Flavopiridol in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

ClinicalTrials.gov

2016-06-27

Adult Lymphocyte Depletion Hodgkin Lymphoma; Adult Lymphocyte Predominant Hodgkin Lymphoma; Adult Mixed Cellularity Hodgkin Lymphoma; Adult Nodular Sclerosis Hodgkin Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Waldenström Macroglobulinemia

Autologous Stem Cell Transplant Followed By Maintenance Therapy in Treating Elderly Patients With Multiple Myeloma

ClinicalTrials.gov

2018-02-27

Extramedullary Plasmacytoma; Isolated Plasmacytoma of Bone; Light Chain Deposition Disease; Primary Systemic Amyloidosis; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage III Multiple Myeloma

Immunoglobulin A multiple myeloma with cutaneous involvement in a dog.

PubMed

Mayer, Monique N; Kerr, Moira E; Grier, Candace K; Macdonald, Valerie S

2008-07-01

An 8-year-old rottweiler, diagnosed with multiple myeloma and multiple sites of cutaneous involvement, was treated with chemotherapy and radiation therapy. The diagnostic criteria for canine multiple myeloma, limitations of diagnostic testing for light chain proteinuria in dogs, and the role of radiation therapy in multiple myeloma patients is discussed.

PD-1 blockade enhances elotuzumab efficacy in mouse tumor models

PubMed Central

Jhatakia, Amy; Kearney, Alper Y.; Brender, Ty; Maurer, Mark; Henning, Karla; Jenkins, Misty R.; Rogers, Amy J.; Neeson, Paul J.; Korman, Alan J.; Robbins, Michael D.; Graziano, Robert F.

2017-01-01

Elotuzumab, a humanized monoclonal antibody that binds human signaling lymphocytic activation molecule F7 (hSLAMF7) on myeloma cells, was developed to treat patients with multiple myeloma (MM). Elotuzumab has a dual mechanism of action that includes the direct activation of natural killer (NK) cells and the induction of NK cell–mediated antibody-dependent cellular cytotoxicity. This study aimed to characterize the effects of elotuzumab on NK cells in vitro and in patients with MM and to determine whether elotuzumab antitumor activity was improved by programmed death receptor-1 (PD-1) blockade. Elotuzumab promoted NK cell activation when added to a coculture of human NK cells and SLAMF7-expressing myeloma cells. An increased frequency of activated NK cells was observed in bone marrow aspirates from elotuzumab-treated patients. In mouse tumor models expressing hSLAMF7, maximal antitumor efficacy of a murine immunoglobulin G2a version of elotuzumab (elotuzumab-g2a) required both Fcγ receptor–expressing NK cells and CD8+ T cells and was significantly enhanced by coadministration of anti–PD-1 antibody. In these mouse models, elotuzumab-g2a and anti–PD-1 combination treatment promoted tumor-infiltrating NK and CD8+ T-cell activation, as well as increased intratumoral cytokine and chemokine release. These observations support the rationale for clinical investigation of elotuzumab/anti–PD-1 combination therapy in patients with MM. PMID:29296719

Immunoglobulin A multiple myeloma with cutaneous involvement in a dog

PubMed Central

Mayer, Monique N.; Kerr, Moira E.; Grier, Candace K.; MacDonald, Valerie S.

2008-01-01

An 8-year-old rottweiler, diagnosed with multiple myeloma and multiple sites of cutaneous involvement, was treated with chemotherapy and radiation therapy. The diagnostic criteria for canine multiple myeloma, limitations of diagnostic testing for light chain proteinuria in dogs, and the role of radiation therapy in multiple myeloma patients is discussed. PMID:18827847

A compound chimeric antigen receptor strategy for targeting multiple myeloma.

PubMed

Chen, K H; Wada, M; Pinz, K G; Liu, H; Shuai, X; Chen, X; Yan, L E; Petrov, J C; Salman, H; Senzel, L; Leung, E L H; Jiang, X; Ma, Y

2018-02-01

Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.

Interferon-alpha in the treatment of multiple myeloma.

PubMed

Khoo, Teh Liane; Vangsted, Annette Juul; Joshua, Douglas; Gibson, John

2011-03-01

Interferons are soluble proteins produced naturally by cells in response to viruses. It has both anti-proliferative and immunomodulating properties and is one of the first examples of a biological response modifier use to treat the haematological malignancy multiple myeloma. Interferon has been used in this clinical practice for over thirty years. However, despite considerable efforts, numerous clinical trials and two large meta-analysis, its exact role in the management of multiple myeloma still remains unclear. Its role in the treatment of multiple myeloma has been as a single induction agent, a co-induction agent with other chemotherapy regimens, and as maintenance therapy after conventional chemotherapy or complete remission after autologous or allogeneic transplantation. Interferon as a single induction agent or co-induction agent with other chemotherapy agents appears only to have minimal benefit in myeloma. Its role as maintenance therapy in the plateau phase of myeloma also remains uncertain. More recently, the use of interferon must now compete with the "new drugs"--thalidomide, lenalidomide and bortezomib in myeloma treatment. Will there be a future role of interferon in the treatment of multiple myeloma or will interferon be resigned to the history books remains to be seen.

Radiotherapy in the treatment of multiple myeloma.

PubMed

Bosch, A; Frias, Z

1988-12-01

Fifty-nine patients with multiple myeloma referred for treatment of painful bony lesions received irradiation to 95 local areas, and 16 of the 59 were irradiated using hemibody techniques. Pain relief was obtained in practically all of the irradiated regions. Most local areas were treated to doses of 3000 cGy in 10 to 15 fractions. Patients with generalized pain due to multiple site involvement were treated with single dose hemibody irradiation, to doses of 600 cGy to the upper hemibody, and of 800 cGy to the lower hemibody. This treatment was well tolerated and side effects minimal. Median survival from diagnosis was 30 months and the survival at 1, 3, and 5 years was 80%, 42%, and 12% respectively. Key articles on radiation therapy of multiple myeloma are reviewed and discussed. Since all patients eventually relapse after chemotherapy, the role of radiotherapy using present techniques should be fully evaluated and considered as an alternative in the primary treatment of multiple myeloma.

Multiple myeloma

MedlinePlus

Plasma cell dyscrasia; Plasma cell myeloma; Malignant plasmacytoma; Plasmacytoma of bone; Myeloma - multiple ... Multiple myeloma most commonly causes: Low red blood cell count ( anemia ), which can lead to fatigue and ...

Follow-up of bone lesions in an experimental multiple myeloma mouse model: description of an in vivo technique using radiography dedicated for mammography.

PubMed Central

Vanderkerken, K.; Goes, E.; De Raeve, H.; Radl, J.; Van Camp, B.

1996-01-01

The evolution of bone lesions in transplantable C57BL/KaLwRjj 5T mouse myeloma (MM) has been followed in vivo. Mice were anaesthetised and a radiograph of the pelvis and hind legs was performed by a radiograph dedicated for mammography. This is the first description of an in vivo technique under experimental conditions whereby the development of bone lesions owing to the MM growth was demonstrated. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 PMID:8664113

Hypercoagulable states in patients with multiple myeloma can affect the thalidomide-associated venous thromboembolism.

PubMed

Talamo, Giampaolo P; Ibrahim, Sulfi; Claxton, David; Tricot, Guido J; Fink, Louis M; Zangari, Maurizio

2009-07-01

The therapeutic use of thalidomide in patients with multiple myeloma is often complicated by the development of venous thromboembolism. The objective of the present study was to identify hypercoagulable states associated with development of venous thromboembolism in thalidomide-treated multiple myeloma patients. We screened 49 consecutive multiple myeloma patients treated with thalidomide at baseline for hypercoagulability. With a median follow-up of 11 months, 10 of 49 multiple myeloma patients developed a thrombotic episode. Laboratory assays revealed an underlying abnormality in nine of the 10 patients; hypercoagulable screenings were normal in 36 of the 39 patients who did not develop venous thromboembolism (P < 0.0001). Our retrospective study results suggest that the multiple myeloma patients with thromboembolic complications during treatment with thalidomide have a frequent concomitant underlying thrombophilic state.

Multiple myeloma and related disorders. Lessons from an animal model.

PubMed

Radl, J

1999-02-01

This short review of our own work presents two aspects of the studies on multiple myeloma (MM) in an animal model--the aging C57BL/KaLwRij mouse: 1. the immunological/biological aspect of the development of monoclonal B-cell proliferative disorders, the so-called monoclonal gammopathies (MG), and 2. the use of the mouse myeloma of the 5TMM lines for studies on the etiology/pathogenesis of MM and for developing new ways of treatment of this disease. Our research revealed that there are at least four major mechanisms in the development of MG. Many of the results were confirmed in clinical studies and lead to a new classification of MG according to their biology and possible pathogenesis. Most of MG can be classified into one of the following categories: 1. B-cell malignancies, 2. B-cell benign neoplasia, 3. MG due to an immunodeficiency with T/B cell imbalance, and 4. Antigen driven MG.

Dilemmas in Treating Smoldering Multiple Myeloma

PubMed Central

Ahn, Inhye E.; Mailankody, Sham; Korde, Neha; Landgren, Ola

2015-01-01

Novel therapies hold promise for high-risk smoldering multiple myeloma (SMM). Recent studies suggest that modern combination approaches can be options for high-risk SMM to obtain deep molecular responses with favorable toxicity profiles. Although pioneering treatment trials based on small numbers of patients suggest progression-free and overall survival benefits, application of the data to real-life practice remains to be validated. Therapeutic modulation of disease tempo, disease burden, clonal evolution, and tumor microenvironment in SMM remains to be understood and calls for reliable biomarkers reflective of disease biology. Here, we review studies that open a new management platform for SMM, address ongoing dilemmas in practice and under investigation, and highlight emerging scientific questions in the era of SMM treatment. PMID:25422486

Multiple myeloma with extramedullary disease.

PubMed

Oriol, Albert

2011-11-01

Plasmacytoma is a tumor mass consisting of atypical plasma cells. Incidence of plasmacytomas associated with multiple myeloma range from 7% to 17% at diagnosis and from 6% to 20% during the course of the disease. In both situations, occurrence of extramedullary disease has been consistently associated with a poorer prognosis of myeloma. Extramedullary relapse or progression occurs in a variety of clinical circumstances and settings, and therefore requires individualization of treatment. Alkylating agents, bortezomib, and immunomodulatory drugs, along with corticoids, have been used to treat extramedullary relapse but, because of the relatively low frequency or detection rate of extramedullary relapse, no efficacy data are available from controlled studies in this setting.

Busulfan, Fludarabine, Donor Stem Cell Transplant, and Cyclophosphamide in Treating Patients With Multiple Myeloma or Myelofibrosis

ClinicalTrials.gov

2018-01-31

Anemia; ASXL1 Gene Mutation; EZH2 Gene Mutation; IDH1 Gene Mutation; IDH2 Gene Mutation; Plasma Cell Myeloma; Primary Myelofibrosis; Recurrent Plasma Cell Myeloma; Secondary Myelofibrosis; Thrombocytopenia

Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy

PubMed Central

Chesi, Marta; Matthews, Geoffrey M.; Garbitt, Victoria M.; Palmer, Stephen E.; Shortt, Jake; Lefebure, Marcus; Stewart, A. Keith; Johnstone, Ricky W.

2012-01-01

The attrition rate for anticancer drugs entering clinical trials is unacceptably high. For multiple myeloma (MM), we postulate that this is because of preclinical models that overemphasize the antiproliferative activity of drugs, and clinical trials performed in refractory end-stage patients. We validate the Vk*MYC transgenic mouse as a faithful model to predict single-agent drug activity in MM with a positive predictive value of 67% (4 of 6) for clinical activity, and a negative predictive value of 86% (6 of 7) for clinical inactivity. We identify 4 novel agents that should be prioritized for evaluation in clinical trials. Transplantation of Vk*MYC tumor cells into congenic mice selected for a more aggressive disease that models end-stage drug-resistant MM and responds only to combinations of drugs with single-agent activity in untreated Vk*MYC MM. We predict that combinations of standard agents, histone deacetylase inhibitors, bromodomain inhibitors, and hypoxia-activated prodrugs will demonstrate efficacy in the treatment of relapsed MM. PMID:22451422

Metformin Hydrochloride and Ritonavir in Treating Patients With Relapsed or Refractory Multiple Myeloma or Chronic Lymphocytic Leukemia

ClinicalTrials.gov

2018-03-22

Anemia; Fatigue; Fever; Lymphadenopathy; Lymphocytosis; Night Sweats; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Refractory Chronic Lymphocytic Leukemia; Refractory Plasma Cell Myeloma; Splenomegaly; Thrombocytopenia; Weight Loss

Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma.

PubMed

Wang, Q; Lu, Y; Li, R; Jiang, Y; Zheng, Y; Qian, J; Bi, E; Zheng, C; Hou, J; Wang, S; Yi, Q

2018-01-01

Our previous studies showed that macrophages (MФs), especially myeloma-associated MФs (MAMs), induce chemoresistance in human myeloma. Here we explored the potential of targeting MФs, by using colony-stimulating factor 1 receptor (CSF1R)-blocking mAbs, to treat myeloma. Our results showed that CSF1R blockade specifically inhibited the differentiation, proliferation and survival of murine M2 MФs and MAMs, and repolarized MAMs towards M1-like MФs in vitro. CSF1R blockade alone inhibited myeloma growth in vivo, by partially depleting MAMs, polarizing MAMs to the M1 phenotype, and inducing a tumor-specific cytotoxic CD4 + T-cell response. Similarly, genetically depleting MФs in myeloma-bearing MM DTR mice retarded myeloma growth in vivo. Furthermore, the combination of CSF1R blockade and chemotherapy such as bortezomib or melphalan displayed an additive therapeutic efficacy against established myeloma. Finally, a fully human CSF1R blocking mAb, similar to its murine counterpart, was able to inhibit the differentiation, proliferation and survival of human MФs. Thus, this study provides the first direct in vivo evidence that MΦs and MAMs are indeed important for myeloma development and progression. Our results also suggest that targeting MAMs by CSF1R blocking mAbs may be promising methods to (re)sensitize myeloma cells to chemotherapy and promote anti-myeloma immune responses in patients.

Introduction: multiple myeloma.

PubMed

Cook, Richard

2008-09-01

Multiple myeloma (MM) is the most common type of primary bone tumor, affecting approximately 50,000 patients in the United States. Although it is currently not curable, recent advancements in treatment are bringing myeloma closer to becoming a chronic disease instead of a terminal illness. To better understand the prevalence of MM as well as provide an overview of the costs associated with treatment. The goals of treatment in MM include eradicating all evidence of disease, controlling disease to prevent damage to target organs, preserving normal function and quality of life, relieving pain, and managing myeloma that is in remission. To achieve these goals, treatment must be individually tailored for each patient based on the patient's age, overall health status, symptoms, and laboratory test results. Advancements in the understanding of the pathogenesis of myeloma and the role of genetic mutations are leading to a new standard of treatment. Advancements in diagnostic technology, such as cytogenetic testing, are also being used to tailor treatment for each individual to work toward achieving better response rates, longer periods of remission, and improved quality of life. Increased costs associated with the improved therapies being used to treat MM, and the comorbid conditions associated with the disease, present a challenge to managed care. Health plans and formulary decision makers need to better understand the complexity of therapy to best use resources. The economic burden to the patient must also be considered when developing treatment strategies. Better understanding of the pathophysiology of MM, including the role of cytogenetics, is leading to the development and use of novel agents and treatment options. Head-to-head studies comparing treatments must be performed to best balance the costs associated with treatment and the benefits of improved survival rates and maintaining quality of life.

Celastrol Attenuates the Invasion and Migration and Augments the Anticancer Effects of Bortezomib in a Xenograft Mouse Model of Multiple Myeloma

PubMed Central

Shanmugam, Muthu K.; Ahn, Kwang S.; Lee, Jong H.; Kannaiyan, Radhamani; Mustafa, Nurulhuda; Manu, Kanjoormana A.; Siveen, Kodappully S.; Sethi, Gautam; Chng, Wee J.; Kumar, Alan P.

2018-01-01

Several lines of evidence have demonstrated that deregulated activation of NF-κB plays a pivotal role in the initiation and progression of a variety of cancers including multiple myeloma (MM). Therefore, novel molecules that can effectively suppress deregulated NF-κB upregulation can potentially reduce MM growth. In this study, the effect of celastrol (CSL) on patient derived CD138+ MM cell proliferation, apoptosis, cell invasion, and migration was investigated. In addition, we studied whether CSL can potentiate the apoptotic effect of bortezomib, a proteasome inhibitor in MM cells and in a xenograft mouse model. We found that CSL significantly reduced cell proliferation and enhanced apoptosis when used in combination with bortezomib and upregulated caspase-3 in these cells. CSL also inhibited invasion and migration of MM cells through the suppression of constitutive NF-κB activation and expression of downstream gene products such as CXCR4 and MMP-9. Moreover, CSL when administered either alone or in combination with bortezomib inhibited MM tumor growth and decreased serum IL-6 and TNF-α levels. Overall, our results suggest that CSL can abrogate MM growth both in vitro and in vivo and may serve as a useful pharmacological agent for the treatment of myeloma and other hematological malignancies. PMID:29773987

Smoldering multiple myeloma requiring treatment: time for a new definition?

