stratified according to PETHEMA (malignant bone marrow plasma cell (BMPC) percentage and immunoparesis) and Mayo system (BMPC infiltration, serum M-protein and serum FLC). Plasma and bone marrow supernatant samples were collected at diagnosis and frozen to -80ºC. In 58 MGUS and SMM cases, sequential plasma samples at 6 months and 1 year were also analyzed. Chymotrypsin-like, caspase-like, and trypsin-like activities from cProt were assayed by continuously monitoring the production of 7-amino-4-methylcoumarin (AMC) from fluorogenic peptides by plasma. Briefly, samples were activated with SDS (for chymotrypsin-like and caspase-like) or 10% Tween-20 (for trypsin-like). The reaction wells contained 30 μL assay buffer (25 mmol/L HEPES), 10 μL activated sample, and 10 μL of the prospective fluorogenic peptide-AMC substrate. To measure the fluorescence release of free AMC with time, the SpectraMax M5 (Molecular Devices) instrument was used with a read interval of 1 min during 30 min at 37ºC. All samples were performed by triplicate. Enzymatic activities were quantified (pmol AMC/s/mL plasma) by generating a standard curve of AMC. Results MGUS patients had zero (38.5%), one (41%) or two risk factors (20.5%) according to the Mayo Clinic model. In contrast, 49% of the patients with SMM were classified as high-risk according to the PETHEMA model, versus 69.8% with 2 or 3 risk factors in the Mayo Clinic model. Chymotrypsin activity levels in plasma were statistically correlated with serum M-protein concentration and total IgG concentration (p<0.001). Chymotrypsin-like activity was differentially expressed in plasma across the different groups of patients (p=0.009; Figure 1). Particularly, SMM and MM showed higher levels than healthy controls and MGUS patients. In SMM, patients with highest-risk of transformation showed a higher levels of this chymotrypsin-like activity than the other groups (p=0.02). When only IgG SMM and MGUS patients were considered, a correlation with immunoparesis (reduction of IgM and IgA), BMPC infiltration, relative lower hemoglobin levels and higher FLC ratio (p<0.05) was observed. Caspase-like activity was also associated with diagnosis, showing higher levels in symptomatic and SMM patients than healthy donors and MGUS (p=0.016) (Figure 2) and correlated with IgG and serum M-protein (p=0.01 and p=0.006). In contrast, trypsin-like levels were negatively correlated along the spectrum of tumoral mass in the four groups (p=0.004) (Figure 3). Bone marrow supernatant chymotrypsin activity was higher in symptomatic MM than MGUS patients (p=0.004), with a trend for caspase. Conclusion Chymotrypsin-and caspase-like activity of circulating proteasome in asymptomatic gammopathies is related to tumoral mass and immunoparesis degree. MGUS patients are close to healthy individuals, with SMM not so different than symptomatic patients. Prognostic significance of these findings after longer follow-up is warranted. Disclosures: No relevant conflicts of interest to declare.

Secretome Analyses of Primary Bone Marrow Fibroblasts Isolated From MGUS and Multiple Myeloma Show a Stepwise Occurrence of Alterations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1801-1801
Author(s):  
Johannes Drach ◽  
Astrid Slany ◽  
Thomas Mohr ◽  
Johannes Griss ◽  
Christoph C Zielinski ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Growth Factor ◽  
Plasma Cell ◽  
Conflicts Of Interest ◽  
Cell Clone ◽  
Serum Levels ◽  
Plasma Cell Dyscrasia ◽  
Healthy Donors ◽  
Bone Marrow Fibroblasts

