Prediction of cytogenetic abnormalities with gene expression profiles.

Cytogenetic abnormalities are important clinical parameters in various types of cancer, including multiple myeloma. We developed a model to predict cytogenetic abnormalities in patients with multiple myeloma using gene expression profiling and validated it by different cytogenetic techniques. The model has an accuracy rate up to 0.

Therapeutic effects of intrabone and systemic mesenchymal stem cell cytotherapy on myeloma bone disease and tumor growth.

The cytotherapeutic potential of mesenchymal stem cells (MSCs) has been evaluated in various disorders including those involving inflammation, autoimmunity, bone regeneration, and cancer. Multiple myeloma (MM) is a systemic malignancy associated with induction of osteolytic lesions that often are not repaired even after prolonged remission. The aims of this study were to evaluate the effects of intrabone and systemic injections of MSCs on MM bone disease, tumor growth, and tumor regrowth in the severe combined immunodeficiency (SCID)-rab model and to shed light on the exact localization of systemically injected MSCs.

Highly activated and expanded natural killer cells for multiple myeloma immunotherapy.

Background: Patients with gene expression profiling-defined high-risk myeloma in relapse have poor outcomes with current therapies. We tested whether natural killer cells expanded by co-culture with K562 cells transfected with 41BBL and membrane-bound interleukin-15 could kill myeloma cells with a high-risk gene expression profile in vitro and in a unique model which recapitulates human myeloma.

Design And Methods: OPM2 and high-risk primary myeloma tumors were grown in human fetal bone implanted into non-obese diabetic severe combined immunodeficiency mice with a deficient interleukin-2 receptor gamma chain.

Unilateral conjunctival AL kappa amyloidosis with trace evidence of systemic amyloidosis.

Background: Amyloidosis is a systemic disorder that results from the tissue deposition of various proteins with distinctive morphological characteristics. Conjunctival amyloidosis is a rare variant which is generally localized and not associated with systemic involvement.

Case Report: We present here a case of 47-year-old female patient with right eyelid swelling that progressed over a 12 year period and eventually underwent surgery with pathology showing AL conjunctival amyloidosis.

Rituximab and intravenous immunoglobulin (IVIG) for the management of acquired factor VIII inhibitor in multiple myeloma: case report and review of literature.

Acquired factor VIII inhibitor (AFI) is a rare disorder and is even more uncommon in multiple myeloma patients, with only five cases reported in literature. Solid and hematologic malignancies, autoimmune conditions, drugs, and infections are the conditions commonly associated with the development of this condition, with mucocutaneous bleeding being the most common presenting sign. Diagnosis is usually made with the laboratory finding of an elevated partial thromboplastin time aPTT that cannot be corrected by plasma mixing, and further confirmed by low factor VIII activity/antigen levels along with elevated factor VIII inhibitor levels using the Bethesda assay.

An intermediate-risk multiple myeloma subgroup is defined by sIL-6r: levels synergistically increase with incidence of SNP rs2228145 and 1q21 amplification.

IL-6 signaling can be enhanced through transsignaling by the soluble IL-6 receptor (sIL-6r), allowing for the pleiotropic cytokine to affect cells it would not ordinarily have an effect on. Serum levels of sIL-6r can be used as an independent prognostic indicator and further stratify the GEP 70-gene low-risk group to identify an intermediate-risk group in multiple myeloma (MM). By analyzing more than 600 MM patients with ELISA, genotyping, and gene expression profiling tools, we show how the combination of 2 independent molecular genetic events is related to synergistic increases in sIL-6r levels.

The use of molecular-based risk stratification and pharmacogenomics for outcome prediction and personalized therapeutic management of multiple myeloma.

Despite improvement in therapeutic efficacy, multiple myeloma (MM) remains incurable with a median survival of approximately 10 years. Gene-expression profiling (GEP) can be used to elucidate the molecular basis for resistance to chemotherapy through global assessment of molecular alterations that exist at diagnosis, after therapeutic treatment and that evolve during tumor progression. Unique GEP signatures associated with recurrent chromosomal translocations and ploidy changes have defined molecular classes with differing clinical features and outcomes.

Aldehyde dehydrogenase as an alternative to enumeration of total and viable CD34(+) cells in autologous hematopoietic progenitor cell transplantation.