PubMed Central

Stewart, A. Keith; Chanan-Khan, Asher; Rajkumar, S. Vincent; Kyle, Robert A.; Fonseca, Rafael; Kapoor, Prashant; Bergsagel, P. Leif; McCurdy, Arleigh; Gertz, Morie A.; Lacy, Martha Q.; Lust, John A.; Russell, Stephen J.; Zeldenrust, Steven R.; Reeder, Craig; Roy, Vivek; Buadi, Francis; Dingli, David; Hayman, Suzanne R.; Leung, Nelson; Lin, Yi; Mikhael, Joseph; Kumar, Shaji K.

2013-01-01

Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved. PMID:24144641

[Multiple myeloma and HIV infection: report of 3 cases].

PubMed

Elira Dokekias, A; Moutschen, M; Purhuence, M F; Malanda, F; Moyikoua, A

2004-02-01

HIV infection rages at the endemic state in Sub Saharan African and especially in Congo Brazzaville. We report the observation of three female patients infected with HIV and developing multiple myeloma. The three patients were treated at the University hospital of Brazzaville between 2000 and 2002. In two cases multiple myeloma was discovered after the diagnosis of HIV infection. In the other case, the diagnosis of HIV infection was posterior to the occurrence of multiple myeloma. HIV infection was symptomatic in two cases who received consequently antiviral treatment. Multiple myeloma was diagnosed at an advanced stage in the three cases. The paraprotein was an IgG in two cases and an IgA in the other one. The CD4 counts before treatment were around 200/mm3 in two cases and within normal limits in the third case. Viral load was not measured. VMCP and VAMCP regimens were administered without major complications and under anti-infectious prophylaxis. The follow-up is still insufficient to assess the medium-term evolution and to determine the prognosis of multiple myeloma. The description of these three cases confirms the involvement of HIV in B cell lymphoma genesis.

A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial.

PubMed

Boyd, K D; Ross, F M; Chiecchio, L; Dagrada, G P; Konn, Z J; Tapper, W J; Walker, B A; Wardell, C P; Gregory, W M; Szubert, A J; Bell, S E; Child, J A; Jackson, G H; Davies, F E; Morgan, G J

2012-02-01

The association of genetic lesions detected by fluorescence in situ hybridization (FISH) with survival was analyzed in 1069 patients with newly presenting myeloma treated in the Medical Research Council Myeloma IX trial, with the aim of identifying patients associated with the worst prognosis. A comprehensive FISH panel was performed, and the lesions associated with short progression-free survival and overall survival (OS) in multivariate analysis were +1q21, del(17p13) and an adverse immunoglobulin heavy chain gene (IGH) translocation group incorporating t(4;14), t(14;16) and t(14;20). These lesions frequently co-segregated, and there was an association between the accumulation of these adverse FISH lesions and a progressive impairment of survival. This observation was used to define a series of risk groups based on number of adverse lesions. Taking this approach, we defined a favorable risk group by the absence of adverse genetic lesions, an intermediate group with one adverse lesion and a high-risk group defined by the co-segregation of >1 adverse lesion. This genetic grouping was independent of the International Staging System (ISS) and so was integrated with the ISS to identify an ultra-high-risk group defined by ISS II or III and >1 adverse lesion. This group constituted 13.8% of patients and was associated with a median OS of 19.4 months.

Mangiferin Protects Retinal Ganglion Cells in Ischemic Mouse Retina via SIRT1.

PubMed

Kim, Soo-Jin; Sung, Mi-Sun; Heo, Hwan; Lee, Jae-Hyuk; Park, Sang-Woo

2016-06-01

To investigate whether mangiferin can increase the viability of retinal ganglion cells (RGCs) in ischemic mouse retina, and to determine the possible mechanism of neuroprotection. C57BL/6J mice underwent constant elevation of intraocular pressure for 60 min and received saline or mangiferin (30 mg/kg) intraperitoneally once daily until sacrifice. HIF-1α, GFAP and SIRT1 expression was assessed at 1, 4, and 7 days after retinal ischemia. Bax and Bcl-2 expression was also analyzed at 1 and 4 days. RGC survival was assessed by labeling flat-mounted retinas with Brn3a at 2 weeks after retinal ischemia. The effect of co-treatment with mangiferin and sirtinol (SIRT1 inhibitor) was also evaluated. The expression of HIF-1α and GFAP was upregulated in saline-treated retinas within 7 days after ischemia. Mangiferin treatment suppressed this upregulation. The expression of SIRT1 was downregulated in saline-treated ischemic retinas. This downregulation was reversed by mangiferin treatment, resulting in a significant difference from saline-treated ischemic retinas. In mangiferin-treated ischemic retinas, Bax expression was downregulated, whereas Bcl-2 expression was upregulated in comparison with saline-treated ischemic retinas. Mangiferin treatment protected ischemic retinas against RGC loss. Treatment of sirtinol decreased the neuroprotective effect of mangiferin. Our findings suggest that mangiferin has a neuroprotective effect on RGC through downregulation of HIF-1a and GFAP, and upregulation of SIRT1 in ischemic mouse retinas. We suggest that mangiferin might be a potential neuroprotective agent against RGC loss under oxidative stress.

Apo2L/TRAIL Inhibits Tumor Growth and Bone Destruction in a Murine Model of Multiple Myeloma

PubMed Central

Labrinidis, Agatha; Diamond, Peter; Martin, Sally; Hay, Shelley; Liapis, Vasilios; Zinonos, Irene; Sims, Natalie A.; Atkins, Gerald J.; Vincent, Cristina; Ponomarev, Vladimir; Findlay, David M.; Zannettino, Andrew C.W.; Evdokiou, Andreas

2017-01-01

Purpose Multiple myeloma is an incurable disease, for which the development of new therapeutic approaches is required. Here, we report on the efficacy of recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to inhibit tumor progression and bone destruction in a xenogeneic model of human multiple myeloma. Experimental Design We established a mouse model of myeloma, in which Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells, tagged with a triple reporter gene construct (NES-HSV-TK/GFP/Luc), were transplanted directly into the tibial marrow cavity of nude mice. Tumor burden was monitored progressively by bioluminescence imaging and the development of myeloma-induced osteolysis was measured using high resolution in vivo micro-computed tomography. Results Tumor burden increased progressively in the tibial marrow cavity of mice transplanted with Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells associated with extensive osteolysis directly in the area of cancer cell transplantation. Treatment of mice with recombinant soluble Apo2L/TRAIL reduced myeloma burden in the bone marrow cavity and significantly protected against myeloma-induced osteolysis. The protective effects of Apo2L/TRAIL treatment on bone were mediated by the direct apoptotic actions of Apo2L/TRAIL on myeloma cells within the bone microenvironment. Conclusions This is the first in vivo study that investigates the efficacy of recombinant Apo2L/TRAIL on myeloma burden within the bone microenvironment and associated myeloma-induced bone destruction. Our findings that recombinant soluble Apo2L/TRAIL reduces myeloma burden within the bone microenvironment and protects the bone from myeloma-induced bone destruction argue against an inhibitory role of osteoprotegerin in Apo2L/TRAIL-induced apoptosis in vivo and highlight the need to clinically evaluate Apo2L/TRAIL in patients with multiple myeloma. PMID:19276263

The spectrum and clinical impact of epigenetic modifier mutations in myeloma

PubMed Central

Pawlyn, Charlotte; Kaiser, Martin F; Heuck, Christoph; Melchor, Lorenzo; Wardell, Christopher P; Murison, Alex; Chavan, Shweta; Johnson, David C; Begum, Dil; Dahir, Nasrin; Proszek, Paula; Cairns, David A; Boyle, Eileen M; Jones, John R; Cook, Gordon; Drayson, Mark T; Owen, Roger G; Gregory, Walter M; Jackson, Graham H; Barlogie, Bart; Davies, Faith E; Walker, Brian A; Morgan, Gareth J

2016-01-01

Purpose Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike in other B cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been previously reported. We sought to address this using results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison. Experimental Design Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences. We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease. Results In diagnostic myeloma patient samples we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX. The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers. Conclusions Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. PMID:27235425

Multiple Myeloma

MedlinePlus

... myeloma is a cancer that begins in plasma cells, a type of white blood cell. These cells are part of your immune system, which helps ... germs and other harmful substances. In time, myeloma cells collect in the bone marrow and in the ...

Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: an International Myeloma Working Group collaborative project.

PubMed

Avet-Loiseau, H; Durie, B G M; Cavo, M; Attal, M; Gutierrez, N; Haessler, J; Goldschmidt, H; Hajek, R; Lee, J H; Sezer, O; Barlogie, B; Crowley, J; Fonseca, R; Testoni, N; Ross, F; Rajkumar, S V; Sonneveld, P; Lahuerta, J; Moreau, P; Morgan, G

2013-03-01

The combination of serum β2-microglobulin and albumin levels has been shown to be highly prognostic in myeloma as the International Staging System (ISS). The aim of this study was to assess the independent contributions of ISS stage and cytogenetic abnormalities in predicting outcomes. A retrospective analysis of international studies looking at both ISS and cytogenetic abnormalities was performed in order to assess the potential role of combining ISS stage and cytogenetics to predict survival. This international effort used the International Myeloma Working Group database of 12 137 patients treated worldwide for myeloma at diagnosis, of whom 2309 had cytogenetic studies and 5387 had analyses by fluorescent in situ hybridization (iFISH). Comprehensive analyses used 2642 patients with sufficient iFISH data available. Using the comprehensive iFISH data, combining both t(4;14) and deletion (17p), along with ISS stage, significantly improved the prognostic assessment in terms of progression-free survival and overall survival. The additional impact of patient age and use of high-dose therapy was also demonstrated. In conclusion, the combination of iFISH data with ISS staging significantly improves risk assessment in myeloma.

Phospholipid epitopes for mouse antibodies against bromelain-treated mouse erythrocytes.

PubMed Central

Kawaguchi, S

1987-01-01

The reactivity of mouse antibodies against bromelain-treated mouse erythrocytes (BrMRBC) with phospholipid epitopes was assessed by ELISA, using four clones of monoclonal anti-BrMRBC antibodies that had idiotypes distinct from one another. The four antibodies could bind to low-density lipoproteins (LDL) from human and chicken, but not to LDL from mouse and rat. As to liposomes of natural phospholipids, all the clones reacted with liposomes of phosphatidylcholine, and some of them could react with liposomes of sphingomyelin, phosphatidylglycerol, phosphatidylic acid or cardiolipin. For liposomes of synthetic phosphatidylcholine with different fatty acids, the length of carbon chains and the number of unsaturated carbon chains of the fatty acids markedly affected the binding of each monoclonal antibody to the liposomes. The addition of dicetyl phosphate or stearylamine to phosphatidylcholine liposomes changed the reactivity of the liposomes. These results support the view that mouse anti-BrMRBC antibodies can recognize appropriately spaced phosphorylcholine residues on the surface of phospholipid liposomes, LDL and cells. The four clones had similar capacities for binding to LDL as well as to BrMRBC, but they had obviously different capacities for binding to phospholipid liposomes; the epitopes on phospholipid liposomes used in the present study were not so perfect as to react well with every anti-BrMRBC antibody. PMID:2443446

Multiple myeloma on polycythemia vera following radioactive phosphorus therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

West, W.O.

1976-11-01

A 74-year-old white man with established polycythemia vera was treated with radioactive phosphorus after phlebotomies alone failed to control his disease. About 2/sup 3///sub 4/ years later he died of multiple myeloma. The mutagenic effect of radioactive phosphorus may have caused or possibly accelerated preexisting myeloma. Basic nonmalignant disease deserves careful consideration before radiation or radiomimetic agents are used. One might consider a probably less mutagenic drug such as hydroxyurea in patients with polycythemia vera when phlebotomy alone does not give good control of red cell mass and thrombocytosis.

Inhibition of Fatty Acid Metabolism Reduces Human Myeloma Cells Proliferation

PubMed Central

Tirado-Vélez, José Manuel; Joumady, Insaf; Sáez-Benito, Ana; Cózar-Castellano, Irene; Perdomo, Germán

2012-01-01

Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40–70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma. PMID:23029529

Constitutive activation of p38 MAPK in tumor cells contributes to osteolytic bone lesions in multiple myeloma

PubMed Central

Yang, Jing; He, Jin; Wang, Ji; Cao, Yabing; Ling, Jianhua; Qian, Jianfei; Lu, Yong; Li, Haiyan; Zheng, Yuhuan; Lan, Yongsheng; Hong, Sungyoul; Matthews, Jairo; Starbuck, Michael W; Navone, Nora M; Orlowski, Robert Z.; Lin, Pei; Kwak, Larry W.; Yi, Qing

2012-01-01

Bone destruction is a hallmark of multiple myeloma and affects more than 80% of patients. However, current therapy is unable to completely cure and/or prevent bone lesions. Although it is accepted that myeloma cells mediate bone destruction by inhibition of osteoblasts and activation of osteoclasts, the underlying mechanism is still poorly understood. This study demonstrates that constitutive activation of p38 mitogen-activated protein kinase in myeloma cells is responsible for myeloma-induced osteolysis. Our results show that p38 is constitutively activated in most myeloma cell lines and primary myeloma cells from patients. Myeloma cells with high/detectable p38 activity, but not those with low/undetectable p38 activity, injected into SCID or SCID-hu mice caused bone destruction. Inhibition or knockdown of p38 in human myeloma reduced or prevented myeloma-induced osteolytic bone lesions without affecting tumor growth, survival, or homing to bone. Mechanistic studies showed that myeloma cell p38 activity inhibited osteoblastogenesis and bone formation and activated osteoclastogenesis and bone resorption in myeloma-bearing SCID mice. This study elucidates a novel molecular mechanism—sactivation of p38 signaling in myeloma cells—by which myeloma cells induce osteolytic bone lesions and indicates that targeting myeloma cell p38 may be a viable approach to treating or preventing myeloma bone disease. PMID:22425892

Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease.

PubMed

Nyman, Jeffry S; Merkel, Alyssa R; Uppuganti, Sasidhar; Nayak, Bijaya; Rowland, Barbara; Makowski, Alexander J; Oyajobi, Babatunde O; Sterling, Julie A

2016-10-01

Multiple myeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2-/-) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease. Published by Elsevier Inc.

Cultivation of activated sludge using sea mud as seed to treat industrial phenolic wastewater with high salinity.

PubMed

Tan, Songwen; Cui, Chunzhi; Hou, Yang; Chen, Xuncai; Xu, Aiqin; Li, Weiguo; You, Hong

2017-01-30

A technique is proposed to treat saline hazardous wastewater by using marine activated sludge, cultivated with sea mud as seed. Since the developed marine activated sludge had phenol-tolerant microorganisms (MAS-1, MAS-2 and MAS-3) which originated from the ocean, it was envisaged that these bacteria could survive and breakdown phenol in saline environments. In this work, typical phenol-tolerant microorganisms were isolated from the marine activated sludge and identified. After a hierarchical acclimation process, the marine activated sludge was used to treat the industrial phenolic wastewater with high salinity. The marine activated sludge was able to break down phenol and other organic components effectively and efficiently in treating the wastewater with salinity of 5.7% w/v. The results showed a high removal of phenol (99%), COD (80%) and NH 3 -N (68%). Copyright © 2016 Elsevier Ltd. All rights reserved.

Recent advances in multiple myeloma.

PubMed

Sjak-Shie, N N; Vescio, R A; Berenson, J R

2000-07-01

Multiple myeloma is the second most common hematologic malignancy, with approximately 15,000 new cases each year in the United States. Our understanding of the pathophysiology underlying myeloma continues to expand, but the cause of this plasma cell dyscrasia remains unclear. Though controversy remains regarding a possible viral cause of myeloma, evidence suggesting a role for the human herpesvirus-8 is mounting. The roles of cytogenetic abnormalities as well as aberrant angiogenesis and cytokine expression in the etiology of myeloma continue to be explored and may lead to future therapeutic strategies. Transplantation in myeloma is rarely curative but offers clinical benefit not only for young but possibly for older myeloma patients as well. Newer bisphosphonates may offer greater ease of administration, improved efficacy, and possibly even enhanced antitumor effect. Finally, thalidomide offers significant clinical benefit to patients with myeloma previously refractory to multiple agents, and its role in early stages of the disease is under investigation.

Survival of elderly patients with multiple myeloma-Effect of upfront autologous stem cell transplantation.

PubMed

Merz, Maximilian; Jansen, Lina; Castro, Felipe A; Hillengass, Jens; Salwender, Hans; Weisel, Katja; Scheid, Christof; Luttmann, Sabine; Emrich, Katharina; Holleczek, Bernd; Katalinic, Alexander; Nennecke, Alice; Straka, Christian; Langer, Christian; Engelhardt, Monika; Einsele, Hermann; Kröger, Nicolaus; Beelen, Dietrich; Dreger, Peter; Brenner, Hermann; Goldschmidt, Hartmut

2016-07-01

The aim of this study was to determine the value of upfront autologous transplantation (ASCT) in elderly patients (60-79 years) with myeloma. We analysed relative survival (RS) of patients diagnosed in 1998-2011 and treated with ASCT within 12 months after diagnosis in Germany (n = 3591; German Registry of Stem Cell Transplantation) and compare RS with survival of myeloma patients diagnosed in the same years in Germany (n = 13,903; population-based German Cancer Registries). Utilisation of ASCT has increased rapidly between 2000-2002 and 2009-2011 (60-64years: 7.0-43.0%; 65-69 years: 6.6-23.7%; 70-79 years: 0.4-4.0%). Comparison of 5-year RS of patients from the general German myeloma population who have survived the first year after diagnosis with 5-year RS of patients treated with ASCT revealed higher survival for transplanted patients among all age groups (60-64: 59.2% versus 66.1%; 65-69: 57.4% versus 61.7%; 70-79: 51.0% versus 56.6%). RS increased strongly between 2003-2005 and 2009-2011 for the general German myeloma population (+8.5%) and for patients treated with ASCT (+11.8%). Differences in RS between these groups increased over time from +1.9% higher age-standardised survival in transplanted patients in 2003-2005 to 5.2% higher survival in 2009-2011. We conclude that upfront ASCT might be a major contributor to improved survival for elderly myeloma patients in Germany. Copyright © 2016 Elsevier Ltd. All rights reserved.

A xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishimura, Nao; Endo, Shinya; Ueno, Shikiko

We previously demonstrated that PU.1 expression is down-regulated in the majority of myeloma cell lines and primary myeloma cells from patients. We introduced the tet-off system into the human myeloma cell lines U266 and KMS12PE that conditionally express PU.1 and demonstrated that PU.1 induces cell cycle arrest and apoptosis in myeloma cells in vitro. Here, we established a mouse xenograft model of myeloma using these cell lines to analyze the effects of PU.1 on the phenotype of myeloma cells in vivo. When doxycycline was added to the drinking water of mice engrafted with these myeloma cells, all mice had continuous growth ofmore » subcutaneous tumors and could not survived more than 65 days. In contrast, mice that were not exposed to doxycycline did not develop subcutaneous tumors and survived for at least 100 days. We next generated mice engrafted with subcutaneous tumors 5–10 mm in diameter that were induced by exposure to doxycycline. Half of the mice stopped taking doxycycline-containing water, whereas the other half kept taking the water. Although the tumors in the mice taking doxycycline continued to grow, tumor growth in the mice not taking doxycycline was significantly suppressed. The myeloma cells in the tumors of the mice not taking doxycycline expressed PU.1 and TRAIL and many of such cells were apoptotic. Moreover, the expression of a cell proliferation marker Ki67 was significantly decreased in tumors from the mice not taking doxycycline, compared with that of tumors from the mice continuously taking doxycycline. The present data strongly suggest that PU.1 functions as a tumor suppressor of myeloma cells in vivo. - Highlights: • PU.1 suppresses xenograft myeloma cell growth and prolongs survival periods of mice. • PU.1 induces TRAIL expression and apoptosis in myeloma cells in vivo. • PU.1 suppresses Ki67 expression in myeloma cells in vivo. • Up-regulation of PU.1 is a promising strategy for generating anti-myeloma agents.« less

AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies

PubMed Central

Chesi, Marta; Robbiani, Davide F.; Sebag, Michael; Chng, Wee Joo; Affer, Maurizio; Tiedemann, Rodger; Valdez, Riccardo; Palmer, Stephen E.; Haas, Stephanie S.; Stewart, A. Keith; Fonseca, Rafael; Kremer, Richard; Cattoretti, Giorgio; Bergsagel, P. Leif

2008-01-01

Summary By misdirecting the activity of Activation-Induced Deaminase (AID) to a conditional MYC transgene, we have achieved sporadic, AID-dependent MYC activation in germinal center B-cells of Vk*MYC mice. Whereas control C57BL/6 mice develop benign monoclonal gammopathy with age, all Vk*MYC mice progress to an indolent multiple myeloma associated with the biological and clinical features highly characteristic of the human disease. Furthermore, antigen-dependent myeloma could be induced by immunization with a T-dependent antigen. Consistent with these findings in mice, more frequent MYC rearrangements, elevated levels of MYC mRNA and MYC target genes distinguish human patients with multiple myeloma from individuals with monoclonal gammopathy, implicating a causal role for MYC in the progression of monoclonal gammopathy to multiple myeloma in man. PMID:18242516

Programmed death receptor-1/programmed death receptor ligand-1 blockade after transient lymphodepletion to treat myeloma.

PubMed

Kearl, Tyce J; Jing, Weiqing; Gershan, Jill A; Johnson, Bryon D

2013-06-01

Early phase clinical trials targeting the programmed death receptor-1/ligand-1 (PD-1/PD-L1) pathway to overcome tumor-mediated immunosuppression have reported promising results for a variety of cancers. This pathway appears to play an important role in the failure of immune reactivity to malignant plasma cells in multiple myeloma patients, as the tumor cells express relatively high levels of PD-L1, and T cells show increased PD-1 expression. In the current study, we demonstrate that PD-1/PD-L1 blockade with a PD-L1-specific Ab elicits rejection of a murine myeloma when combined with lymphodepleting irradiation. This particular combined approach by itself has not previously been shown to be efficacious in other tumor models. The antitumor effect of lymphodepletion/anti-PD-L1 therapy was most robust when tumor Ag-experienced T cells were present either through cell transfer or survival after nonmyeloablative irradiation. In vivo depletion of CD4 or CD8 T cells completely eliminated antitumor efficacy of the lymphodepletion/anti-PD-L1 therapy, indicating that both T cell subsets are necessary for tumor rejection. Elimination of myeloma by T cells occurs relatively quickly as tumor cells in the bone marrow were nearly nondetectable by 5 d after the first anti-PD-L1 treatment, suggesting that antimyeloma reactivity is primarily mediated by preactivated T cells, rather than newly generated myeloma-reactive T cells. Anti-PD-L1 plus lymphodepletion failed to improve survival in two solid tumor models, but demonstrated significant efficacy in two hematologic malignancy models. In summary, our results support the clinical testing of lymphodepletion and PD-1/PD-L1 blockade as a novel approach for improving the survival of patients with multiple myeloma.

Cost savings of home bortezomib injection in patients with multiple myeloma treated by a combination care in Outpatient Hospital and Hospital care at Home.

PubMed

Touati, Mohamed; Lamarsalle, Ludovic; Moreau, Stéphane; Vergnenègre, Françoise; Lefort, Sophie; Brillat, Catherine; Jeannet, Laetitia; Lagarde, Aline; Daulange, Annick; Jaccard, Arnaud; Vergnenègre, Alain; Bordessoule, Dominique

2016-12-01

At home injectable chemotherapy for patients receiving treatment for hematological diseases is still in debate. Given the expense of new innovative medicines, at home treatment has been proposed as a suitable option for improving patient quality of life and decreasing treatment costs. We decided to assess the cost of bortezomib administration in France among multiple myeloma patients from an economic standpoint. Patients in this study were treated within a regional hematological network combining outpatient hospital care and Hospital care at Home administration. To make the cost comparison, our team simulated outpatient hospital care expenses. Fifty-four consecutive multiple myeloma patients who received at least one injection of bortezomib in Hospital care at Home from January 2009 to December 2011 were included in the study. The median number of injections was 12 (range 1-44) at home and 6 (range 0-30) in the outpatient care unit. When compared with the cost simulation of outpatient hospital care alone, bortezomib administration with combined care was significantly less expensive for the National Health Insurance (NHI) budget. The mean total cost per patient and per injection was 954.20 € for combined outpatient and Hospital care at Home vs 1143.42 € for outpatient hospital care alone. This resulted in an estimated 16.5 % cost saving (Wilcoxon signed-rank test, p < 0.0001). The greatest savings were observed in administration costs (37.5 % less) and transportation costs (68.1 % less). This study reflects results for a regionally implemented program for multiple myeloma patients treated with bortezomib in routine practice in a large rural area.

A GRP78-Directed Monoclonal Antibody Recaptures Response in Refractory Multiple Myeloma with Extramedullary Involvement.

PubMed

Rasche, Leo; Menoret, Emmanuelle; Dubljevic, Valentina; Menu, Eline; Vanderkerken, Karin; Lapa, Constantin; Steinbrunn, Torsten; Chatterjee, Manik; Knop, Stefan; Düll, Johannes; Greenwood, Deanne L; Hensel, Frank; Rosenwald, Andreas; Einsele, Hermann; Brändlein, Stephanie

2016-09-01

Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens. GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti-multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide. Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra- and extramedullary lesions. PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 22(17); 4341-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Myeloma cell-induced disruption of bone remodelling compartments leads to osteolytic lesions and generation of osteoclast-myeloma hybrid cells.

PubMed

Andersen, Thomas L; Søe, Kent; Sondergaard, Teis E; Plesner, Torben; Delaisse, Jean-Marie

2010-02-01

Osteolytic lesions are a hallmark of multiple myeloma. They are due to the hyperactivity of bone resorbing osteoclasts and hypoactivity of bone forming osteoblasts, in response to neighbouring myeloma cells. This study identified a structure that deeply affects this response, because of its impact on the physical organisation of the myeloma cell microenvironment. The proximity between myeloma cells and osteoclasts or osteoblasts was shown to be conditioned by the recently discovered layer of flat cells that separates the osteoclasts and osteoblasts from the bone marrow, by forming a canopy over bone remodelling compartment (BRC). These canopies are frequently disrupted in myeloma, and this disruption correlates with increased proximity and density of myeloma cells. In vitro evidence indicates that this disruption may be due to direct contact between myeloma and BRC canopy cells. Importantly, this disruption and increased proximity and density of myeloma cells coincides with key myeloma-induced bone events, such as osteolytic lesions, impaired bone formation despite increased bone resorption, and fusion of myeloma cells with osteoclasts thereby forming myeloma-osteoclast hybrid cells. These findings strongly support a critical role of BRC canopies in myeloma-induced bone disease. BRC canopies could therefore be considered as a new therapeutic target.

Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease

PubMed Central

Garcia-Gomez, Antonio; Las Rivas, Javier De; Ocio, Enrique M.; Díaz-Rodríguez, Elena; Montero, Juan C.; Martín, Montserrat; Blanco, Juan F.; Sanchez-Guijo, Fermín M.; Pandiella, Atanasio; San Miguel, Jesús F.; Garayoa, Mercedes

2014-01-01

Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease. PMID:25268740

Single fraction spine radiosurgery for myeloma epidural spinal cord compression.

PubMed

Jin, Ryan; Rock, Jack; Jin, Jian-Yue; Janakiraman, Nalini; Kim, Jae Ho; Movsas, Benjamin; Ryu, Samuel

2009-01-01

Radiosurgery delivers highly focused radiation beams to the defined target with high precision and accuracy. It has been demonstrated that spine radiosurgery can be safely used for treatment of spine metastasis with rapid and durable pain control, but without detrimental effects to the spinal cord. This study was carried out to determine the role of single fraction radiosurgery for epidural spinal cord compression due to multiple myeloma. A total of 31 lesions in 24 patients with multiple myeloma, who presented with epidural spinal cord compression, were treated with spine radiosurgery. Single fraction radiation dose of 10-18 Gy (median of 16 Gy) was administered to the involved spine including the epidural or paraspinal tumor. Patients were followed up with clinical exams and imaging studies. Median follow-up was 11.2 months (range 1-55). Primary endpoints of this study were pain control, neurological improvement, and radiographic tumor control. Overall pain control rate was 86%; complete relief in 54%, and partial relief in 32% of the patients. Seven patients presented with neurological deficits. Five patients neurologically improved or became normal after radiosurgery. Complete radiographic response of the epidural tumor was noted in 81% at 3 months after radiosurgery. During the follow-up time, there was no radiographic or neurological progression at the treated spine. The treatment was non-invasive and well tolerated. Single fraction radiosurgery achieved an excellent clinical and radiographic response of myeloma epidural spinal cord compression. Radiosurgery can be a viable treatment option for myeloma epidural compression.

A Phthalimide Derivative That Inhibits Centrosomal Clustering Is Effective on Multiple Myeloma

PubMed Central

Shiheido, Hirokazu; Terada, Fukiko; Tabata, Noriko; Hayakawa, Ichigo; Matsumura, Nobutaka; Takashima, Hideaki; Ogawa, Yoko; Du, Wenlin; Yamada, Taketo; Shoji, Mitsuru; Sugai, Takeshi; Doi, Nobuhide; Iijima, Shiro; Hattori, Yutaka; Yanagawa, Hiroshi

2012-01-01

Despite the introduction of newly developed drugs such as lenalidomide and bortezomib, patients with multiple myeloma are still difficult to treat and have a poor prognosis. In order to find novel drugs that are effective for multiple myeloma, we tested the antitumor activity of 29 phthalimide derivatives against several multiple myeloma cell lines. Among these derivatives, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3- dione (TC11) was found to be a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9. This compound also showed in vivo activity against multiple myeloma cell line KMS34 tumor xenografts in ICR/SCID mice. By means of mRNA display selection on a microfluidic chip, the target protein of TC11 was identified as nucleophosmin 1 (NPM). Binding of TC11 and NPM monomer was confirmed by surface plasmon resonance. Immunofluorescence and NPM knockdown studies in HeLa cells suggested that TC11 inhibits centrosomal clustering by inhibiting the centrosomal-regulatory function of NPM, thereby inducing multipolar mitotic cells, which undergo apoptosis. NPM may become a novel target for development of antitumor drugs active against multiple myeloma. PMID:22761710

The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in in vitro and in vivo models of multiple myeloma by blockade of Ikaros and MYC signaling

PubMed Central

Díaz, Tania; Rodríguez, Vanina; Lozano, Ester; Mena, Mari-Pau; Calderón, Marcos; Rosiñol, Laura; Martínez, Antonio; Tovar, Natalia; Pérez-Galán, Patricia; Bladé, Joan; Roué, Gaël; de Larrea, Carlos Fernández

2017-01-01

Most patients with multiple myeloma treated with current therapies, including immunomodulatory drugs, eventually develop relapsed/refractory disease. Clinical activity of lenalidomide relies on degradation of Ikaros and the consequent reduction in IRF4 expression, both required for myeloma cell survival and involved in the regulation of MYC transcription. Thus, we sought to determine the combinational effect of an MYC-interfering therapy with lenalidomide/dexamethasone. We analyzed the potential therapeutic effect of the combination of the BET bromodomain inhibitor CPI203 with the lenalidomide/dexamethasone regimen in myeloma cell lines. CPI203 exerted a dose-dependent cell growth inhibition in cell lines, indeed in lenalidomide/dexamethasone-resistant cells (median response at 0.5 μM: 65.4%), characterized by G1 cell cycle blockade and a concomitant inhibition of MYC and Ikaros signaling. These effects were potentiated by the addition of lenalidomide/dexamethasone. Results were validated in primary plasma cells from patients with multiple myeloma co-cultured with the mesenchymal stromal cell line stromaNKtert. Consistently, the drug combination evoked a 50% reduction in cell proliferation and correlated with basal Ikaros mRNA expression levels (P=0.04). Finally, in a SCID mouse xenotransplant model of myeloma, addition of CPI203 to lenalidomide/dexamethasone decreased tumor burden, evidenced by a lower glucose uptake and increase in the growth arrest marker GADD45B, with simultaneous downregulation of key transcription factors such as MYC, Ikaros and IRF4. Taken together, our data show that the combination of a BET bromodomain inhibitor with a lenalidomide-based regimen may represent a therapeutic approach to improve the response in relapsed/refractory patients with multiple myeloma, even in cases with suboptimal prior response to immunomodulatory drugs. PMID:28751557

Immunomodulation of multiple myeloma.

PubMed

Tohnya, Tanyifor M; Figg, William D

2004-11-01

Multiple myeloma is a multi-process disease, and these different processes are responsible for the reduced sensitivity to chemotherapy and radiotherapy, hence the relapse and refractory nature of multiple myeloma. Emphasis is now placed on the hypothesis that myeloma cell growth, inhibition of apoptosis and drug resistance are dependent on immunomodulatory cytokines such as IL-6 and pro-angiogenic factors such as VEGF. In addition to its anti-angiogenic effects, the immunomodulatory properties of thalidomide make it a possible therapy for patients with advanced multiple myeloma. This has lead to the clinical development of a number of immunomodulatory thalidomide analogues (IMiDs) which are more potent and have less side effects than the parent drug, thalidomide. In the August 15(th) issue of Journal of Clinical Oncology, Schey SA et al. suggested that an IMiD (CC-4047) maybe efficacious due to T-cell co-stimulation, and safe in patients with relapsed or refractory multiple myeloma. This article demonstrates a supporting role for IMiDs as immunomodulatory adjuvant therapy.

Multiple myeloma. Houses and spouses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kyle, R.A.; Greipp, P.R.

1983-02-15

Two families in which successive spouses who lived in the same house developed multiple myeloma are reported. In the first instance, a man whose first wife died of multiple myeloma remarried, and his second wife also developed myeloma. In the second family, a woman's first husband died of multiple myeloma and her second husband did too. Radiation studies of the houses and yards showed no increased radioactivity. No evidence was found for excessive exposure to chemicals or other environmental agents, for contact with other patients having similar malignancies, or for exposure to viruses or other transmissible factors. The significance ofmore » the occurrence of multiple myeloma in subsequent spouses is unknown. It is hoped that this report will stimulate research for other instances and lead to careful epidemiologic, radiologic, and virologic studies.« less

Thirteen treated of acute renal failure secondary to multiple myeloma with high cut off filters.