Abstract Abstract 1801 Poster Board I-827 The microenvironment of tumor cells in the bone marrow was demonstrated to contribute to tumor promotion and survival. The role of bone marrow fibroblasts (BMFs) in supporting the malignant plasma cell clone in multiple myeloma (MM) has been established, but it remains unclear to which extent the BM microenvironment in general and BMFs in particular are involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. Therefore we performed proteomics studies on the secretome of BMFs isolated from healthy donors, patients suffering from MGUS and patients suffering from MM. Compared to normal background, BMFs derived from MGUS secreted elevated levels of proteins indicating mitogenic activity and moderate inflammation. These proteins included periostin, IL-6, CXCL5 and CSF-1. Insulin-like growth factor II, which is normally not expressed by normal BMFs, was secreted by BMF cells derived from MGUS as well as from MM. In addition to those and other proteins, BMF cells derived from MM were found to specifically secrete stem cell growth factor, MMP-28 and stanniocalcin-1. These data indicate a step-wise alteration of BMF secretion activity related to the stage of the underlying plasma cell dyscrasia. Therefore BMF might support the progression from MGUS to MM. In order to correlate the secretion performance of BMF with blood serum levels of candidate marker proteins, Luminex assays are employed. Based upon these results, it is our aim to identify serum biomarkers which allow to assess the functional state of BMF and thus the risk for the progression of MGUS to MM. Disclosures No relevant conflicts of interest to declare.

CD81: A Novel, Specific and Highly Sensitive Marker in Flow Cytometric Diagnosis of Plasma Cell Dyscrasia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2880-2880
Author(s):  
Prashant Ramesh Tembhare ◽  
Constance Yuan ◽  
Neha Korde ◽  
Irina Maric ◽  
Katherine Calvo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Antigen Expression ◽  
Plasma Cell Dyscrasia ◽  
Fluorescent Intensity ◽  
Reliable Marker ◽  
Sensitive Marker

Abstract Abstract 2880 Background: The percent abnormal plasma cells (aPC) as determined by flow cytometry (FC) has been shown to be an independent risk factor for progression from myeloma precursor disease (monoclonal gammopathy of uncertain significance, MGUS; smoldering multiple myeloma, SMM) to multiple myeloma (MM). However, differentiation of aPCs from normal PCs (nPCs) in these patients is challenging. MM cell lines are know to underexpress the tetraspanin proteins (e.g. CD81, CD82) in comparison to nPCs. Although CD81, a nonglycosylated tetraspanin, is robustly expressed on the surface of nPCs, little information is available regarding its expression in the aPCs of MM, SMM and MGUS. In this study we evaluate the expression of CD81 in conjunction with CD19, CD45 and CD56 in bone marrow aPCs and nPCs from patients with MM, SMM and MGUS. Methods: Bone marrow aspirates from 41 patients (9 MGUS, 22 SMM, 7 MM, 3 non-neoplastic with clinical suspicion of MGUS) were analyzed with 8-color multiparametric FC using a panel of antibodies (CD138, CD38, CD19, CD20, CD27, CD28, CD45, CD56, CD81, CD13, CD14, CD16, CD3, CD34 and intracellular kappa & lambda light chains). The pattern of surface antigen and intracellular light chain expression was utilized to determine the percent aPC (defined as monoclonal with aberrant antigen expression) and percent nPC (defined as polyclonal with normal antigen expression). In all cases the pattern of antigen expression was evaluated in the aPCs; additionally, in cases with greater than 5% nPCs (19/41 patients: 8 MGUS, 8 SMM and 3 non-neoplastic) the pattern of antigen expression was evaluated in the nPCs. The ability to detect clonal aPC by evaluation of FC pattern of antigen expression was determined and compared for CD19, CD45, CD56 and CD81. We also examined the sensitivity and specificity of the CD19 and CD81 combination verses the conventional combination of CD19, CD56 and CD45 (Perez-Persona et al, Blood 2007) for the detection of clonal aPC. Results: CD81 was strongly expressed by nPC (average mean fluorescent intensity (MFI): 11500, standard deviation (SD): 5061, range: 5347–21657) in contrast to aPC with abnormally weak expression (average MFI: 1487, SD: 887, range: 647–4311). CD81 was a highly reliable marker for the detection of clonal PC; with 90% sensitivity and 100% specificity. It was the most specific and second most sensitive marker in our study (Table 1). CD81 was equally sensitive in detection of aPCs in MGUS, SMM and MM. Evaluation of the combined pattern of expression of CD19 and CD81 resulted in 100% sensitivity and 100% specificity for detection of aPC, which is greater than the conventional combination of CD19, CD56 and CD45, yielding 100% sensitivity but 90% specificity, for diagnostic evaluation of aPC. Conclusions: CD81 is a highly reliable marker in the detection of abnormal plasma cells in MM, SMM and MGUS. The combined approach of CD19 and CD81 is superior to other conventional marker combinations (i.e. CD19, CD45, and CD56) in terms of detection of clonal plasma cells and may replace their use in the clinical evaluation of bone marrow aspirates for plasma cell processes. Furthermore, it should help widening the applicability of minimal residual disease testing in MM. Disclosures: No relevant conflicts of interest to declare.