We validated the correlation of aldehyde dehydrogenase ALDH(br) cells with total and viable CD34(+) cells in fresh and thawed hematopoietic progenitor cell (HPC) products, and looked for a correlation with time to white blood cell (WBC) and platelet engraftment after autologous transplantation, using simple linear regression analyzes. We found a significant correlation between pre-freeze ALDH(br) cell numbers and pre-freeze total CD34(+) (P < 0.001), viable CD34(+) (P < 0.

Human placenta-derived adherent cells prevent bone loss, stimulate bone formation, and suppress growth of multiple myeloma in bone.

Human placenta has emerged as a valuable source of transplantable cells of mesenchymal and hematopoietic origin for multiple cytotherapeutic purposes, including enhanced engraftment of hematopoietic stem cells, modulation of inflammation, bone repair, and cancer. Placenta-derived adherent cells (PDACs) are mesenchymal-like stem cells isolated from postpartum human placenta. Multiple myeloma is closely associated with induction of bone disease and large lytic lesions, which are often not repaired and are usually the sites of relapses.

Prophylactic recombinant erythropoietin therapy and thalidomide are predictors of venous thromboembolism in patients with multiple myeloma: limited effectiveness of thromboprophylaxis.

Background: Venous thromboembolism (VTE) is a significant but poorly understood complication in patients with newly diagnosed multiple myeloma (NDMM). As a result, most patients receive thromboprophylaxis with low molecular weight heparin (LMWH). The purpose of this retrospective study was to identify risk factors for VTE in NDMM and evaluate the effectiveness of LMWH.

Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3.

Gene expression profiling (GEP) of purified plasma cells 48 hours after thalidomide and dexamethasone test doses showed these agents' mechanisms of action and provided prognostic information for untreated myeloma patients on Total Therapy 2 (TT2). Bortezomib was added in Total Therapy 3 (TT3), and 48 hours after bortezomib GEP analysis identified 80 highly survival-discriminatory genes in a training set of 142 TT3A patients that were validated in 128 patients receiving TT3B. The 80-gene GEP model (GEP80) also distinguished outcomes when applied at baseline in both TT3 and TT2 protocols.

Autologous stem cell transplantation as a care option in Waldenström's macroglobulinemia.

The optimal management of Waldenstrom's macroglobulinemia (WM) is in evolution, especially since the introduction of novel agents for its sister disease, multiple myeloma. Literature on the utility of autologous stem cell transplantation (ASCT) in WM, albeit mostly retrospective, supports its efficacy for symptomatic disease in eligible patients. Here, we present the experience of managing WM at our single institution.

Metaphase cytogenetic techniques in multiple myeloma.

Metaphase chromosome studies in multiple myeloma (MM) are performed as part of the diagnostic workup, as surveillance to monitor the therapeutic response, and at relapse to help direct therapy. Unfortunately, the abnormal clones in many patients have a low proliferative activity and therefore, in many cases, the analyzable metaphase cells are derived from normal hematopoiesis. This limitation has been overcome in part by the use of fluorescence in situ hybridization (FISH) of interphase nuclei, which is an important adjunct to metaphase analysis.

The prognostic significance of cytogenetics and molecular profiling in multiple myeloma.

Multiple myeloma (MM) is a plasma cell malignancy characterized by very complex cytogenetic and molecular genetic aberrations. In newly diagnosed symptomatic patients, the modal chromosome number is usually either hyperdiploid with multiple trisomies or hypodiploid with one of several types of immunoglobulin heavy chain (Ig) translocations. The chromosome ploidy status and Ig rearrangements are two genetic criteria that are used to help stratify patients into prognostic groups based on the findings of conventional cytogenetics and fluorescence in situ hybridization (FISH).

Consequences of daily administered parathyroid hormone on myeloma growth, bone disease, and molecular profiling of whole myelomatous bone.

Background: Induction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates.

Methodology/principal Findings: We tested the effects of daily administered parathyroid hormone (PTH) on bone disease and myeloma growth, and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary myeloma cells engrafted in SCID-rab and SCID-hu mouse models.

Epigenetic modulation of MAGE-A3 antigen expression in multiple myeloma following treatment with the demethylation agent 5-azacitidine and the histone deacetlyase inhibitor MGCD0103.