PubMed

Berni Wennekers, Ana; Martín Azara, María Pilar; Dourdil Sahun, Victoria; Bergasa Liberal, Beatriz; Ruiz Laiglesia, José Esteban; Vernet Perna, Patricia; Alvarez Lipe, Rafael

2016-01-01

Multiple myeloma (MM) is a haematological tumour that is characterised by uncontrolled proliferation of plasma cells and a significant volume of serum free light chains (sFLCs), which can cause acute renal failure due to intratubular precipitation, resulting in cast nephropathy. Acute renal failure is a complication that can arise in more than 20% of patients with multiple myeloma, half of which will require dialysis. We report our experience with 13 patients who were treated with dialysis using high cut off filters (HCO) between July 2011 and February 2015. A total of 6 consecutive 6-hour sessions were performed using a 2.1 m(2) HCO filter (Theralite® by Gambro®). Afterwards, further 6-hour sessions were continued on alternate days. A total of 151 sessions were conducted, with an average of 11.6 sessions per patient (range 6-27). The treatment proved to be effective in removing both kappa and lambda sFLCs, resulting in a 93.7% fall in sFLCs by the end of treatment. The average reduction was 57.7% per dialysis session. 10 out of the 13 cases recovered sufficient renal function to become independent of dialysis. There were no major changes in albumin levels using an infusion protocol of 2 50-mL vials of 20% albumin at the end of the dialysis session. Combination treatment with chemotherapy and long dialysis with HCO filters was effective in reducing the sFLC levels and recovering sufficient renal function in 77% of cases. With HCO filters, significant cost savings are achieved, contrary to what was previously believed. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

[Therapy of multiple myeloma. What is confirmed?].

PubMed

Peest, D; Ganser, A; Einsele, H

2013-12-01

Multiple myeloma (MM) is a malignant plasma cell disorder with clonal development. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are precursor stages of MM and both have to be differentiated from MM which is characterized by organ complications. High-dose chemotherapy combined with autologous stem cell support is the therapy of choice for most patients in order to achieve long-lasting complete remission with few symptoms, prevention of new organ complications and survival prolongation. Patients who cannot be intensively treated due to advanced age and comorbidities should be treated with low-dose chemotherapy, normally alkylating agents, for improved quality of life and also survival prolongation. Including thalidomide, lenalidomide, pomalidomide, bortezomib or carfilzomib in both high-dose and low-dose chemotherapy concepts results in a significantly higher remission rate and longer survival. Allogeneic stem cell transplantation is associated with a relatively high mortality during the first year after transplantation which will be refined with the aim of healing in various trials and is an alternative treatment approach for selected patients. A treatment concept for MM patients has to be individually complemented by local irradiation, administration of bisphosphonates and supportive infusions of immunoglobulins.

Combined treatment with a transforming growth factor beta inhibitor (1D11) and bortezomib improves bone architecture in a mouse model of myeloma-induced bone disease

PubMed Central

Nyman, Jeffry S.; Merkel, Alyssa R.; Uppuganti, Sasidhar; Nayak, Bijaya; Rowland, Barbara; Makowski, Alexander J.; Oyajobi, Babatunde O.; Sterling, Julie A.

2016-01-01

Multiplemyeloma (MM) patients frequently develop tumor-induced bone destruction, yet no therapy completely eliminates the tumor or fully reverses bone loss. Transforming growth factor-β (TGF-β) activity often contributes to tumor-induced bone disease, and pre-clinical studies have indicated that TGF-β inhibition improves bone volume and reduces tumor growth in bone metastatic breast cancer. We hypothesized that inhibition of TGF-β signaling also reduces tumor growth, increases bone volume, and improves vertebral body strength in MM-bearing mice. We treated myeloma tumor-bearing (immunocompetent KaLwRij and immunocompromised Rag2 −/−) mice with a TGF-β inhibitory (1D11) or control (13C4) antibody, with or without the anti-myeloma drug bortezomib, for 4 weeks after inoculation of murine 5TGM1 MM cells. TGF-β inhibition increased trabecular bone volume, improved trabecular architecture, increased tissue mineral density of the trabeculae as assessed by ex vivo micro-computed tomography, and was associated with significantly greater vertebral body strength in biomechanical compression tests. Serum monoclonal paraprotein titers and spleen weights showed that 1D11 monotherapy did not reduce overall MM tumor burden. Combination therapy with 1D11 and bortezomib increased vertebral body strength, reduced tumor burden, and reduced cortical lesions in the femoral metaphysis, although it did not significantly improve cortical bone strength in three-point bending tests of the mid-shaft femur. Overall, our data provides rationale for evaluating inhibition of TGF-β signaling in combination with existing anti-myeloma agents as a potential therapeutic strategy to improve outcomes in patients with myeloma bone disease. PMID:27423464

Induction of potent NK cell-dependent anti-myeloma cytotoxic T cells in response to combined mapatumumab and bortezomib.

PubMed

Neeson, Paul J; Hsu, Andy K; Chen, Yin R; Halse, Heloise M; Loh, Joanna; Cordy, Reece; Fielding, Kate; Davis, Joanne; Noske, Josh; Davenport, Alex J; Lindqvist-Gigg, Camilla A; Humphreys, Robin; Tai, Tsin; Prince, H Miles; Trapani, Joseph A; Smyth, Mark J; Ritchie, David S

2015-09-01

There is increasing evidence that some cancer therapies can promote tumor immunogenicity to boost the endogenous antitumor immune response. In this study, we used the novel combination of agonistic anti-TRAIL-R1 antibody (mapatumumab, Mapa) with low dose bortezomib (LDB) for this purpose. The combination induced profound myeloma cell apoptosis, greatly enhanced the uptake of myeloma cell apoptotic bodies by dendritic cell (DC) and induced anti-myeloma cytotoxicity by both CD8 + T cells and NK cells. Cytotoxic lymphocyte expansion was detected within 24 h of commencing therapy and was maximized when myeloma-pulsed DC were co-treated with low dose bortezomib and mapatumumab (LDB+Mapa) in the presence of NK cells. This study shows that Mapa has two distinct but connected modes of action against multiple myeloma (MM). First, when combined with LDB, Mapa produced powerful myeloma cell apoptosis; secondly, it promoted DC priming and an NK cell-mediated expansion of anti-myeloma cytotoxic lymphocyte (CTL). Overall, this study indicates that Mapa can be used to drive potent anti-MM immune responses.

Induction of potent NK cell-dependent anti-myeloma cytotoxic T cells in response to combined mapatumumab and bortezomib

PubMed Central

Neeson, Paul J; Hsu, Andy K; Chen, Yin R; Halse, Heloise M; Loh, Joanna; Cordy, Reece; Fielding, Kate; Davis, Joanne; Noske, Josh; Davenport, Alex J; Lindqvist-Gigg, Camilla A; Humphreys, Robin; Tai, Tsin; Prince, H Miles; Trapani, Joseph A; Smyth, Mark J; Ritchie, David S

2015-01-01

There is increasing evidence that some cancer therapies can promote tumor immunogenicity to boost the endogenous antitumor immune response. In this study, we used the novel combination of agonistic anti-TRAIL-R1 antibody (mapatumumab, Mapa) with low dose bortezomib (LDB) for this purpose. The combination induced profound myeloma cell apoptosis, greatly enhanced the uptake of myeloma cell apoptotic bodies by dendritic cell (DC) and induced anti-myeloma cytotoxicity by both CD8+ T cells and NK cells. Cytotoxic lymphocyte expansion was detected within 24 h of commencing therapy and was maximized when myeloma-pulsed DC were co-treated with low dose bortezomib and mapatumumab (LDB+Mapa) in the presence of NK cells. This study shows that Mapa has two distinct but connected modes of action against multiple myeloma (MM). First, when combined with LDB, Mapa produced powerful myeloma cell apoptosis; secondly, it promoted DC priming and an NK cell-mediated expansion of anti-myeloma cytotoxic lymphocyte (CTL). Overall, this study indicates that Mapa can be used to drive potent anti-MM immune responses. PMID:26405606

Management of high-risk Myeloma: an evidence-based review of treatment strategies.

PubMed

Lehners, Nicola; Hayden, Patrick J; Goldschmidt, Hartmut; Raab, Marc-Steffen

2016-08-01

Despite the progress made in the treatment of patients with multiple myeloma over recent decades, a significant cohort with high-risk disease as defined by specific clinical and genetic criteria continue to respond poorly to standard treatment. These patients represent a particular challenge to the treating physician and require early identification as well as personalized treatment strategies. In this review, we discuss the prognostic impact of adverse clinical, radiological and genetic factors, evaluate available scoring systems and highlight key aspects of the therapeutic management of high-risk myeloma. MEDLINE and recent scientific meetings' databases were searched for the keywords 'high-risk' and 'multiple myeloma' and relevant studies relating to both diagnostic and therapeutic approaches were identified. Expert commentary: A case is made for intensive induction using combinations of novel agents, early high-dose therapy supported by autologous stem cell transplantation and the widespread use of maintenance therapies. Novel therapeutic options, especially in the field of immunotherapy, are currently explored in clinical trials and have the potential to further improve outcomes for patients with high-risk multiple myeloma.

Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma

PubMed Central

Vasir, Baldev; Uhl, Lynne; Blotta, Simona; MacNamara, Claire; Somaiya, Poorvi; Wu, Zekui; Joyce, Robin; Levine, James D.; Dombagoda, Dilani; Yuan, Yan Emily; Francoeur, Karen; Fitzgerald, Donna; Richardson, Paul; Weller, Edie; Anderson, Kenneth; Kufe, Donald; Munshi, Nikhil; Avigan, David

2011-01-01

We have developed a tumor vaccine in which patient-derived myeloma cells are chemically fused with autologous dendritic cells (DCs) such that a broad spectrum of myeloma-associated antigens are presented in the context of DC-mediated costimulation. We have completed a phase 1 study in which patients with multiple myeloma underwent serial vaccination with the DC/multiple myeloma fusions in conjunction with granulocyte-macrophage colony-stimulating factor. DCs were generated from adherent mononuclear cells cultured with granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor-α and fused with myeloma cells obtained from marrow aspirates. Vaccine generation was successful in 17 of 18 patients. Successive cohorts were treated with 1 × 106, 2 × 106, and 4 × 106 fusion cells, respectively, with 10 patients treated at the highest dose level. Vaccination was well tolerated, without evidence of dose-limiting toxicity. Vaccination resulted in the expansion of circulating CD4 and CD8 lymphocytes reactive with autologous myeloma cells in 11 of 15 evaluable patients. Humoral responses were documented by SEREX (Serologic Analysis of Recombinant cDNA Expression Libraries) analysis. A majority of patients with advanced disease demonstrated disease stabilization, with 3 patients showing ongoing stable disease at 12, 25, and 41 months, respectively. Vaccination with DC/multiple myeloma fusions was feasible and well tolerated and resulted in antitumor immune responses and disease stabilization in a majority of patients. PMID:21030562

Osteosclerotic myeloma with polyneuropathy and hypocalcemia.

PubMed

Ludescher, C; Grünewald, K; Fend, F; Dietze, O; Thaler, J; Schmid, K W

1989-04-01

A case is presented of a 46-year-old man with multifocal osteosclerotic bone lesions, peripheral polyneuropathy and hypocalcemia. Histologic examination of a bone marrow biopsy disclosed a multiple myeloma. Immunoelectrophoresis revealed a small M-component identified as IgG-lambda. Osteosclerotic myeloma lacking any osteolytic lesions seems to be very rare and shows several different features as compared with classical myeloma. A review of the current literature suggests that multiple myeloma is not a uniform disease but rather a group of clinical syndromes characterized by the special properties of their proliferating plasma cell clones.

Interleukin-6 counteracts therapy-induced cellular oxidative stress in multiple myeloma by up-regulating manganese superoxide dismutase.

PubMed

Brown, Charles O; Salem, Kelley; Wagner, Brett A; Bera, Soumen; Singh, Neeraj; Tiwari, Ajit; Choudhury, Amit; Buettner, Garry R; Goel, Apollina

2012-06-15

IL (interleukin)-6, an established growth factor for multiple myeloma cells, induces myeloma therapy resistance, but the resistance mechanisms remain unclear. The present study determines the role of IL-6 in re-establishing intracellular redox homoeostasis in the context of myeloma therapy. IL-6 treatment increased myeloma cell resistance to agents that induce oxidative stress, including IR (ionizing radiation) and Dex (dexamethasone). Relative to IR alone, myeloma cells treated with IL-6 plus IR demonstrated reduced annexin/propidium iodide staining, caspase 3 activation, PARP [poly(ADP-ribose) polymerase] cleavage and mitochondrial membrane depolarization with increased clonogenic survival. IL-6 combined with IR or Dex increased early intracellular pro-oxidant levels that were causally related to activation of NF-κB (nuclear factor κB) as determined by the ability of N-acetylcysteine to suppress both pro-oxidant levels and NF-κB activation. In myeloma cells, upon combination with hydrogen peroxide treatment, relative to TNF (tumour necrosis factor)-α, IL-6 induced an early perturbation in reduced glutathione level and increased NF-κB-dependent MnSOD (manganese superoxide dismutase) expression. Furthermore, knockdown of MnSOD suppressed the IL-6-induced myeloma cell resistance to radiation. MitoSOX Red staining showed that IL-6 treatment attenuated late mitochondrial oxidant production in irradiated myeloma cells. The present study provides evidence that increases in MnSOD expression mediate IL-6-induced resistance to Dex and radiation in myeloma cells. The results of the present study indicate that inhibition of antioxidant pathways could enhance myeloma cell responses to radiotherapy and/or chemotherapy.

Interleukin-6 counteracts therapy-induced cellular oxidative stress in multiple myeloma by up-regulating manganese superoxide dismutase

PubMed Central

Brown, Charles O.; Salem, Kelley; Wagner, Brett A.; Bera, Soumen; Singh, Neeraj; Tiwari, Ajit; Choudhury, Amit; Buettner, Garry R.; Goel, Apollina

2012-01-01

IL (interleukin)-6, an established growth factor for multiple myeloma cells, induces myeloma therapy resistance, but the resistance mechanisms remain unclear. The present study determines the role of IL-6 in re-establishing intracellular redox homoeostasis in the context of myeloma therapy. IL-6 treatment increased myeloma cell resistance to agents that induce oxidative stress, including IR (ionizing radiation) and Dex (dexamethasone). Relative to IR alone, myeloma cells treated with IL-6 plus IR demonstrated reduced annexin/propidium iodide staining, caspase 3 activation, PARP [poly(ADP-ribose) polymerase] cleavage and mitochondrial membrane depolarization with increased clonogenic survival. IL-6 combined with IR or Dex increased early intracellular pro-oxidant levels that were causally related to activation of NF-κB (nuclear factor κB) as determined by the ability of N-acetylcysteine to suppress both pro-oxidant levels and NF-κB activation. In myeloma cells, upon combination with hydrogen peroxide treatment, relative to TNF (tumour necrosis factor)-α, IL-6 induced an early perturbation in reduced glutathione level and increased NF-κB-dependent MnSOD (manganese superoxide dismutase) expression. Furthermore, knockdown of MnSOD suppressed the IL-6-induced myeloma cell resistance to radiation. MitoSOX Red staining showed that IL-6 treatment attenuated late mitochondrial oxidant production in irradiated myeloma cells. The present study provides evidence that increases in MnSOD expression mediate IL-6-induced resistance to Dex and radiation in myeloma cells. The results of the present study indicate that inhibition of antioxidant pathways could enhance myeloma cell responses to radiotherapy and/or chemotherapy. PMID:22471522

Polycythaemia: an unusual presentation of multiple myeloma.

PubMed

Hutchison, Elaine J; Taverna, Josephine A; Yu, Qi; Yeager, Andrew M

2016-09-20

In contrast to anaemia, polycythaemia is a distinctly uncommon finding in patients with multiple myeloma. We describe the presence of otherwise unexplained polycythaemia in a 57-year-old Caucasian man who was found to have IgG κ multiple myeloma. After treatment of myeloma, the polycythaemia resolved. We reviewed previous reports of polycythaemia associated with multiple myeloma and discuss potential pathophysiological mechanisms that link these 2 conditions. 2016 BMJ Publishing Group Ltd.

Second malignancies after multiple myeloma: from 1960s to 2010s

PubMed Central

Thomas, Anish; Mailankody, Sham; Korde, Neha; Kristinsson, Sigurdur Y.; Turesson, Ingemar

2012-01-01

Based on small numbers, recent reports from 3 randomized trials have consistently demonstrated more hematologic malignancies in patients treated with lenalidomide as maintenance (vs placebo). This fact has prompted concern and highlighted the association between multiple myeloma and second malignancies. Furthermore, an excess of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) after multiple myeloma has been known for over 4 decades. Most prior studies have been restricted because of small numbers of patients, inadequate follow-up, and limitations of ascertainment of second malignancies. Although the underlying biologic mechanisms of AML/MDS after multiple myeloma are unknown, treatment-related factors are presumed to be responsible. Recently, an excess risk of AML/MDS was found among 5652 patients with IgG/IgA (but not IgM) monoclonal gammopathy of undetermined significance, supporting a role for disease-related factors. Furthermore, there is evidence to suggest that polymorphisms in germline genes may contribute to a person's susceptibility to subsequent cancers, whereas the potential influence of environmental and behavioral factors remains poorly understood. This review discusses current knowledge regarding second malignancies after multiple myeloma and gives future directions for efforts designed to characterize underlying biologic mechanisms, with the goal to maximize survival and minimize the risk for second malignancies for individual patients. PMID:22310913

MRI features of extramedullary myeloma.

PubMed

Tirumani, Sree Harsha; Shinagare, Atul B; Jagannathan, Jyothi P; Krajewski, Katherine M; Munshi, Nikhil C; Ramaiya, Nikhil H

2014-04-01

The purpose of this study was to describe the MRI features of extramedullary myeloma and to evaluate the role of MRI in extramedullary myeloma. The cases of 28 patients (15 men, 13 women; mean age, 57.53 years; range, 34-83 years) with extramedullary myeloma who underwent MRI at one institution from January 2004 through December 2012 were retrospectively identified through an electronic search of an institutional radiology database. Two radiologists reviewed images from 44 MRI examinations in consensus to document the morphologic, signal-intensity, and enhancement characteristics of extramedullary myeloma. Electronic medical records were reviewed to document the indication for MRI and subsequent management of extramedullary myeloma. A total of 72 sites of extramedullary myeloma were noted, most commonly the paraspinal-epidural location (28/72, 39%). Two radiologic patterns were identified: lesions contiguous with bone (n = 44) and lesions noncontiguous with bone (n = 28). Lesions contiguous with bone were larger (p = 0.001; Student t test). Of 28 paraspinal-epidural lesions, 13 compressed the cord. Compared with skeletal muscle, most of the lesions were hypointense to isointense on T1-weighted images (67/72, 93.1%) and isointense to hyperintense on T2-weighted images (62/72, 86.1%). Lesions noncontiguous with bone were more often hypointense on T2-weighted images (8/28 vs 2/44; p = 0.006; Fisher exact test). Neurologic symptoms prompted MRI in most cases (n = 32/44). MRI was helpful in management by radiotherapy and surgery (19/28). Extramedullary myeloma can be contiguous or noncontiguous with bone. Lesions contiguous with bone are larger, often occur in a paraspinal or epidural location, and can cause cord compression. Lesions noncontiguous with bone can be T2 hypointense. MRI helps in treatment planning.

The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma.

PubMed

Tu, Yong-Sheng; He, Jin; Liu, Huan; Lee, Hans C; Wang, Hua; Ishizawa, Jo; Allen, Joshua E; Andreeff, Michael; Orlowski, Robert Z; Davis, Richard E; Yang, Jing

2017-10-01

In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for new drugs that can overcome drug resistance and prolong patient survival after failure of standard therapies. The imipridone ONC201 causes downstream inactivation of ERK1/2 signaling and has tumoricidal activity against a variety of tumor types, while its efficacy in preclinical models of myeloma remains unclear. In this study, we treated human myeloma cell lines and patient-derived tumor cells with ONC201. Treatment decreased cellular viability and induced apoptosis in myeloma cell lines, with IC50 values of 1 to 1.5 μM, even in those with high risk features or TP53 loss. ONC201 increased levels of the pro-apoptotic protein Bim in myeloma cells, resulting from decreased phosphorylation of degradation-promoting Bim Ser69 by ERK1/2. In addition, myeloma cell lines made resistant to several standard-of-care agents (by chronic exposure) were equally sensitive to ONC201 as their drug-naïve counterparts, and combinations of ONC201 with proteasome inhibitors had synergistic anti-myeloma activity. Overall, these findings demonstrate that ONC201 kills myeloma cells regardless of resistance to standard-of-care therapies, making it promising for clinical testing in relapsed/refractory myeloma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Myeloma

MedlinePlus

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The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective

PubMed Central

Fernández de Larrea, Carlos; Leleu, Xavier; Heusschen, Roy; Zojer, Niklas; Decaux, Olivier; Kastritis, Efstathios; Minnema, Monique; Jurczyszyn, Artur; Beguin, Yves; Wäsch, Ralph; Palumbo, Antonio; Dimopoulos, Meletios; Mateos, Maria Victoria; Ludwig, Heinz; Engelhardt, Monika

2016-01-01

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammopathy of undetermined significance to multiple myeloma (MM), based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related events and better overall survival among patients with high-risk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention, although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use. Risk factors have now been defined, and a subset of ultra-high-risk patients have been reclassified by the International Myeloma Working Group as MM, and thus will require optimal MM treatment, based on biomarkers that identify patients with a >80% risk of progression. The number of these redefined patients is small (∼10%), but important to unravel, because their risk of progression to overt MM is substantial (≥80% within 2 years). Patients with a high-risk cytogenetic profile are not yet considered for early treatment, because groups are heterogeneous and risk factors other than cytogenetics are deemed to weight higher. Because patients with ultra-high-risk SMM are now considered as MM and may be treated as such, concerns exist that earlier therapy may increase the risk of selecting resistant clones and induce side effects and costs. Therefore, an even more accurate identification of patients who would benefit from interventions needs to be performed, and clinical judgment and careful discussion of pros and cons of treatment initiation need to be undertaken. For the majority of SMM patients, the standard of care remains observation until development of symptomatic MM occurs, encouraging participation in ongoing and upcoming SMM/early MM clinical trials, as well as consideration of bisphosphonate use in

Management of multiple myeloma in resource-constrained settings.

PubMed

Kumar, Lalit; Kumar Sahoo, Ranjit

2016-12-01

The prognosis of patients with multiple myeloma (MM) has improved significantly in the past two decades. This is attributed to use of novel agents for induction, high-dose chemotherapy and autologous stem cell transplantation (ASCT), maintenance therapy, and improved supportive care. Currently, evidence-based management guidelines/recommendations developed by International societies/groups are being followed partially in low-resource settings. Lack of quality diagnostics (eg, cytogenetics/fluorescence in situ hybridization (FISH), serum free light chains), novel therapeutics, and trained manpower, and limited financial resources are key challanges. An optimal utilization of available resources with continued educational activities of treating physicians focused on improving knowledge in the management of such patients may be a way forward to improve the outcome of myeloma patients in these countries. Our current approach to the management of this disease is presented here through a discussion of clinical vignettes. Copyright © 2016 Elsevier Inc. All rights reserved.

Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells.

PubMed

Evans, Robert; Naber, Claudia; Steffler, Tara; Checkland, Tamara; Keats, Jonathan; Maxwell, Christopher; Perry, Troy; Chau, Heidi; Belch, Andrew; Pilarski, Linda; Reiman, Tony

2008-03-01

The expression of RHAMM and other centrosome-associated genes are known to correlate with the extent of centrosome amplification in multiple myeloma, and with poor prognosis. RHAMM has a significant interaction with TPX2, a protein which regulates the localization and action of Aurora A kinase (AURKA) at the spindle poles. AURKA is known to be a central determinant of centrosome and spindle function and is a target for cancer therapy. Given these observations, we investigated the role of Aurora kinases as therapeutic targets in myeloma. Here we report that AURKA is expressed ubiquitously in myeloma, to varying degrees, in both cell lines and patients' bone marrow plasma cells. siRNA targeting AURKA induces apoptotic cell death in myeloma cell lines. The Aurora kinase inhibitor VE-465 also induces apoptosis and death in myeloma cell lines and primary myeloma plasma cells. The combination of VE-465 and dexamethasone improves cell killing compared with the use of either agent alone, even in cells resistant to the single agents. The phenotype of myeloma cells treated with VE-465 is consistent with published reports on the effects of Aurora kinase inhibition. Aurora kinase inhibitors should be pursued as potential treatments for myeloma.

Role of active drug transporters in refractory multiple myeloma.

PubMed

Tucci, Marco; Quatraro, Cosima; Dammacco, Franco; Silvestris, Franco

2009-01-01

Drug resistance is a major drawback for cancer chemotherapy protocols and previous studies have demonstrated the overexpression of the P-glycoprotein (P-gp) as mechanism by which myeloma cells develop multidrug resistance (MDR). However, other molecules may apparently promote MDR in multiple myeloma (MM). They include both lung resistance-related protein (LRP) and p53 activation. The inhibition of P-gp in MM patients treated with melphalan (PAM) has been associated to increased toxicity, whereas defective apoptosis due to down-modulation of the NF-kB is a feature of MDR+ myeloma cells. On the contrary, clinical trials with proteasome inhibitors have been successfully carried out to overcome MDR despite their toxicity profile. Recently, sigma receptors (sigmaR)(S), namely sigmaR(1) and sigmaR(2), have been found to be overexpressed in breast cancer cells. In addition, their levels correlate with both P-gp upregulation and MDR development. By contrast, selective inhibitors of sigmaR(S) as PB28, disrupt the P-gp signals and restore the apoptosis machinery in malignant cells. We have reviewed the major pathogenetic events promoting MDR in MM and focused on the sigmaR(S) as potential mechanism driving this function. We demonstrate that MDR+ myeloma cells overexpress the sigmaR(2) and that the treatment with PB28 induces P-gp down-modulation through the activation of the caspases enrolled in both extrinsic and intrinsic apoptotic pathways. Thus, sigmaR(2) inhibitors may be tentatively proposed for the treatment of PAM-resistant MM patients.

Multiple myeloma.

PubMed Central

MacLennan, I. C.; Drayson, M.; Dunn, J.

1994-01-01

Multiple myeloma occurs in over 2000 new patients in England and Wales each year. It presents most frequently as bone pain and patients tend to become dehydrated and may develop renal failure. No available treatment is curative, but about two thirds of patients achieve a stable response with low dose combination chemotherapy. Combination chemotherapy including doxorubicin and carmustine with the alkylating agents cyclophosphamide and melphalan achieve a higher stable response rate than conventional treatment with melphalan and prednisone without additional haematological toxicity. These responses are associated with loss of bone pain and patients remain symptom free for months without further treatment. Relapse occurs on average in a little under two years and, though second responses are frequently obtained, the disease eventually becomes refractory. This paper looks at who should be treated and the benefits that may be expected from the treatments available. PMID:8068084

Magic year for multiple myeloma therapeutics: Key takeaways from the ASH 2015 annual meeting.

PubMed

Zhang, Kejie; Desai, Aakash; Zeng, Dongfeng; Gong, Tiejun; Lu, Peihua; Wang, Michael

2017-02-07

Despite the availability of various anticancer agents, Multiple Myeloma (MM) remains incurable in most cases, along with high relapse rate in the patients treated with these agents. The year 2015 saw major advancements in our battle against multiple myeloma. In 2015, the U.S. Food and Drug Administration (FDA) approved three new therapies for multiple myeloma, namely Ixazomib (an oral proteasome inhibitor), Daratumumab and Elotuzumab (monoclonal antibodies against CD38 and SLAMF7 respectively). The purpose of this review is to provide a detailed analysis of these aforementioned breakthrough therapies and two other newer agents, Filanesib (kinesis spindle inhibitor) and selinexor (SINE inhibitor), presented at the 2015 annual meeting of American Society of Hematology (ASH). We also describe the role of agents targeting PD-1 axis and chimeric antigen receptor T (CAR-T) cells in the treatment of MM.

Biological Effects of the Pim Kinase Inhibitor, SGI-1776, in Multiple Myeloma

PubMed Central

Cervantes-Gomez, Fabiola; Chen, Lisa S.; Orlowski, Robert Z.; Gandhi, Varsha

2013-01-01

Pim kinases are constitutively active serine/threonine/tyrosine kinases that are overexpressed in hematological malignancies such as multiple myeloma. Pim kinase substrates are involved in transcription, protein translation, cell proliferation, and apoptosis. SGI-1776 is a potent Pim kinase inhibitor that has proven to be cytotoxic to leukemia and lymphoma cells. Based on this background, we hypothesized that SGI-1776 treatment would result in myeloma cytotoxicity. To test this, myeloma cell lines and primary CD138+ cells from myeloma patients were treated with SGI-1776 in a dose- and time-dependent manner and effect on cell death and proliferation, induction of autophagy, as wells as changes in cell cycle profile were measured. SGI-1776 treatment resulted in limited apoptosis in cell lines (mean 30%) and CD138+ cells (<10%) as assessed by Annexin-V/PI. Limited effect was observed in cell cycle profile or growth in cell lines. However, DNA synthesis was decreased by 70% at 3 μM (all time points) in U266 though this was not observed in MM.1S. In accordance, immunoblot analyses revealed no change in transcription (c-Myc and H3), or apoptotic (Bad) proteins that are substrates of Pim kinases. In contrast, autophagy, as assessed by acridine orange staining, was induced with SGI-1776 treatment in both cell lines (U266 25-70%; MM.1S 8-52%) and CD138+ cells (19-21%). Immunoblot analyses of autophagy LC3b marker and translation initiation proteins (phospho p70S6K and 4E-BP1) corroborated autophagy induction. These data indicate that SGI-1776 treatment in myeloma cell lines and CD138+ myeloma cells elicits its deleterious effects through inhibition of translation and induction of autophagy. PMID:23988451

Biological effects of the Pim kinase inhibitor, SGI-1776, in multiple myeloma.

PubMed

Cervantes-Gomez, Fabiola; Chen, Lisa S; Orlowski, Robert Z; Gandhi, Varsha

2013-09-01

Pim kinases are constitutively active serine/threonine/tyrosine kinases that are overexpressed in hematological malignancies such as multiple myeloma. Pim kinase substrates are involved in transcription, protein translation, cell proliferation, and apoptosis. SGI-1776 is a potent Pim kinase inhibitor that has proven to be cytotoxic to leukemia and lymphoma cells. Based on this background, we hypothesized that SGI-1776 treatment would result in myeloma cytotoxicity. To test this, myeloma cell lines and primary CD138(+) cells from myeloma patients were treated with SGI-1776 in a dose- and time-dependent manner, and effect on cell death and proliferation, induction of autophagy, and changes in cell cycle profile were measured. SGI-1776 treatment resulted in limited apoptosis in cell lines (mean 30%) and CD138(+) cells (< 10%) assessed using Annexin-V/propidium iodide. Limited effect was observed in cell cycle profile or growth in cell lines. However, DNA synthesis was decreased by 70% at 3 μM (all time points) in U266 though this was not observed in MM.1S. In accordance, immunoblot analyses revealed no change in transcription (c-Myc and H3), or apoptotic (Bad) proteins that are substrates of Pim kinases. In contrast, autophagy, assessed using acridine orange staining, was induced with SGI-1776 treatment in both cell lines (U266, 25%-70%; MM.1S, 8%-52%) and CD138(+) cells (19%-21%). Immunoblot analyses of the autophagy LC3b marker and translation initiation proteins (phospho-p70S6K and 4E-BP1) corroborated autophagy induction. These data indicate that SGI-1776 treatment in myeloma cell lines and CD138(+) myeloma cells elicits its deleterious effects through inhibition of translation and induction of autophagy. Copyright © 2013 Elsevier Inc. All rights reserved.

Paraneoplastic Sarcoidosis in Multiple Myeloma.

PubMed

Kusaba, Kana; Kojima, Kensuke; Naito, Shinji; Taba, Mitsuru; Kai, Keita; Ureshino, Hiroshi; Nishida, Yuki; Kimura, Shinya

2017-01-01

Sarcoidosis predominantly affects the lungs, intrathoracic lymph nodes, and eyes; it less frequently affects the musculoskeletal system. We herein report a case of paraneoplastic sarcoidosis in a patient presenting with multiple myeloma. The patient developed ocular sarcoidosis and showed an increased 18 F-fluorodeoxyglucose uptake in the mediastinal lymph nodes and vertebral column. A lymph node specimen showed the histological features of sarcoidosis, while an examination of the vertebral tumor revealed myeloma. Although the simultaneous occurrence of sarcoidosis and myeloma is extremely rare, our case indicates the importance of exculing any underlying malignancies before establishing a diagnosis of skeletal sarcoidosis when bone lesions are observed at unusual sites.

Diagnosis and Treatment of Bone Disease in Multiple Myeloma: Spotlight on Spinal Involvement

PubMed Central

Tosi, Patrizia

2013-01-01

Bone disease is observed in almost 80% of newly diagnosed symptomatic multiple myeloma patients, and spine is the bone site that is more frequently affected by myeloma-induced osteoporosis, osteolyses, or compression fractures. In almost 20% of the cases, spinal cord compression may occur; diagnosis and treatment must be carried out rapidly in order to avoid a permanent sensitive or motor defect. Although whole body skeletal X-ray is considered mandatory for multiple myeloma staging, magnetic resonance imaging is presently considered the most appropriate diagnostic technique for the evaluation of vertebral alterations, as it allows to detect not only the exact morphology of the lesions, but also the pattern of bone marrow infiltration by the disease. Multiple treatment modalities can be used to manage multiple myeloma-related vertebral lesions. Surgery or radiotherapy is mainly employed in case of spinal cord compression, impending fractures, or intractable pain. Percutaneous vertebroplasty or balloon kyphoplasty can reduce local pain in a significant fraction of treated patients, without interfering with subsequent therapeutic programs. Systemic antimyeloma therapy with conventional chemotherapy or, more appropriately, with combinations of conventional chemotherapy and compounds acting on both neoplastic plasma cells and bone marrow microenvironment must be soon initiated in order to reduce bone resorption and, possibly, promote bone formation. Bisphosphonates should also be used in combination with antimyeloma therapy as they reduce bone resorption and prolong patients survival. A multidisciplinary approach is thus needed in order to properly manage spinal involvement in multiple myeloma. PMID:24381787

Salinization and Saline Environments

NASA Astrophysics Data System (ADS)

Vengosh, A.

2003-12-01

-arid zones. The increasing demand for water has created tremendous pressures on water resources that have resulted in lowering water level and increasing salinization. For example, in the Middle East salinity is the main factor that limits water utilization, and future prospects for water use in Israel, Palestinian Authority, and Jordan are overshadowed by the increasing salinization (Vengosh and Rosenthal, 1994; Salameh, 1996). The salinity problem has numerous grave economic, social, and political consequences, particularly in cross-boundary basins that are shared by different communities (e.g., Salinas Valley California; Vengosh et al., 2002a), friendly states (e.g., salinization of the Colorado River along Mexico-US border; Stanton et al., 2001), and hostile states (e.g., the Jordan River, Vengosh et al., 2001; Aral Basin, Weinthal, 2002; Euphrates River, Beaumont, 1996; and the Nile River, Ohlsson, 1995).Salinization of water resources also affects agricultural management. The type of irrigation water and its quality determine the salinity and fertility of the soil and eventually the quality of the underlying water resource. The use of treated wastewater or other marginal water (e.g., brackish water) depends on the salinity and the chemical composition of the water. Treated wastewater with high contents of chloride, sodium, and boron is suitable only for salt-tolerant crops and requires special treatment of the soil. Finally, high boron in irrigation water and consequently in soil water is also an important limiting factor for crops, as boron is an essential micronutrient for plants but becomes toxic at high levels (typically >0.75 mg L-1 in irrigation water).This chapter investigates the different mechanisms and geochemistry of salinization in different parts of the world. The role of the unsaturated zone in shaping the chemical composition of dryland salinization is discussed. Special emphasis is on the anthropogenic effects and to man-made fluids and reused water

Renal complications in multiple myeloma and related disorders: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board.

PubMed

Faiman, Beth M; Mangan, Patricia; Spong, Jacy; Tariman, Joseph D

2011-08-01

Kidney dysfunction is a common clinical feature of symptomatic multiple myeloma. Some degree of renal insufficiency or renal failure is present at diagnosis or will occur during the course of the disease and, if not reversed, will adversely affect overall survival and quality of life. Chronic insults to the kidneys from other illnesses, treatment, or multiple myeloma itself can further damage renal function and increase the risk for additional complications, such as anemia. Patients with multiple myeloma who have light chain (Bence Jones protein) proteinuria may experience renal failure or progress to end-stage renal disease (ESRD) and require dialysis because of light chain cast nephropathy. Kidney failure in patients with presumed multiple myeloma also may result from amyloidosis, light chain deposition disease, or acute tubular necrosis caused by nephrotoxic agents; therefore, identification of patients at risk for kidney damage is essential. The International Myeloma Foundation's Nurse Leadership Board has developed practice recommendations for screening renal function, identifying positive and negative contributing risk and environmental factors, selecting appropriate therapies and supportive care measures to decrease progression to ESRD, and enacting dialysis to reduce and manage renal complications in patients with multiple myeloma.

ARQ-197, a small-molecule inhibitor of c-Met, reduces tumour burden and prevents myeloma-induced bone disease in vivo.

PubMed

Lath, Darren L; Buckle, Clive H; Evans, Holly R; Fisher, Matthew; Down, Jenny M; Lawson, Michelle A; Chantry, Andrew D

2018-01-01

The receptor tyrosine kinase c-Met, its ligand HGF, and components of the downstream signalling pathway, have all been implicated in the pathogenesis of myeloma, both as modulators of plasma cell proliferation and as agents driving osteoclast differentiation and osteoblast inhibition thus, all these contribute substantially to the bone destruction typically caused by myeloma. Patients with elevated levels of HGF have a poor prognosis, therefore, targeting these entities in such patients may be of substantial benefit. We hypothesized that ARQ-197 (Tivantinib), a small molecule c-Met inhibitor, would reduce myeloma cell growth and prevent myeloma-associated bone disease in a murine model. In vitro we assessed the effects of ARQ-197 on myeloma cell proliferation, cytotoxicity and c-Met protein expression in human myeloma cell lines. In vivo we injected NOD/SCID-γ mice with PBS (non-tumour bearing) or JJN3 cells and treated them with either ARQ-197 or vehicle. In vitro exposure of JJN3, U266 or NCI-H929 cells to ARQ-197 resulted in a significant inhibition of cell proliferation and an induction of cell death by necrosis, probably caused by significantly reduced levels of phosphorylated c-Met. In vivo ARQ-197 treatment of JJN3 tumour-bearing mice resulted in a significant reduction in tumour burden, tumour cell proliferation, bone lesion number, trabecular bone loss and prevented significant decreases in the bone formation rate on the cortico-endosteal bone surface compared to the vehicle group. However, no significant differences on bone parameters were observed in non-tumour mice treated with ARQ-197 compared to vehicle, implying that in tumour-bearing mice the effects of ARQ-197 on bone cells was indirect. In summary, these res ults suggest that ARQ-197 could be a promising therapeutic in myeloma patients, leading to both a reduction in tumour burden and an inhibition of myeloma-induced bone disease.

Minocycline Reduces Spontaneous Hemorrhage in Mouse Models of Cerebral Amyloid Angiopathy

PubMed Central

Liao, Fan; Xiao, Qingli; Kraft, Andrew; Gonzales, Ernie; Perez, Ron; Greenberg, Steven M.; Holtzman, David; Lee, Jin-Moo

2015-01-01

Background and Purpose Cerebral Amyloid Angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage (ICH) in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and -9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine if spontaneous ICH could be reduced. Methods Tg2576 (n=16) and 5×FAD/ApoE4 knock-in mice (n=16), aged to 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, i.p.) or saline every other day for two months. Brains were extracted and stained with X-34 (to quantify amyloid), Perl’s blue (to quantify hemorrhage), and immunostained to examined Aβ load, gliosis (GFAP, Iba-1), and vascular markers of blood-brain-barrier integrity (ZO-1 and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes. Results Minocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5×FAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (MMP-9, Nox4, CD45, S-100b, Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls. Conclusions Minocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in two different mouse models of CAA, supporting the importance of MMP-related and inflammatory pathways in ICH pathogenesis. As an FDA-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related ICH. PMID:25944329

Acute myelofibrosis and acute lymphoblastic leukemia in an elderly patient with previously treated multiple myeloma.

PubMed

Gonzalez, Maria M; Kidd, Laura; Quesada, Jorge; Nguyen, Nghia; Chen, Lei

2013-01-01

Multiple myeloma (MM) is a plasma cell neoplasm involving the bone marrow with organ damage and/or a monoclonal protein (M-spike in the serum and/or urine). This neoplasm typically affects adults over the age of 50. Acute lymphoblastic leukemia (ALL) is a hematological disorder involving at least 20% lymphoblasts in the bone marrow of the B-cell lineage. Acute lymphoblastic leukemia most commonly affects young children with 75% of cases occurring in children less than 6 years old. This case report describes a patient diagnosed with MM in 2000 who achieved a complete remission in 2006 after chemotherapy. Four years later, the patient presented with sudden pancytopenia. A bone marrow biopsy was obtained revealing a B lymphoblastic leukemia in an extensively fibrotic marrow without evidence of MM. A diagnosis of ALL with myelofibrosis is rare in the adult population, acute myelofibrosis (AMF) is more commonly associated with myeloproliferative disorders, and the development of acute leukemia in myeloma is rare. To the best of our knowledge, the presence of MM, ALL, and myelofibrosis in one patient has never been reported.

Evaluating acetate metabolism for imaging and targeting in multiple myeloma

PubMed Central

Fontana, Francesca; Ge, Xia; Su, Xinming; Hathi, Deep; Xiang, Jingyu; Cenci, Simone; Civitelli, Roberto; Shoghi, Kooresh I.; Akers, Walter J.; D’avignon, Andre

2016-01-01

Purpose We hypothesized that in multiple myeloma cells (MMC), high membrane biosynthesis will induce acetate uptake in vitro and in vivo. Here, we studied acetate metabolism and targeting in MMC in vitro and tested the efficacy of 11C-acetate-PET (positron emission tomography) to detect and quantitatively image myeloma treatment response in vivo. Experimental design Acetate fate tracking using 13C-edited-1H NMR (nuclear magnetic resonance) was performed to study in vitro acetate uptake and metabolism in MMC. Effects of pharmacological modulation of acetate transport or acetate incorporation into lipids on MMC cell survival and viability were assessed. Preclinical mouse MM models of subcutaneous and bone tumors were evaluated using 11C-acetate-PET/CT imaging and tissue biodistribution. Results In vitro, NMR showed significant uptake of acetate by MMC, and acetate incorporation into intracellular metabolites and membrane lipids. Inhibition of lipid synthesis and acetate transport was toxic to MMC, while sparing resident bone cells or normal B cells. In vivo, 11C-acetate uptake by PET imaging was significantly enhanced in subcutaneous and bone MMC tumors compared to unaffected bone or muscle tissue. Likewise, 11C-acetate uptake was significantly reduced in MM tumors after treatment. Conclusions Uptake of acetate from the extracellular environment was enhanced in MMC and was critical to cellular viability. 11C-acetate-PET detected the presence of myeloma cells in vivo, including uptake in intramedullary bone disease. 11C-acetate-PET also detected response to therapy in vivo. Our data suggested that acetate metabolism and incorporation into lipids was crucial to MM cell biology and that 11C-acetate-PET is a promising imaging modality for MM. PMID:27486177

Young Adult and Usual Adult Body Mass Index and Multiple Myeloma Risk: A Pooled Analysis in the International Multiple Myeloma Consortium (IMMC).

PubMed

Birmann, Brenda M; Andreotti, Gabriella; De Roos, Anneclaire J; Camp, Nicola J; Chiu, Brian C H; Spinelli, John J; Becker, Nikolaus; Benhaim-Luzon, Véronique; Bhatti, Parveen; Boffetta, Paolo; Brennan, Paul; Brown, Elizabeth E; Cocco, Pierluigi; Costas, Laura; Cozen, Wendy; de Sanjosé, Silvia; Foretová, Lenka; Giles, Graham G; Maynadié, Marc; Moysich, Kirsten; Nieters, Alexandra; Staines, Anthony; Tricot, Guido; Weisenburger, Dennis; Zhang, Yawei; Baris, Dalsu; Purdue, Mark P

2017-06-01

Background: Multiple myeloma risk increases with higher adult body mass index (BMI). Emerging evidence also supports an association of young adult BMI with multiple myeloma. We undertook a pooled analysis of eight case-control studies to further evaluate anthropometric multiple myeloma risk factors, including young adult BMI. Methods: We conducted multivariable logistic regression analysis of usual adult anthropometric measures of 2,318 multiple myeloma cases and 9,609 controls, and of young adult BMI (age 25 or 30 years) for 1,164 cases and 3,629 controls. Results: In the pooled sample, multiple myeloma risk was positively associated with usual adult BMI; risk increased 9% per 5-kg/m 2 increase in BMI [OR, 1.09; 95% confidence interval (CI), 1.04-1.14; P = 0.007]. We observed significant heterogeneity by study design ( P = 0.04), noting the BMI-multiple myeloma association only for population-based studies ( P trend = 0.0003). Young adult BMI was also positively associated with multiple myeloma (per 5-kg/m 2 ; OR, 1.2; 95% CI, 1.1-1.3; P = 0.0002). Furthermore, we observed strong evidence of interaction between younger and usual adult BMI ( P interaction <0.0001); we noted statistically significant associations with multiple myeloma for persons overweight (25-<30 kg/m 2 ) or obese (30+ kg/m 2 ) in both younger and usual adulthood (vs. individuals consistently <25 kg/m 2 ), but not for those overweight or obese at only one time period. Conclusions: BMI-associated increases in multiple myeloma risk were highest for individuals who were overweight or obese throughout adulthood. Impact: These findings provide the strongest evidence to date that earlier and later adult BMI may increase multiple myeloma risk and suggest that healthy BMI maintenance throughout life may confer an added benefit of multiple myeloma prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 876-85. ©2017 AACR . ©2017 American Association for Cancer Research.

Multiple myeloma involving the cricoid cartilage.

PubMed

Floré, B; Hermans, R

2013-01-01

We present the case of a man with dyspnea due to a mass in the cricoid cartilage that turns out to be an extramedullary plasmocytoma. Although the patient has a history of multiple myeloma, the disease only rarely affects the cricoid cartilage. Other subglottic lesions possibly involving the cricoid cartilage are squamous cell carcinoma, chondroma, chondrosarcoma and metastasis. The imaging characteristics suggesting extramedullary plasmocytoma arising from the cricoid consist of thinning and expansion of the cartilage laminae without mucosal lesions nor soft tissue mass adjacent to the cricoid cartilage. The patient was successfully treated with radiation therapy and peroral steroids.

Nucleotide excision repair is a potential therapeutic target in multiple myeloma

PubMed Central

Szalat, R; Samur, M K; Fulciniti, M; Lopez, M; Nanjappa, P; Cleynen, A; Wen, K; Kumar, S; Perini, T; Calkins, A S; Reznichenko, E; Chauhan, D; Tai, Y-T; Shammas, M A; Anderson, K C; Fermand, J-P; Arnulf, B; Avet-Loiseau, H; Lazaro, J-B; Munshi, N C

2018-01-01

Despite the development of novel drugs, alkylating agents remain an important component of therapy in multiple myeloma (MM). DNA repair processes contribute towards sensitivity to alkylating agents and therefore we here evaluate the role of nucleotide excision repair (NER), which is involved in the removal of bulky adducts and DNA crosslinks in MM. We first evaluated NER activity using a novel functional assay and observed a heterogeneous NER efficiency in MM cell lines and patient samples. Using next-generation sequencing data, we identified that expression of the canonical NER gene, excision repair cross-complementation group 3 (ERCC3), significantly impacted the outcome in newly diagnosed MM patients treated with alkylating agents. Next, using small RNA interference, stable knockdown and overexpression, and small-molecule inhibitors targeting xeroderma pigmentosum complementation group B (XPB), the DNA helicase encoded by ERCC3, we demonstrate that NER inhibition significantly increases sensitivity and overcomes resistance to alkylating agents in MM. Moreover, inhibiting XPB leads to the dual inhibition of NER and transcription and is particularly efficient in myeloma cells. Altogether, we show that NER impacts alkylating agents sensitivity in myeloma cells and identify ERCC3 as a potential therapeutic target in MM. PMID:28588253

NCCN Guidelines Insights: Multiple Myeloma, Version 3.2018.

PubMed

Kumar, Shaji K; Callander, Natalie S; Alsina, Melissa; Atanackovic, Djordje; Biermann, J Sybil; Castillo, Jorge; Chandler, Jason C; Costello, Caitlin; Faiman, Matthew; Fung, Henry C; Godby, Kelly; Hofmeister, Craig; Holmberg, Leona; Holstein, Sarah; Huff, Carol Ann; Kang, Yubin; Kassim, Adetola; Liedtke, Michaela; Malek, Ehsan; Martin, Thomas; Neppalli, Vishala T; Omel, James; Raje, Noopur; Singhal, Seema; Somlo, George; Stockerl-Goldstein, Keith; Weber, Donna; Yahalom, Joachim; Kumar, Rashmi; Shead, Dorothy A

2018-01-01

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines. Copyright © 2018 by the National Comprehensive Cancer Network.

Progress in myeloma stem cells

PubMed Central

Cruz, Richard Dela; Tricot, Guido; Zangari, Maurizio; Zhan, Fenghuang

2011-01-01

Multiple myeloma (MM) is the second most common hematologic malignancy in the United States and affects about 4 in 100,000 Americans. Even though much progress has been made in MM therapy, MM remains an incurable disease for the vast majority of patients. The existence of MM stem cell is considered one of the major causes of MM drug-resistance, leading to relapse. This highlights the importance and urgency of developing approaches to target MM stem cells. However, very little is known about the molecular characteristics of the MM stem cells, which makes it difficult to target MM stem cells therapeutically. Evidence of the existence of a myeloma stem cell has been provided by Matsui et al. showing that the CD138- and CD20+ fraction, which is a minor population of the MM cells, has a greater clonogenic potential and has the phenotype of a memory B-cell (CD19+, CD27+). In this review, we report recent progress of cell surface markers in cancer stem cells, especially in myeloma and the molecular mechanisms related to drug resistance and myeloma disease progression. PMID:22432075

Anthropometric characteristics and risk of multiple myeloma.

PubMed

Blair, Cindy K; Cerhan, James R; Folsom, Aaron R; Ross, Julie A

2005-09-01

Few studies have examined obesity and risk for multiple myeloma, and the results are inconsistent. Laboratory evidence suggests mechanisms through which obesity could influence carcinogenesis of this hematopoietic malignancy. We examined the association between anthropometric characteristics and incident multiple myeloma in a prospective, population-based sample of 37,083 postmenopausal women. In 1986, the women completed a mailed questionnaire that included self-report of height and weight, and friend measurement of waist and hip circumferences. During 16 years of follow up, 95 cases of multiple myeloma were identified through linkage to the Iowa Cancer Registry. In an age-adjusted model, women in the highest category of several anthropometric measurements compared with the lowest category were at increased risk of developing multiple myeloma. For body mass index (kg/m), the rate ratio (95% confidence interval) was 1.5 (0.92-2.6); for weight, 1.9 (1.1-3.4); for waist circumference, 2.0 (1.1-3.5); and for hip circumference, 1.8 (1.0-3.0). Greater adiposity may increase the risk of multiple myeloma.

Novel therapy in multiple myeloma.

PubMed

Avilés, Agustin; Neri, Natividad; Nambo, M Jesús; Cleto, Sergio; Castañeda, Claudia; González, Martha; Talavera, Alejandra; Huerta-Guzmán, Judith

2005-10-01

Treatment in patients with multiple myeloma remain to be defined. Younger patients (defined as a cut-off level < 65 years old) will be treated with chemotherapy and transplant procedures. However, most patients > 65 years old are not candidates for this therapeutic approach and the use of intensive chemotherapy could be associated to severe toxicity. We developed an new, not-cytotoxic regimen with dexamethasone 30 mg/m(2), iv, days 1 to 4, all trans retinoic acid 45 mg/m(2), po, days 5 to 14 and interferon alfa 2a 4.5 MU, sc, daily, days 5 to 14 (DAI regimen) administered every 28 days in number of 6 cycles, at this point patients were restaging, if they showed complete response, objective response or partial response they were conducted to received thalidomide 100-200 mg po, daily and dexamethasone 10 mg/2, po days 1 to 4 at monthly intervals, for 18 months. Forty one patients were enrolled in an Phase II study. In an intent to treat analysis all patients were evaluable. Complete response was observed in 18 cases (43%), objective response in 10 patients (24%) and partial response in 5 patients (12%), overall response rate was 80%. Eight patients were considered failures. At an median of 36 months, no relapse of progression disease has been observed, thus actuarial curves at 3-years showed that event free survival is 100% and overall survival is 91%. Toxicity was mild, all patients received the planned dose in time. This regimen appear to be useful in older patients with multiple myeloma, the response rate is higher and toxicity was mild. Controlled clinical trials comparing with conventional chemotherapy will be conducted to define the role of this therapeutic approach.

International Myeloma Working Group recommendations for global myeloma care.

PubMed

Ludwig, H; Miguel, J S; Dimopoulos, M A; Palumbo, A; Garcia Sanz, R; Powles, R; Lentzsch, S; Ming Chen, W; Hou, J; Jurczyszyn, A; Romeril, K; Hajek, R; Terpos, E; Shimizu, K; Joshua, D; Hungria, V; Rodriguez Morales, A; Ben-Yehuda, D; Sondergeld, P; Zamagni, E; Durie, B

2014-05-01

Recent developments have led to remarkable improvements in the assessment and treatment of patients with multiple myeloma (MM). New technologies have become available to precisely evaluate the biology and extent of the disease, including information about cytogenetics and genetic abnormalities, extramedullary manifestations and minimal residual disease. New, more effective drugs have been introduced into clinical practice, which enable clinicians to significantly improve the outcome of patients but also pose new challenges for the prevention and management of their specific side effects. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of patients, as access to the most sophisticated advances may vary depending on local circumstances. Here, we propose the minimal requirements and possible options for diagnosis, monitoring and treatment of patients with multiple myeloma.

Multiple Myeloma

MedlinePlus

... a type of white blood cell called a plasma cell. Plasma cells help you fight infections by making antibodies ... Doctors know that myeloma begins with one abnormal plasma cell in your bone marrow — the soft, blood- ...

Plasmacytoma Infiltrating Leiomyoma in Multiple Myeloma

DTIC Science & Technology

2018-01-19

genital tract. Here, we report the case of a 55 year-old female with a history of multiple myeloma who presented with a six month history of...history of multiple myeloma who presented with a six month history of postmenopausal vaginal bleeding. Speculum exam revealed a mass protruding through

Economic and clinical impact of multiple myeloma to managed care.

PubMed

Cook, Richard

2008-09-01

Because of the development of novel agents such as immunomodulators, proteasome inhibitors, and bisphosphonates, the standards of care for the multiple myeloma (MM) patient have changed. The costs associated with current and emerging therapies, as well as supportive care, are significant and pose a tremendous financial burden to both patients and managed care. To review the economic impact of MM and to weigh the advantages and disadvantages of current treatments in bringing value for prolonged life versus the cost of treatment. This chapter will also discuss the need for thorough data review and pharmacoeconomic analyses to determine the most cost-effective therapies. Although MM accounts for only a small percentage of all cancer types, the costs associated with treating and managing it are among the highest. Recent developments in diagnosing, treating, and managing myeloma have led to novel treatment strategies. Immunomodulators, proteasome inhibitors, and bisphosphonates are improving response rates and preserving quality of life. However, these agents are not replacing older treatment modalities, but being used in addition to them. Intensive chemotherapy, stem cell transplantation, and supportive care are all important components in achieving treatment goals. Costs associated with stem cell transplants and complications of the disease add to the economic burden of myeloma. Additional costs for routine diagnostics to measure the progression of the disease or response to treatment need to be considered. Complications (e.g., lytic bone disease, infection, anemia, and renal failure) also add to morbidity and mortality, thus increasing the burden to the patient and the health care system as a whole. Financial and time constraints of caregivers must also be considered, as well as the added administrative burdens to health care providers. New standards of care in the treatment and management of myeloma are likely to lead to significant increases in costs. Although

[Multiple myeloma: current therapeutic approaches].

PubMed

Troussard, X; Bauduer, F; Leporrier, M

1992-01-01

The therapeutic strategy in multiple myeloma depends on age and tumor mass. Stage I must not be treated. The Melphalan Prednisone regimen is the reference for induction therapy because polychemotherapies are generally not superior. At this phase, the addition of Interferon alpha seems to be interesting. This drug has an important role during the steady-state phase. VAD represents the most efficient chemotherapy. Body hemi-irradiation is also useful. The analgesic effect and the decrease in the tumoral mass are the striking effects of this treatment. In young patients, high dose chemotherapy with bone marrow transplantation is proposed. Verapamil and anti-IL6 antibodies are currently being evaluated. Symptomatic treatment is essential in this non curable disease.

Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)

ClinicalTrials.gov

2018-06-25

Advanced Malignant Solid Neoplasm; Bladder Carcinoma; Breast Carcinoma; Cervical Carcinoma; Colon Carcinoma; Colorectal Carcinoma; Endometrial Carcinoma; Esophageal Carcinoma; Gastric Carcinoma; Glioma; Head and Neck Carcinoma; Kidney Carcinoma; Liver and Intrahepatic Bile Duct Carcinoma; Lung Carcinoma; Lymphoma; Malignant Uterine Neoplasm; Melanoma; Ovarian Carcinoma; Pancreatic Carcinoma; Plasma Cell Myeloma; Prostate Carcinoma; Rectal Carcinoma; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Cervical Carcinoma; Recurrent Colon Carcinoma; Recurrent Colorectal Carcinoma; Recurrent Esophageal Carcinoma; Recurrent Gastric Carcinoma; Recurrent Glioma; Recurrent Head and Neck Carcinoma; Recurrent Liver Carcinoma; Recurrent Lung Carcinoma; Recurrent Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Melanoma; Recurrent Ovarian Carcinoma; Recurrent Pancreatic Carcinoma; Recurrent Plasma Cell Myeloma; Recurrent Prostate Carcinoma; Recurrent Rectal Carcinoma; Recurrent Skin Carcinoma; Recurrent Thyroid Gland Carcinoma; Recurrent Uterine Corpus Carcinoma; Refractory Lymphoma; Refractory Malignant Solid Neoplasm; Refractory Plasma Cell Myeloma; Skin Carcinoma; Thyroid Gland Carcinoma; Uterine Corpus Cancer

Wogonin induces apoptosis in RPMI 8226, a human myeloma cell line, by downregulating phospho-Akt and overexpressing Bax.

PubMed

Zhang, Meng; Liu, Li-Ping; Chen, Yuling; Tian, Xiao-ying; Qin, Jian; Wang, Dongmei; Li, Zhi; Mo, Sui-Lin

2013-01-17

Wogonin is one of the major constituents derived from Scutellaria Baicalensis, which has been reported to inhibit cell growth and/or induce apoptosis in various cancer cell lines. We aim to investigate the anticancer effects and associated mechanisms of wogonin on human multiple myeloma cell line in vitro. Effects of wogonin on the proliferation, cell cycle progression, and apoptosis of human myeloma cells were examined in vitro. The proteins associated with the biological effects of wogonin were analyzed by immunoblotting and immunocytochemical staining. In addition, the binding mode of wogonin within crystal structure of Akt1 protein was also evaluated by molecular docking analysis using the CDOCKER algorithm in Discovery Studio. Myeloma cell growth was attenuated by wogonin (70.4-352.0 μM) in a concentration-dependent manner. Cell cycle progression analysis and TUNEL assay showed that apoptosis was enhanced in wogonin-treated cells. Increased apoptosis was accompanied by decreased level of total-PARP, the arisen of PARP cleavage, significantly increased level of Bax protein and decreased level of Bcl-2 protein. Akt activity was suppressed and phosphorylation of Ser 473 residue was decreased in the wogonin-treated cells. Molecular docking analysis revealed wogonin could be stably docked into the ligand binding domain of Akt1 protein, and presented unique features of binding to Akt1, which indicated detailed interaction between wogonin and Akt signaling pathway. As wogonin was effective in vitro in promotion of apoptosis of myeloma cell by Akt-modulated, Bax and Bcl-2 related intrinsic apoptotic pathway, wogonin may be a potential therapeutic agent against multiple myeloma. Copyright © 2012 Elsevier Inc. All rights reserved.

Neutral tumor evolution in myeloma is associated with poor prognosis.

PubMed

Johnson, David C; Lenive, Oleg; Mitchell, Jonathan; Jackson, Graham; Owen, Roger; Drayson, Mark; Cook, Gordon; Jones, John R; Pawlyn, Charlotte; Davies, Faith E; Walker, Brian A; Wardell, Christopher; Gregory, Walter M; Cairns, David; Morgan, Gareth J; Houlston, Richard S; Kaiser, Martin F

2017-10-05

Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcomes, we analyzed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase 3 trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory drug (IMiD) therapy. By analyzing mutant allele frequency distributions in tumors, we found that 17% to 20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in nonintensively treated patients, which is consistent with the reduced therapeutic efficacy of microenvironment-modulating IMiDs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcomes and personalizing therapy. © 2017 by The American Society of Hematology.

Extraskeletal multiple myeloma presenting with an atrial mass: a case report and a review of the literature.

PubMed

Vigo, Federica; Ciammella, Patrizia; Valli, Riccardo; Cagni, Elisabetta; Iotti, Cinzia

2012-08-10

Extraskeletal presentation at diagnosis or during the course of multiple myeloma is a rare event. The prognosis is usually very poor. At the moment there is no agreed gold standard for the treatment of this presentation. A 79-year-old Caucasian woman was treated at our hospital for right atrial myeloma localization. Our patient showed the following signs and symptoms of congestive heart failure: dyspnea, hypotension, cyanosis and facial edema. Surgery was not considered feasible due to the extent of the disease. Our patient underwent external-beam radiation therapy using an intensity modulated technique, thus obtaining a persistent complete remission. Our patient has been in continuous complete local remission for 25 months since the end of radiotherapy. The role of radiotherapy is not defined in multiple myeloma with extraskeletal presentation. Our regimen seems to be effective in controlling the disease in this patient.This case report adds to the existing literature as it describes an unusual presentation of the disease and a new therapeutic approach to this rare presentation of multiple myeloma.

Combined TRAF6 Targeting and Proteasome Blockade Has Anti-myeloma and Anti-Bone Resorptive Effects.

PubMed

Chen, Haiming; Li, Mingjie; Sanchez, Eric; Wang, Cathy S; Lee, Tiffany; Soof, Camilia M; Casas, Christian E; Cao, Jasmin; Xie, Colin; Udd, Kyle A; DeCorso, Kevin; Tang, George Y; Spektor, Tanya M; Berenson, James R

2017-05-01

TNF receptor-associated factor 6 (TRAF6) has been implicated in polyubiquitin-mediated IL1R/TLR signaling through activation of IκB kinase (IKK) to regulate the NF-κB and JNK signaling pathways. Here, TRAF6 protein was determined to be overexpressed in bone marrow mononuclear cells (BMMC) from patients with multiple myeloma. TRAF6 expression in BMMCs from patients with progressive disease is significantly elevated as compared with individuals in complete remission, with monoclonal gammopathy of undetermined significance, or healthy subjects. Furthermore, TRAF6 dominant-negative (TRAF6dn) peptides were constructed which specifically reduced TRAF6 signaling and activation of IKK. TRAF6 not only reduced cellular growth but also increased the apoptosis of multiple myeloma tumor cells in a concentration-dependent fashion. Because TRAF6 activates IKK through polyubiquitination, independent of its proteasome activity, a TRAF6dn peptide was combined with the proteasome inhibitors bortezomib or carfilzomib to treat multiple myeloma. Importantly, targeting of TRAF6 in the presence of proteasome inhibition enhanced anti-multiple myeloma effects and also decreased TLR/TRAF6/NF-κB-related signaling. Finally, TRAF6dn dose dependently inhibited osteoclast cell formation from CD14 + monocytes, induced with RANKL and mCSF , and markedly reduced bone resorption in dentin pits. In all, these data demonstrate that blocking TRAF6 signaling has anti-multiple myeloma effects and reduces bone loss. Implications: The ability to target TRAF6 signaling and associated pathways in multiple myeloma suggests a promising new therapeutic approach. Mol Cancer Res; 15(5); 598-609. ©2017 AACR . ©2017 American Association for Cancer Research.

A novel nano-immunoassay method for quantification of proteins from CD138-purified myeloma cells: biological and clinical utility

PubMed Central

Misiewicz-Krzeminska, Irena; Corchete, Luis Antonio; Rojas, Elizabeta A.; Martínez-López, Joaquín; García-Sanz, Ramón; Oriol, Albert; Bladé, Joan; Lahuerta, Juan-José; Miguel, Jesús San; Mateos, María-Victoria; Gutiérrez, Norma C.

2018-01-01

Protein analysis in bone marrow samples from patients with multiple myeloma has been limited by the low concentration of proteins obtained after CD138+ cell selection. A novel approach based on capillary nano-immunoassay could make it possible to quantify dozens of proteins from each myeloma sample in an automated manner. Here we present a method for the accurate and robust quantification of the expression of multiple proteins extracted from CD138-purified multiple myeloma samples frozen in RLT Plus buffer, which is commonly used for nucleic acid preservation and isolation. Additionally, the biological and clinical value of this analysis for a panel of 12 proteins essential to the pathogenesis of multiple myeloma was evaluated in 63 patients with newly diagnosed multiple myeloma. The analysis of the prognostic impact of CRBN/Cereblon and IKZF1/Ikaros mRNA/protein showed that only the protein levels were able to predict progression-free survival of patients; mRNA levels were not associated with prognosis. Interestingly, high levels of Cereblon and Ikaros proteins were associated with longer progression-free survival only in patients who received immunomodulatory drugs and not in those treated with other drugs. In conclusion, the capillary nano-immunoassay platform provides a novel opportunity for automated quantification of the expression of more than 20 proteins in CD138+ primary multiple myeloma samples. PMID:29545347

A novel nano-immunoassay method for quantification of proteins from CD138-purified myeloma cells: biological and clinical utility.

PubMed

Misiewicz-Krzeminska, Irena; Corchete, Luis Antonio; Rojas, Elizabeta A; Martínez-López, Joaquín; García-Sanz, Ramón; Oriol, Albert; Bladé, Joan; Lahuerta, Juan-José; Miguel, Jesús San; Mateos, María-Victoria; Gutiérrez, Norma C

2018-05-01

Protein analysis in bone marrow samples from patients with multiple myeloma has been limited by the low concentration of proteins obtained after CD138 + cell selection. A novel approach based on capillary nano-immunoassay could make it possible to quantify dozens of proteins from each myeloma sample in an automated manner. Here we present a method for the accurate and robust quantification of the expression of multiple proteins extracted from CD138-purified multiple myeloma samples frozen in RLT Plus buffer, which is commonly used for nucleic acid preservation and isolation. Additionally, the biological and clinical value of this analysis for a panel of 12 proteins essential to the pathogenesis of multiple myeloma was evaluated in 63 patients with newly diagnosed multiple myeloma. The analysis of the prognostic impact of CRBN /Cereblon and IKZF1 /Ikaros mRNA/protein showed that only the protein levels were able to predict progression-free survival of patients; mRNA levels were not associated with prognosis. Interestingly, high levels of Cereblon and Ikaros proteins were associated with longer progression-free survival only in patients who received immunomodulatory drugs and not in those treated with other drugs. In conclusion, the capillary nano-immunoassay platform provides a novel opportunity for automated quantification of the expression of more than 20 proteins in CD138 + primary multiple myeloma samples. Copyright © 2018 Ferrata Storti Foundation.

Amifostine reduces gastro-intestinal toxicity after autologous transplantation for multiple myeloma.

PubMed

Malek, Ehsan; Gupta, Vinita; Creger, Richard; Caimi, Paolo; Vatsayan, Anant; Covut, Fahrettin; Bashir, Qaiser; Champlin, Richard; Delgado, Ruby; Rondon, Gabriela; Cooper, Brenda; de Lima, Marcos; Lazarus, Hillard M; Qazilbash, Muzaffar

2018-01-02

High-dose melphalan (HDM) followed by autologous hematopoietic cell transplantation (auto-HCT) remains the standard-of-care therapy for multiple myeloma (MM) even with the availability of proteasome inhibitors and immunomodulatory drugs. Gastrointestinal (GI) toxicity is the main cause of morbidity after HDM. Amifostine, a cytoprotective agent, may reduce HDM-associated GI toxicity. We conducted a case control study comparing HDM + auto-HCT with or without amifostine for MM patients. One hundred and seven patients treated at University Hospitals Cleveland Medical Center who received pre-transplant amifostine were compared to 114 patients treated at MD Anderson Cancer Center without use of this agent. Amifostine 740 mg/m 2 was administered as a bolus infusion at 24 h and 15 min before HDM. Patients' characteristics were similar in both the groups. Amifostine therapy was well tolerated without any significant adverse effects. Grade II or greater oral mucositis (27.1% vs 47.4%; p = .002), nausea (31.8% vs. 86.0%; p = .0001), vomiting (18.7% vs. 52.6%; p = .0001) and diarrhea (56.1% vs. 72.7%; p = .006) occurred less frequently in the amifostine-treated group. There was no discernable effect of amifostine on engraftment, progression-free or overall survival. Our results indicate that amifostine decreases GI toxicity while preserving anti-myeloma efficacy of HDM and auto-HCT.