Risk of Early Mortality in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5306-5306
Author(s):  
Chia-Jen Liu ◽  
Pei Hsu ◽  
Ting-Wei Lin ◽  
Jyh-Pyng Gau ◽  
Liang-Tsai Hsiao ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Serum Albumin ◽  
Serum Calcium ◽  
Conflicts Of Interest ◽  
Significant Risk ◽  
High Serum ◽  
Early Mortality ◽  
Newly Diagnosed ◽  
Low Serum

Abstract Background The overall survival of patients with multiple myeloma has been improved greatly over the last two decades with the advances of treatment. Several studies reported that this improvement in survival has been ascribed to the broader use of novel drugs and autologous tandem transplantation. However, there were still a certain portion of myeloma patients died early after diagnosis. We therefore aim to investigate the risk factors of early mortality (death within 60 days after diagnosis) in patients with multiple myeloma. Patients and Methods We included in this study 451 consecutive patients with multiple myeloma, newly diagnosed at an Asian tertiary medical center between January 1, 2002 and April 30, 2015. A total 57 subjects who developed early mortality were identified. Risk factors for early mortality in myeloma patients were collected and analyzed. Results Compared with non-early mortality myeloma patients, early mortality patients had higher probability of being male, primary plasma cell leukemia, low platelet count, low serum albumin, high corrected serum calcium, high serum creatinine, high LDH, high serum β2-microglobulin, poor performance status, and high ISS stage. With multivariate analysis, we found that male (adjusted OR 2.93, 95% CI 1.17-7.31), serum albumin < 3.5g/dl (adjusted OR 2.76, 95% CI 1.17-6.52), corrected serum calcium ≥ 12mg/dl (adjusted OR 3.56, 95% CI 1.47-8.63) and LDH ≥ 250U/L (adjusted OR 3.30, 95% CI 1.62-6.74) were significant risk factors of early mortality. Pneumonia represented as the leading cause of early mortality in myeloma patients (n = 18, 31.5%), followed by renal failure (n = 7, 12.2%). Conclusion Early mortality rate is high (12.6%) in patients with multiple myeloma. Patients of male gender, low serum albumin, high corrected serum calcium and LDH are at risk of early mortality. More than one third myeloma patients (21 out of 57) who developed early mortality are died of infection. Identifying the risk group and providing prompt intervention, such as prophylaxis antibiotics, may reduce the incidence rate of early mortality and improve the life expectancy of myeloma patients. Disclosures No relevant conflicts of interest to declare.

Multiclonality In Multiple Myeloma: A Retrospective Analysis Of Clonal Progression and Selection

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3147-3147
Author(s):  
Gwynivere Davies ◽  
Ian H. Chin-Yee
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Systemic Therapy ◽  
Partial Remission ◽  
M Protein ◽  
Treatment Modalities ◽  
Plasma Cell Dyscrasia ◽  
Inclusion Criteria ◽  
Over Time

Abstract Introduction Genomic instability and multiclonality is the hallmark of many cancers including multiple myeloma (MM). Genetic alterations and clonal prominence occur over time as patients undergo various treatment modalities and can be followed by examining factors such as copy number abnormalities. Occasionally more than one monoclonal spike is noted on the serum protein electrophoresis (SPEP) indicating the existence of several distinct populations of clonal plasma cells producing a measurable amount of monoclonal (M) protein. Using routinely measureable clinical assays, SPEP and serum free light chains (SFL), we set out to identify the prevalence of multiclonality in patients with plasma cell dyscrasia, and to examine the natural history and effect treatment practices have on clones over time. Methods We retrospectively identified adult patients who were registered with the London Regional Cancer Program (LRCP), a tertiary care referral center in London, Ontario, Canada, since 2000 with a diagnosis of monoclonal gammopathy of uncertain significance (MGUS), smoldering myeloma, multiple myeloma or solitary plasmacytoma. Our current SPEP quantitation method has been in use since September 2004, so these SPEP results of patients identified from our initial search were examined for evidence of multiple monoclonal peaks as a surrogate marker for multiclonality. Inclusion criteria required a new diagnosis of plasma cell dyscrasia since the year 2000 and biclonal/multiclonal M protein peaks on SPEP followed through the LRCP. Demographics, SPEP results, treatment modalities and last recorded follow up or death for these patients was recorded. Outcome measures included quantification of complete remission, partial remission, very good partial remission and no response following systemic therapy to look for concordance in clone response. Results Since 2000, 1402 patients met the inclusion criteria; 144 patients met our surrogate criteria for multiclonality, representing a prevalence of approximately 10%. The majority of patients had MGUS (58, 40.3%) or MM (70, 48.6%) at first identification. Of these patients, 96 (66.7%) were male and the average age at diagnosis was 65.9 years. 58 (40.3%), primarily with MGUS, had no treatment and thus cannot be examined for treatment selective pressures. The number of clones identified ranged from two (114, 79.2%) to five. 62 (43.1%) had clones that were of similar immunoglobulin and light chain subtype, and half of patients had multiple clones identified at the same time point compared with development of clones during follow up investigations. In order to examine for concordance in treatment response between clones, we required that clones have a pre- and post- treatment value and have received systemic therapy with a measurable nadir. Only 26 patients had values that met these criteria, mainly due to clones disappearing with time, including 7 patients with no treatment, or oral treatment without recurrence and thus not quantifiable for comparison. Of these 26, approximately half showed discordance between clones, even in those with clones of the same M protein subtype. Of note, 4 discordant patients initially showed the same response to treatment and later developed divergent responses. Discussion Multiclonality in plasma cell neoplasms is a common occurrence, with a prevalence of 10% in our patient population. The use of SPEP and SFL as surrogate markers for multiclonality likely underestimates the true prevalence of multiple clones measured by genetic methods due to insensitivity to resolved non secretory clones or multiple clones secreting similar immunoglobulin. As seen in previous studies, our results demonstrate that plasma cell clone response can diverge over time, potentially spontaneously or as a result of selection pressures imposed by therapy. These findings may help direct therapy and suggests prognosis as clonal divergence could herald genetic changes associated with therapy resistant disease. Disclosures: No relevant conflicts of interest to declare.

HGF Measurement in AL Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1783-1783
Author(s):  
Julie Abraham ◽  
Estelle Desport ◽  
Benoit Marin ◽  
Sebastien Bender ◽  
Corinne Lacombe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Roc Curve ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Renal Involvement ◽  
Threshold Value ◽  
Serum Levels ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis

Abstract Abstract 1783 Poster Board I-809 Purpose Hepatocyte Growth Factor (HGF) is a pro-angiogenic cytokine and a mitogenic, motogenic and morphogenic factor involved in tumor growth. Previous studies have shown that HGF is secreted by plasma cells in multiple myeloma and that HGF serum levels are higher in patients with multiple myeloma and correlate with disease activity. A previous study reported that serum HGF levels were significantly higher in patients with AL amyloidosis compared to patients with multiple myeloma (Iwasaki et al. Br J Haematol. 2002;116:796-802). A preliminary study of 18 AA and AL amyloidosis patients (Shikano et al, Intern Med. 2000;39:715-9) suggested that measurement of HGF might be useful for the diagnosis of amyloidosis. To determine whether HGF may be used as a relevant diagnosis marker and prognosis factor in AL amyloidosis, we have measured HGF serum levels in patients with AL amyloidosis and patients with plasma cell dyscrasia without amyloidosis. Patients and Methods Two groups of patients were included; patients with biopsy proven AL amyloidosis and patients with plasma cell dyscrasia (MGUS, multiple myeloma, POEMS) without amyloidosis as controls. Levels of HGF were measured by ELISA at diagnosis in the two groups, before any treatment (Quantikine® R&D Systems). Clinical features were recorded for AL patients. A Receiver Operating Characteristic curve (ROC) analysis was performed to assess the diagnostic accuracy of HGF for identification of amyloidosis cases among patients with monoclonal gammopathy. The area under the ROC curve (AUC) which can be interpreted as the probability that a randomly chosen amyloidosis patient has a test result greater than that of a randomly chosen non-amyloidosis patient, was calculated with its 95% confidence interval (95%CI). The ROC curve was also used to determine the best threshold for HGF. Using this threshold, sensitivity and specificity were calculated. Survival analyses were performed for patients suffering from AL amyloidosis. Baseline time was time from first HGF assessment to death or censoring date. Univariate analysis were done using Kaplan Meier and Cox proportional hazard models. Results Sixty-nine AL amyloidosis patients diagnosed between 2004 and 2008 and 76 controls (56 patients with MGUS, 17 with multiple myeloma, three with POEMS) were included. The median age was 61 (32-90) for AL patients and 60 (39-86) for controls. Median creatinine levels were respectively 86μmol/l (39-500) and 79μmol/l (44-317); 57 AL patients (82.6%) had renal involvement and 40 had (57.9%) cardiac disease. Monoclonal protein isotype was lambda in 69.6% of AL patients and kappa in 30.4%. HGF serum levels were significantly higher in patients with AL amyloidosis: 11.2ng/ml (0.5-200.4) compared with controls: 1.5ng/ml (0.8-8.2), p<0.0001 (healthy controls 0.9 ng/ml). HGF levels at diagnosis seemed to be discriminant with area under the ROC curve at 0.896 IC95% [0.834-0.94] p=0.0001. The threshold value of 2.4ng/ml conferred the best sensitivity : 82.6% IC95% [71.6-90.7] and specificity : 89.5% IC95% [80.3-95.3] for the diagnosis of AL amyloidosis. Patients were treated mainly by conventional chemotherapy (M-Dex), 65 % of AL patients were alive after a median follow up of 18 months. Univariate analysis showed a relative risk of mortality of 1.70 in AL patients with HGF levels upper than 11ng/ml, compared to those with HGF levels under 11 ng/l who showed a trend for better survival (p=0.22). Conclusion This study confirms that HGF levels are elevated in patients with AL amyloidosis, significantly higher than in patients with other plasma cell disorders. A threshold value of 2.4ng/ml confers a good sensitivity (80%) and specificity (90%) to suggest AL amyloidosis. HGF measurement may be used in patients with plasma cell dyscrasia to determine which patient should be considered for a biopsy. We found a trend towards reduced survival in patients with the highest levels of HGF. This, and the usefulness of HGF measurement in predicting clinical responses should be confirmed on larger studies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Super-Enhancer Profiling Identifies Novel Oncogenes and Therapeutic Targets in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 362-362
Author(s):  
Jianbiao Zhou ◽  
Yunlu Jia ◽  
Tze King Tan ◽  
Tae-Hoon Chung ◽  
Takaomi Sanda ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Plasma Cell ◽  
Conflicts Of Interest ◽  
Cell Cancer ◽  
Ectopic Expression ◽  
Therapeutic Targets ◽  
Physical Interaction ◽  
Rna Seq ◽  
Normal Plasma

Background: Multiple myeloma (MM) is an aggressive neoplastic plasma cell cancer characterized by diversely cytogenetic abnormalities. MM can be divided into subtypes with immunoglobulin heavy chain (IGH) gene translocations involving CCND1-3, FGFR3/MMSET, MAFs and hyperdiploid myeloma containing trisomies of several odd numbered chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. Although several new drugs have been introduced into clinic, treatment for MM patients remains challenge and refractory/resistant to therapy is often seen. Thus, a better understanding of the molecular pathogenesis of MM can lead to generate new prognostic classification and identify new therapeutic targets. Super-enhancers (SEs) are defined as large clusters of cis-acting enhancers, marked by high level bindings of acetylation of histone H3 lysine 27 (H3K27ac) and mediator complex. SEs have been shown to control genes for maintaining cellular identity and also key tumor drivers in various malignancies. Methods: H3K27Ac ChIP-seq and RNA-seq were performed on primary MM patient samples, MM cell lines. Normal plasma cells and lymphoma cell lines were served as controls. We systematically compared SEs and their associated genes of normal and cancerous tissue. THZ1, a CDK7 inhibitor, was used to efficiently down-regulate SE-associated genes. Combinatory analysis of THZ1-sensitive and SE-associated gene revealed a number of promising MM oncogenes. CRISPR/Cas9 technology and ectopic expression experiments in conjunction with cellular functional assays were performed to determine the effects of candidate SE-genes on MM cells. Circularized chromatin conformation capture followed by sequencing (4C-seq) was applied to explore the direct contact of SE and promoter. Results: SE analysis uncovered some cell lineage-specific transcription factors (TFs) and known oncogenes in MM. Several key TFs, including IRF4, PRDM1, MYC and XBP1, were identified in most MM samples, confirming the origin of MM cells. These data reinforce the concept that SE establishment is a key component of MM biology. The acquisition of SEs around oncogene drivers is widely observed during tumorigenesis. ST3GAL6 and ADM were two known oncogenic drivers in myeloma cells, which were associated with super-enhancers in all MM samples but not in normal plasma cell and lymphoma cells. We also found SE constituents for multiple subtype-specific key oncogenes such as CCND1 in t(11;14) cells, C-MAF in t(14;16) cells, and NSD2 and FGFR3 in t(4;14) cells. Furthermore, THZ1 showed prominent anti-neoplastic effect against MM cells. SE-associated genes were more sensitive to THZ1 compared with those genes associated with typical enhancers (TEs). By overlapping THZ1-sensitve gene with SE-associated genes, we identified a number of novel MM oncogenes, including MAGI2, EDEM3, HJURP, LAMP5, MBD1 and UCK2 as a potential druggable kinase. The expression level of MAGI2 and HJURP confers poor prognosis in several MM datasets. MAGI2 silencing in MM cells decreased cell proliferation and induced apoptosis. qRT-PCR and Western blot analysis confirmed the overexpression of HJURP in t(4;14) cells relative to non-t(4;14) MM cells. Furthermore, 4C-seq analysis revealed the physical interaction between HJURP-SE and promoter and THZ1 treatment diminished this interaction. Motif search at SE constituents revealed a highly significant enrichment of NSD2 recognition. Significant reduction of NSD2 binding at HJURP-SE region was observed in KMS11 infected with NSD2-specific shRNAs. Interestingly, blocking SE sites by CRISPR/Cas9i or silencing HJURP by shRNA led to decreased HJURP expression and cell apoptosis, whereas overexpression of this gene promoted cell growth. Taken together, our data demonstrated that HJURP is a novel SE-associated oncogene in t(4;14) MM. Conclusions: Our integrative approaches by combing H3K27Ac ChIP-seq, RNA-seq and THZ1-sensitive transcript defined the landscape of SE and identified SE-associated novel oncogenes, as well as lineage-specific TFs in MM. Furthermore, we also revealed subtype-specific SE-driving oncogenic program in MM. Taken together, these results not provide novel insight into the MM pathology, but also offer novel, potential therapeutic targets, such as MAGI2, and HJURP for the treatment of MM patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Factors Influencing the Risk of Perforation in Patients with Peptic Ulcers: A Cross-Sectional Study from Central Iraq