Background Aims: Immunotherapy targeting MAGE-A3 in multiple myeloma (MM) could eradicate highly aggressive and proliferative clonal cell populations responsible for relapse. However, expression of many cancer-testis antigens, including MAGE-A3, can be heterogeneous, leading to the potential for tumor escape despite MAGE-A3-induced immunity. We hypothesized that a combination of the hypomethylating agent 5-azacitidine (5AC) and the histone deacetylase inhibitor (HDACi) MGCD0103 (MGC) could induce MAGE-A3 expression in MAGE-A3-negative MM, resulting in recognition and killing of MM cells by MAGE-A3-specific cytotoxic T lymphocytes (CTL).

Prognostic factor analyses of myeloma survival with intergroup trial S9321 (INT 0141): examining whether different variables govern different time segments of survival.

Multiple myeloma (MM) survival plots usually display steeper initial and shallower subsequent slopes reflecting differences in disease biology and likely prognostic factors (PF). S9321 trial was selected to determine PF operative at baseline and subsequent 3, 4, 5, and 7-year landmarks (LM-0, LM-3, LM-4, LM-5, and LM-7). With a median follow-up of 8.

International staging system and metaphase cytogenetic abnormalities in the era of gene expression profiling data in multiple myeloma treated with total therapy 2 and 3 protocols.

Background: Myeloma survival varies markedly with International Staging System classification, presence of cytogenetic abnormalities, and, especially, gene expression profiling-based risk and delTP53 status, whose collective impact has not been examined in the context of specific therapies.

Methods: The authors examined overall survival (OS), event-free survival (EFS), and complete response duration (CRD) in Total Therapy 2 with randomization to a control or thalidomide arm and in Total Therapy 3 with added bortezomib. Among 612 patients with complete data sets, multivariate analyses were used to investigate the relative contributions to OS, EFS, and CRD of International Staging System stage, cytogenetic abnormalities, and gene expression profiling-derived risk and delTP53 status, in the context of the 3 Total Therapy regimens.

Castleman disease in the 21st century: an update on diagnosis, assessment, and therapy.

Castleman disease (CD) is a nonclonal lymphoproliferative disorder that can affect single lymph node stations or, alternatively, can be generalized. Interleukin 6 (IL6) plays a pivotal role in the pathophysiology of CD. Human herpesvirus 8 (HHV8), which encodes a viral homolog of IL6, is the driving force in HIV-positive patients.

Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease.

Purpose: Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of the atypical lymphoproliferative disorder Castleman's disease (CD). Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD.

Methods: We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals.

Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy.

The impact of cumulative dosing and premature drug discontinuation (PMDD) of bortezomib (V), thalidomide (T), and dexamethasone (D) on overall survival (OS), event-free survival (EFS), time to next therapy, and post-relapse survival in Total Therapy 3 were examined, using time-dependent methodology, relevant to induction, peritransplantation, consolidation, and maintenance phases. Univariately, OS and EFS were longer in case higher doses were used of all agents during induction, consolidation (except T), and maintenance (except V and T). The favorable OS and EFS impact of D induction dosing provided the rationale for examining the expression of glucocorticoid receptor NR3C1, top-tertile levels of which significantly prolonged OS and EFS and rendered outcomes independent of D and T dosing, whereas T and D, but not V, dosing was critical to outcome improvement in the bottom-tertile NR3C1 setting.

Reiterative survival analyses of total therapy 2 for multiple myeloma elucidate follow-up time dependency of prognostic variables and treatment arms.

Purpose: In Total Therapy 2, after randomly assigning 323 patients with myeloma to thalidomide and 345 to a control arm, no difference was observed in overall survival, with a median follow-up of 42 months, although at 72 months, survival was superior on the thalidomide arm in the one third exhibiting cytogenetic abnormalities (CA). After further follow-up of 87 months, we examined, in reiterative analyses, the effect of increasing time intervals on clinical outcomes relevant to baseline prognostic variables and treatment randomization.

Patients And Methods: We investigated clinical trial end points as a function of increasing time intervals from protocol enrollment to determine consistencies of results by treatment and prognostic variables.

High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2.

MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail.