scholarly journals Faculty Opinions recommendation of Cytogenetic abnormalities in multiple myeloma: poor prognosis linked to concomitant detection in random and focal lesion bone marrow samples and associated with high-risk gene expression profile.

2009 ◽  
Author(s):  
Xavier Leleu
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Poor Prognosis ◽  
Focal Lesion ◽  
Cytogenetic Abnormalities ◽  
Risk Gene

Only Concomitant Presence of Cytogenetic Abnormalities in Randomly Sampled Bone Marrow and in MRI-Defined Focal Lesions Imparts Poor Prognosis and Is Associated with Gene Expression Profiling (GEP)-Based High-Risk Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1691-1691 ◽  
Author(s):  
Bijay Nair ◽  
Yiming Zhou ◽  
Bart Barlogie ◽  
Jeffrey Sawyer ◽  
Jackie Szymonifka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
High Risk ◽  
Expression Profiling ◽  
Poor Prognosis ◽  
Survival Outcomes ◽  
Focal Lesion ◽  
Newly Diagnosed ◽  
Cytogenetic Abnormalities ◽  
Total Therapy

Abstract Cytogenetic abnormalities (CA) can be detected in one-third of newly diagnosed patients with multiple myeloma (MM), reaching virtually universal presence at the terminal disease stage. According to both histopathological and radiological findings, bone marrow growth patterns are either diffusely infiltrative or characterized by focal lesion (FL) growth, around which typically osteolytic bone destruction develops. The detection of CA at diagnosis confers a poor prognosis, and the sustained suppression of CA is critical for long-term survival. Applying MRI examinations in virtually all newly diagnosed patients prior to protocol-based therapy, FL have been detected in ~80% of patients and impart, along with the detection of CA on random bone marrow examination from the posterior iliac crest, shorter event-free and overall survival. Such MRI-FL harbor viable MM cells often with CA, persist in clinical CR for a median of 1–2 years, eventually resolve in 60% and constitute sites of relapse often without M-protein secretion, collectively suggesting an important role of FL in both disease manifestation and progression. We reviewed our data base of 1202 patients enrolled in Total Therapy (TT) protocols for entries of CT-guided fine needle aspirations (FNA) from MRI-defined FL submitted to cytogenetic analysis at baseline and on any occasion prior to first transplant. We identified 320 patients with cytogenetic information on both randomly sampled (RS) and FNA from FL. Congruency between FL and RS examinations was documented in 71% including 53% without detectable CA and 18% with CA in both sites; 14% had RS-CA without FL-CA and 16% had FL-CA without RS-CA. The overall RS-based CA frequency of 31% was identical to the 31% when all 1202 RS prior to transplant were considered. The relative distribution of standard prognostic factors was similar among the 4 RS-FL constellations in terms of B2M (>5.5mg/L), albumin (<3.5g/dL) and creatinine (>=2mg/dL) levels. The frequency of gene expression profiling (GEP)-defined risk (determined on RS) was 15% among196 patients with concurrent RS and FL sampling and thus virtually identical to the 14% incidence among all 620 subjects with RS information only. However, 53% of the subgroup exhibiting both RS-CA and FL-CA had high-risk disease compared to only 6% in the remainder (p < 0.001). Analysis of overall survival according to the 4 RS-FL CA constellations revealed an adverse impact only of the concomitant presence of RS-CA and FL-CA (Figure), whereas the presence of either RS-CA or FL-CA individually was prognosis-neutral, an observation confirmed by multivariate analysis (HR of 3.27, p<0.001). The much higher frequency of GEP-defined high-risk in patients with concomitant RS-CA and FL-CA requires further study, including the examination by GEP of MM-cells procured from both RS and FL. Figure: Survival outcomes of all patients enrolled in combined Total Therapy protocols according to the presence of cytogenetic abnormalities (CA) in paired random (RS) or focal lesion (FL) sites. Comparisons a v d, p<0.0001; b v d, p<0.0001;c v d, p=0.0063 Figure:. Survival outcomes of all patients enrolled in combined Total Therapy protocols according to the presence of cytogenetic abnormalities (CA) in paired random (RS) or focal lesion (FL) sites. . / Comparisons a v d, p<0.0001; b v d, p<0.0001;c v d, p=0.0063

Novel Murine Model To Study Modulation of Genes and Molecular Pathways Induced Following In Vivo Interaction between Multiple Myeloma Cells and Human BM Milieu.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3409-3409
Author(s):  
Paola Neri ◽  
Pierfrancesco Tassone ◽  
Masood Shammas ◽  
Mariateresa Fulciniti ◽  
Yu-Tzu Tai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Growth ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Murine Model ◽  
Cell Signalling

Abstract Interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment plays a critical role in promoting MM cell growth, survival, migration and development of drug resistance. This interaction within the bone marrow milieu is unique and its understanding is important in evaluating effects of novel agents in vitro and in vivo. We here describe a novel murine model that allows us to study the expression changes in vivo in MM cells within the human BM milieu. In this model, the green fluorescent protein (INA-6 GFP+) transduced IL-6-dependent human MM cell line, INA-6, was injected in human bone chip implanted into SCID mice. At different time points the bone chip was retrieved, cells flushed out and GFP+ MM cells were purified by CD138 MACS microbeads. Similar isolation process was used on INA-6 GFP+ cells cultured in vitro and used as control. Total RNA was isolated from these cells and gene expression profile analyzed using the HG-U133 array chip (Affymetrix) and DChip analyzer program. We have identified significant changes in expression of several genes following in vivo interaction between INA-6 and the BM microenvironment. Specifically, we observed up-regulation of genes associated with cytokines (IL-4, IL-8, IGFB 2–5) and chemokines (CCL2, 5, 6, 18, 24, CCR1, 2, 4), implicated in cell-cell signalling. Moreover genes implicated in DNA transcription (V-Fos, V-Jun, V-kit), adhesion (Integrin alpha 2b, 7, cadherin 1 and 11) and cell growth (CDC14, Cyclin G2, ADRA1A) were also up-regulated and genes involved in apoptosis and cell death (p-57, BCL2, TNF1a) were down-regulated. Using the Ingenuity Pathway Analysis the most relevant pathways modulated by the in vivo interaction between MM cells and BMSCs were IL-6, IGF1, TGF-beta and ERK/MAPK-mediated pathways as well as cell-cycle regulation and chemokine signalling. These results are consistent with previously observed in vitro cell signalling studies. Taken together these results highlight the ability of BM microenvironment to modulate the gene expression profile of the MM cells and our ability to in vivo monitor the changes. This model thus provides us with an ability to study in vivo effects of novel agents on expression profile of MM cells in BM milieu, to pre-clinically characterize their activity.

The Location of Multiple Myeloma Adhesion Variants in Diverse Niches within the Bone Marrow Affects Plasma Cells Enumeration.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5063-5063
Author(s):  
Liat Nadav ◽  
Ben-Zion Katz ◽  
Shoshana Baron ◽  
Lydia Lydia ◽  
Aaron Polliack ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Gene Expression Profile ◽  
Plasma Cell ◽  
Expression Profile ◽  
Plasma Cells ◽  
Response To Therapy ◽  
Morphological Evaluation