2018 ◽  
Vol 35 (4) ◽  
pp. 282-288
Author(s):  
Ibtesam Khalid Salih ◽  
Ali Malik Sheya’a ◽  
Qays Ahmed Hassan ◽  
Ayad Khani Mykhan
Keyword(s):  
Risk Factors ◽  
Peptic Ulcer ◽  
Blood Group ◽  
Significant Risk ◽  
Minor Role ◽  
Peptic Ulcer Perforation ◽  
Peptic Ulcers ◽  
Female Ratio ◽  
Blood Group A ◽  
Group A

Abstract The aim of this study was to evaluate the risk factors that influence the perforation, regardless of the presence of H. pylori infection, in a sample of Iraqi patients with peptic ulcers, admitted to Al-Kindy Teaching Hospital. A total of 90 patients who had perforated peptic ulcer participated in this study. The diagnosis was based on history, clinical examination, laboratory and radiological investigations and was confirmed intraoperatively. A number of probable risk factors for perforation were investigated. Eighty participants were males and 10 were females (male to female ratio 8:1). About 42.2% of patients were in their fifth decade of life. Forty-nine (54.4%) patients were asymptomatic before perforation occurred. Among the risk factors, smoking (66.7%), stress (60%) and blood group A (53.3%) play a significant risk for the occurrence of perforation. We concluded that smoking, stress, non-steroidal anti-inflammatory drugs, and to a lesser extent fasting and blood group A, play a major role as risk factors for the occurrence of peptic ulcer perforation. Other factors seem to play a minor role in this respect.

scholarly journals Predictive value of the risk factors for amputation of lower extremity in patients with diabetic foot in Al-Karama teaching hospital

2019 ◽  
Vol 6 (5) ◽  
pp. 1549
Author(s):  
Mohammed Hillu Surriah ◽  
Amir Naif Kadum Al-Imari ◽  
Amine Mohammed Bakkour ◽  
Riad Rahman Jallod Al-Asadi
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Teaching Hospital ◽  
Diabetic Foot ◽  
Significant Risk ◽  
Female Ratio ◽  
Duration Of Diabetes ◽  
Long Duration ◽  
Control Of Diabetes ◽  
Foot Disease

Background: Diabetic foot disease is a foot that exhibits any pathology that results directly from diabetic mellitus or any long-term chronic complication of diabetes mellitus. The aim of the study was to determine the risk factors and indications for amputations among diabetics.Methods: this clinical prospective study includes 120 diabetic foot patients admitted to AL- Karama teaching hospital from 1st January 2015 to 1st January 2019. All patients assessed for age, gender, duration of diabetes, hyperglycemia at admission and control of diabetes, history of smoking, hypertension, assess dominant foot and examination of diabetic foot lesion and classify it according to Meggit-Wagner grading status, indications for amputation and outcome.Results: The male to female ratio was 2:1. Most frequent age group of patients treated by amputation was between 50-80 years. Among patients treated with amputation (68.33%) of patients had diabetes mellitus for 11-20 years. From patients admitted with diabetic foot (53.33%) were smokers. Regarding hypertension (93.33%) of all patients were hypertensive. It was noted that (65%) of patients lesion occur in dominant foot Regarding Wagner's grading system (36.66%) of patients were grade 4 followed by grade 1 (21.66%). regarding mode of treatment (53.33%) of patients treated by amputation and other treated conservatively. Only 3 patients from 60 died while other discharged well after complete treatment.Conclusions: Increasing in age, long duration of diabetes mellitus, poor control of diabetes, smoking and occurrence of lesion in dominant foot all considered as a significant risk factors for increase liability amputation.

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