Abstract Background - The diagnosis of multiple myeloma (MM) is based on clinical and laboratory criteria combined with bone marrow (BM) plasmocytosis, estimated by inspection of bone marrow aspirates. Recent advances in flow-cytometry (FCM) have provided an additional tool for the diagnosis of MM and for monitoring response to therapy. However, significant discrepancy has been reported regarding the enumeration of plasma cells in marrow samples of MM patients using these two methods. Aims - In this study we compared the bone marrow plasmocytosis by microscopic examination of BM aspirates, to the flow cytometry results in samples obtained form MM patients. We tested whether the noted discrepancy between these two methods applies only to MM, or represents a trend in other hematopoietic malignancies as well. We defined this discrepancy and explained it. Methods - The number of plasma cells or blasts from BM aspirates of 41 MM or seven acute myeloid leukemia (AML) patients respectively were analyzed simultaneously by morphological evaluation and by FCM. Each sample was assessed independently by two qualified laboratory specialists and/or hemato-pathologist. In MM we found plasma cell fractions that were characterized by FCM and gene expression profile. Results - In MM it was evident that FCM under-estimated the number of BM plasma cells samples by an average of 60%, compared with conventional morphological evaluation. On the other hand in AML there was a good correlation between the morphological and FCM assessments of the blast cell population, indicating that the discrepancy observed in the MM BM samples may be related to unique characteristics of the malignant plasma cells. Since flow cytometry is performed on the bone marrow fluid which is depleted of fat tissue-adhesive plasma cells, we disrupted spicules from MM BM samples (by repeated passages through 21g needle) and found a 40% increase in plasma cell compared with the fluid of the same BM samples. In order to determine the FCM profile of the cells in these two fractions, we isolated BM derived spicules from aspirates of MM patients and treated them with extracellular matrix (ECM) degrading enzymes followed by mechanical shearing. This combination released the highly adhesive plasma cells from the spicules. The released myeloma cells displayed a different FCM profile and in particular had a higher level of CD138 expression. Gene expression profile, which was performed on similar adhesion variants of cultured MM cells, demonstrated distinct oncogenic and transcriptional programs. Summary - We have shown a major discrepancy between the percentage of MM cells obtained by routine BM morphology and flow cytometry counts. It is possible that this discrepancy is partially attributable to the two distinct microenvironmental components occupied by MM cells in the BM sample - the lipid spicules, and the fluid phase. MM cells located in different niches of the BM also differ in their FCM and gene expression profile. This study indicates that multiple myeloma patients contain heterogeneous populations of malignant plasma cells. These sub-populations may play distinct roles in the biological and clinical manifestations of the disease and differ in their response to anti-myeloma therapy.

Gene expression profile of ADAMs and ADAMTSs metalloproteinases in normal and malignant plasma cells and in the bone marrow environment

2011 ◽  
Vol 39 (5) ◽  
pp. 546-557.e8 ◽  
Author(s):  
Caroline Bret ◽  
Dirk Hose ◽  
Thierry Reme ◽  
Alboukadel Kassambara ◽  
Anja Seckinger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Plasma Cells

Implications of a prognostic 40-gene expression profile (40-GEP) test for high-risk cutaneous squamous cell carcinoma (cSCC) on staging-based risk assessment and adjuvant therapy trial design.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22091-e22091
Author(s):  
Chrysalyne Schmults ◽  
Kyle R. Covington ◽  
Sarah J. Kurley ◽  
Robert W. Cook
Keyword(s):  
Gene Expression ◽  
Clinical Trial ◽  
High Risk ◽  
Sample Size ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Trial Design ◽  
Multivariable Analysis ◽  
Primary Objective ◽  
Staging Systems

e22091 Background: Deaths due to cSCC are expected to exceed melanoma-specific deaths. With the demonstration of effective therapies for advanced cSCC, and as treatment of patients in the adjuvant setting is considered, accurate prognosis is critical. For improved identification of ‘high-risk’ patients, with biologically aggressive disease capable of metastasis, a prognostic 40-gene expression profile (40-GEP) test was validated using an independent cohort of patients with high-risk cSCC and known clinical outcomes. The test identified three groups with increasing metastasis risk profiles: Class 1 (low risk), Class 2A (high risk), and Class 2B (highest risk) having metastasis rates of 8.9%, 20.4%, and 60%, respectively. Multivariable analysis demonstrated prognostic efficacy of the 40-GEP test alone and in combination with clinicopathological staging systems. This study evaluated risk stratification with concurrent consideration of the 40-GEP result and the Brigham and Women’s Hospital (BWH) stage. The primary objective was evaluation of the potential impact of the 40-GEP on adjuvant clinical trial design. Methods: To determine if a 40-GEP Class 2B result could optimize clinical trial accrual, metastasis rates of BWH high-risk T stage patients (T2b-T3) alone and in combination with 40-GEP results from the validation cohort were used for two-arm trial sample size calculations. Results: Metastasis rates for cases with T2b-T3 tumors increased from 35.1% to 71.4% when selecting for T2b-T3 cases with a 40-GEP Class 2B result. To provide 80% power to detect hazard ratio of 0.6 with 3 years of follow-up (alpha = 0.05), in line with improvement rates by addition of radiation to surgery, 434 T2b-T3 patients are required for randomization. However, sample size could be reduced by 51% to 214 patients by focusing enrollment on T2b-T3 patients with a 40-GEP Class 2B result. Conclusions: These results support the incorporation of the 40-GEP test into selection processes for patients with T2b-T3 tumors who are at the highest risk for metastasis and appropriate for adjuvant clinical trials.

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