International Myeloma Working Group Consensus Statement for the Management, Treatment, and Supportive Care of Patients With Myeloma Not Eligible for Standard Autologous Stem-Cell Transplantation

PubMed Central

Palumbo, Antonio; Rajkumar, S. Vincent; San Miguel, Jesus F.; Larocca, Alessandra; Niesvizky, Ruben; Morgan, Gareth; Landgren, Ola; Hajek, Roman; Einsele, Hermann; Anderson, Kenneth C.; Dimopoulos, Meletios A.; Richardson, Paul G.; Cavo, Michele; Spencer, Andrew; Stewart, A. Keith; Shimizu, Kazuyuki; Lonial, Sagar; Sonneveld, Pieter; Durie, Brian G.M.; Moreau, Philippe; Orlowski, Robert Z.

2014-01-01

Purpose To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. Methods A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Results Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. Conclusion These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice. PMID:24419113

Targeting MET kinase with the small-molecule inhibitor amuvatinib induces cytotoxicity in primary myeloma cells and cell lines

PubMed Central

2013-01-01

Background MET is a receptor tyrosine kinase that is activated by the ligand HGF and this pathway promotes cell survival, migration, and motility. In accordance with its oncogenic role, MET is constitutively active, mutated, or over-expressed in many cancers. Corollary to its impact, inhibition of MET kinase activity causes reduction of the downstream signaling and demise of cells. In myeloma, a B-cell plasma malignancy, MET is neither mutated nor over-expressed, however, HGF is increased in plasma or serum obtained from myeloma patients and this was associated with poor prognosis. The small-molecule, amuvatinib, inhibits MET receptor tyrosine kinase. Based on this background, we hypothesized that targeting the HGF/MET signaling pathway is a rational approach to myeloma therapy and that myeloma cells would be sensitive to amuvatinib. Methods Expression of MET and HGF mRNAs in normal versus malignant plasma cells was compared during disease progression. Cell death and growth as well as MET signaling pathway were assessed in amuvatinib treated primary myeloma cells and cell lines. Results There was a progressive increase in the transcript levels of HGF (but not MET) from normal plasma cells to refractory malignant plasma cells. Amuvatinib readily inhibited MET phosphorylation in primary CD138+ cells from myeloma patients and in concordance, increased cell death. A 48-hr amuvatinib treatment in high HGF-expressing myeloma cell line, U266, resulted in growth inhibition. Levels of cytotoxicity were time-dependent; at 24, 48, and 72 h, amuvatinib (25 μM) resulted in 28%, 40%, and 55% cell death. Consistent with these data, there was an amuvatinib-mediated decrease in MET phosphorylation in the cell line. Amuvatinib at concentrations of 5, 10, or 25 μM readily inhibited HGF-dependent MET, AKT, ERK and GSK-3-beta phosphorylation. MET-mediated effects were not observed in myeloma cell line that has low MET and/or HGF expression. Conclusions These data suggest that at

[Development of a standardized guide for optimizing drug adherence information to be dispensed during a pharmaceutical counseling with a multiple myeloma patient: Initial validation].

PubMed

Favier-Archinard, Camille; Leguelinel-Blache, Géraldine; Dubois, Florent; Le Gall, Tanguy; Bourquard, Pascal; Passemard, Nadège; Tora, Sandrine; Rey, Aurélie; Rossi, Marie; Chevallier, Thierry; Cousin, Christelle; Favier, Mireille

2018-05-01

The safety of the community treatment with oral anticancer therapies is a strong theme of the cancer plan 2014-2019. The objective of this study was to develop a Pharmaceutical Counseling Guide to improve medication adherence in patients treated for multiple myeloma with oral anticancer therapies. A multidisciplinary professional working group selected a list of relevant medication adherence-related items that served as the framework for the design of the pharmaceutical counseling support materials in patient-accessible language. The readability, understanding and memorization of the information were validated in ten patients treated for myeloma. Twelve items were selected for treatment information (5 items), treatment planning (5 items), and adverse drug effects (2 items). A pharmacist guide, a patient guide, a medication schedule, and three self-questionnaires to evaluate medication knowledge and understanding of patients were developed. The patient test resulted in changes in these documents. This study carried out the initial validation of documents to standardize the pharmaceutical counseling for patients treated for myeloma so that it can be reproduced from one patient to another regardless of the pharmacist, by standardizing the information issued. This study needs to be completed by a final validation in myeloma patients, free from oral anticancer therapies. Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma

PubMed Central

Bordini, Jessica; Bertilaccio, Maria Teresa Sabrina; Ponzoni, Maurilio; Fermo, Isabella; Chesi, Marta; Bergsagel, P. Leif; Camaschella, Clara; Campanella, Alessandro

2015-01-01

Multiple myeloma is a malignant disorder characterized by bone marrow proliferation of plasma cells and by overproduction of monoclonal immunoglobulin detectable in the sera (M-spike). Anemia is a common complication of multiple myeloma, but the underlying pathophysiological mechanisms have not been completely elucidated. We aimed to identify the different determinants of anemia using the Vk*MYC mouse, which spontaneously develops an indolent bone marrow localized disease with aging. Affected Vk*MYC mice develop a mild normochromic normocytic anemia. We excluded the possibility that anemia results from defective erythropoietin production, inflammation or increased hepcidin expression. Mature erythroid precursors are reduced in Vk*MYC bone marrow compared with wild-type. Malignant plasma cells express the apoptogenic receptor Fas ligand and, accordingly, active caspase 8 is detected in maturing erythroblasts. Systemic iron homeostasis is not compromised in Vk*MYC animals, but high expression of the iron importer CD71 by bone marrow plasma cells and iron accumulation in bone marrow macrophages suggest that iron competition takes place in the local multiple myeloma microenvironment, which might contribute to anemia. In conclusion, the mild anemia of the Vk*MYC model is mainly related to the local effect of the bone marrow malignant clone in the absence of an overt inflammatory status. We suggest that this reproduces the initial events triggering anemia in patients. PMID:25715406

Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma.

PubMed

Bordini, Jessica; Bertilaccio, Maria Teresa Sabrina; Ponzoni, Maurilio; Fermo, Isabella; Chesi, Marta; Bergsagel, P Leif; Camaschella, Clara; Campanella, Alessandro

2015-06-01

Multiple myeloma is a malignant disorder characterized by bone marrow proliferation of plasma cells and by overproduction of monoclonal immunoglobulin detectable in the sera (M-spike). Anemia is a common complication of multiple myeloma, but the underlying pathophysiological mechanisms have not been completely elucidated. We aimed to identify the different determinants of anemia using the Vk*MYC mouse, which spontaneously develops an indolent bone marrow localized disease with aging. Affected Vk*MYC mice develop a mild normochromic normocytic anemia. We excluded the possibility that anemia results from defective erythropoietin production, inflammation or increased hepcidin expression. Mature erythroid precursors are reduced in Vk*MYC bone marrow compared with wild-type. Malignant plasma cells express the apoptogenic receptor Fas ligand and, accordingly, active caspase 8 is detected in maturing erythroblasts. Systemic iron homeostasis is not compromised in Vk*MYC animals, but high expression of the iron importer CD71 by bone marrow plasma cells and iron accumulation in bone marrow macrophages suggest that iron competition takes place in the local multiple myeloma microenvironment, which might contribute to anemia. In conclusion, the mild anemia of the Vk*MYC model is mainly related to the local effect of the bone marrow malignant clone in the absence of an overt inflammatory status. We suggest that this reproduces the initial events triggering anemia in patients. Copyright© Ferrata Storti Foundation.

Tissue inhibitor of metalloproteinases 1 enhances rod survival in the rd1 mouse retina.

PubMed

Kim, Hwa Sun; Vargas, Andrew; Eom, Yun Sung; Li, Justin; Yamamoto, Kyra L; Craft, Cheryl Mae; Lee, Eun-Jin

2018-01-01

Retinitis pigmentosa (RP), an inherited retinal degenerative disease, is characterized by a progressive loss of rod photoreceptors followed by loss of cone photoreceptors. Previously, when tissue inhibitor of metalloproteinase 1 (TIMP1), a key extracellular matrix (ECM) regulator that binds to and inhibits activation of Matrix metallopeptidase 9 (MMP9) was intravitreal injected into eyes of a transgenic rhodopsin rat model of RP, S334ter-line3, we discovered cone outer segments are partially protected. In parallel, we reported that a specific MMP9 and MMP2 inhibitor, SB-3CT, interferes with mechanisms leading to rod photoreceptor cell death in an MMP9 dependent manner. Here, we extend our initial rat studies to examine the potential of TIMP1 as a treatment in retinal degeneration by investigating neuroprotective effects in a classic mouse retinal degeneration model, rdPde6b-/- (rd1). The results clearly demonstrate that intravitreal injections of TIMP1 produce extended protection to delay rod photoreceptor cell death. The mean total number of rods in whole-mount retinas was significantly greater in TIMP-treated rd1 retinas (postnatal (P) 30, P35 (P<0.0001) and P45 (P<0.05) than in saline-treated rd1 retinas. In contrast, SB-3CT did not delay rod cell death, leading us to further investigate alternative pathways that do not involve MMPs. In addition to inducing phosphorylated ERK1/2, TIMP1 significantly reduces BAX activity and delays attenuation of the outer nuclear layer (ONL). Physiological responses using scotopic electroretinograms (ERG) reveal b-wave amplitudes from TIMP1-treated retinas are significantly greater than from saline-treated rd1 retinas (P<0.05). In later degenerative stages of rd1 retinas, photopic b-wave amplitudes from TIMP1-treated rd1 retinas are significantly larger than from saline-treated rd1 retinas (P<0.05). Our findings demonstrate that TIMP1 delays photoreceptor cell death. Furthermore, this study provides new insights into how TIMP1

Regulation of D-cyclin translation inhibition in myeloma cells treated with mTOR inhibitors: Rationale for combined treatment with ERK inhibitors and rapamycin

PubMed Central

Frost, Patrick; Shi, Yijiang; Hoang, Bao; Gera, Joseph; Lichtenstein, Alan

2009-01-01

We have shown that heightened AKT activity sensitized multiple myeloma (MM) cells to the anti-tumor effects of the mTOR-inhibitor, CCI-779. To test the mechanism of AKT’s regulatory role, we stably transfected U266 MM cell lines with an activated AKT allele or empty vector. The AKT-transfected cells were more sensitive to cytostasis induced in vitro by rapamycin or in vivo by its analog, CCI-779, whereas cells with quiescent AKT were resistant. The ability of mTOR inhibitors to downregulate D-cyclin expression was significantly greater in AKT-transfected MM cells, due in part, to AKT’s ability to curtail cap-independent translation and internal ribosome entry site (IRES) activity of D-cyclin transcripts. Similar AKT-dependent regulation of rapamycin responsiveness was demonstrated in a second myeloma model: the PTEN-null OPM-2 cell line transfected with wild type PTEN. As ERK/p38 activity facilitates IRES-mediated translation of some transcripts, we investigated ERK/p38 as regulators of AKT-dependent effects on rapamycin sensitivity. AKT-transfected U266 cells demonstrated significantly decreased ERK and p38 activity. However, only an ERK inhibitor prevented D-cyclin IRES activity in resistant “low AKT” myeloma cells. Furthermore, the ERK inhibitor successfully sensitized myeloma cells to rapamycin in terms of down regulated D-cyclin protein expression and G1 arrest. However, ectopic over-expression of an activated MEK gene did not increase cap-independent translation of D-cyclin in “high AKT” myeloma cells indicating that MEK/ERK activity was required but not sufficient for activation of the IRES. These data support a scenario where heightened AKT activity down-regulates D-cyclin IRES function in MM cells and ERK facilitates activity. PMID:19139116

Incidence of multiple myeloma in Olmsted County, Minnesota: Trend over 6 decades.

PubMed

Kyle, Robert A; Therneau, Terry M; Rajkumar, S Vincent; Larson, Dirk R; Plevak, Matthew F; Melton, L Joseph

2004-12-01

Previous studies have indicated that the incidence and mortality rates for multiple myeloma have increased in the United States. The authors reported on the incidence of multiple myeloma in Olmsted County, Minnesota, between 1991 and 2001 and on trends in multiple myeloma incidence over the last 56 years. Using the files of the Mayo Clinic and the Olmsted Medical Center (Rochester, MN), the authors identified all residents of Olmsted County who had multiple myeloma, suspected myeloma, or a related disorder. Reports of all laboratory determinations, in addition to autopsy findings and death certificates, were obtained. The criteria for the diagnosis of multiple myeloma have not changed during the last 6 decades. All but 1 of the 47 residents with multiple myeloma first diagnosed between 1991 and 2001 were recognized antemortem. Fifty-five percent had a previous monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma before multiple myeloma was diagnosed. From 1991 to 2001, the overall annual incidence rate, age-adjusted to the 2000 U.S. population, was 4.3 per 100,000 (95% confidence interval, 3.0-5.5 per 100,000). Poisson regression analysis showed no statistically significant trend in Olmsted County incidence rates over 56 years. In similar fashion, the authors adjusted multiple myeloma incidence rates from nine other studies worldwide for which adequate data were available and documented similar findings in each case, except for one study that included patients with smoldering multiple myeloma. The overall incidence of multiple myeloma in Olmsted County, Minnesota, has not changed in almost 6 decades. The apparent increase in incidence elsewhere is unexplained but probably is attributable to improvements in diagnostic techniques, particularly in older patients. (c) 2004 American Cancer Society

RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in Notch4 Induced Mouse Model

DTIC Science & Technology

2017-10-01

mouse genetic breeding, provided genotyping, immunostaining, histological analysis, and molecular expertise. Funding Support NIH/NHLBI Name: Bert...AWARD NUMBER: W81XWH-16-1-0665 TITLE: RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in Notch4-Induced Mouse...2016 - 29 Sep 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in

Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells.

PubMed

Sherbenou, Daniel W; Aftab, Blake T; Su, Yang; Behrens, Christopher R; Wiita, Arun; Logan, Aaron C; Acosta-Alvear, Diego; Hann, Byron C; Walter, Peter; Shuman, Marc A; Wu, Xiaobo; Atkinson, John P; Wolf, Jeffrey L; Martin, Thomas G; Liu, Bin

2016-12-01

Multiple myeloma is incurable by standard approaches because of inevitable relapse and development of treatment resistance in all patients. In our prior work, we identified a panel of macropinocytosing human monoclonal antibodies against CD46, a negative regulator of the innate immune system, and constructed antibody-drug conjugates (ADCs). In this report, we show that an anti-CD46 ADC (CD46-ADC) potently inhibited proliferation in myeloma cell lines with little effect on normal cells. CD46-ADC also potently eliminated myeloma growth in orthometastatic xenograft models. In primary myeloma cells derived from bone marrow aspirates, CD46-ADC induced apoptosis and cell death, but did not affect the viability of nontumor mononuclear cells. It is of clinical interest that the CD46 gene resides on chromosome 1q, which undergoes genomic amplification in the majority of relapsed myeloma patients. We found that the cell surface expression level of CD46 was markedly higher in patient myeloma cells with 1q gain than in those with normal 1q copy number. Thus, genomic amplification of CD46 may serve as a surrogate for target amplification that could allow patient stratification for tailored CD46-targeted therapy. Overall, these findings indicate that CD46 is a promising target for antibody-based treatment of multiple myeloma, especially in patients with gain of chromosome 1q.

Noninvasive imaging of multiple myeloma using near infrared fluorescent molecular probe

NASA Astrophysics Data System (ADS)

Hathi, Deep; Zhou, Haiying; Bollerman-Nowlis, Alex; Shokeen, Monica; Akers, Walter J.

2016-03-01

Multiple myeloma is a plasma cell malignancy characterized by monoclonal gammopathy and osteolytic bone lesions. Multiple myeloma is most commonly diagnosed in late disease stages, presenting with pathologic fracture. Early diagnosis and monitoring of disease status may improve quality of life and long-term survival for multiple myeloma patients from what is now a devastating and fatal disease. We have developed a near-infrared targeted fluorescent molecular probe with high affinity to the α4β1 integrin receptor (VLA-4)overexpressed by a majority of multiple myeloma cells as a non-radioactive analog to PET/CT tracer currently being developed for human diagnostics. A near-infrared dye that emits about 700 nm was conjugated to a high affinity peptidomimmetic. Binding affinity and specificity for multiple myeloma cells was investigated in vitro by tissue staining and flow cytometry. After demonstration of sensitivity and specificity, preclinical optical imaging studies were performed to evaluate tumor specificity in murine subcutaneous and metastatic multiple myeloma models. The VLA-4-targeted molecular probe showed high affinity for subcutaneous MM tumor xenografts. Importantly, tumor cells specific accumulation in the bone marrow of metastatic multiple myeloma correlated with GFP signal from transfected cells. Ex vivo flow cytometry of tumor tissue and bone marrow further corroborated in vivo imaging data, demonstrating the specificity of the novel agent and potential for quantitative imaging of multiple myeloma burden in these models.

Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche

PubMed Central

Lawson, Michelle A.; McDonald, Michelle M.; Kovacic, Natasa; Hua Khoo, Weng; Terry, Rachael L.; Down, Jenny; Kaplan, Warren; Paton-Hough, Julia; Fellows, Clair; Pettitt, Jessica A.; Neil Dear, T.; Van Valckenborgh, Els; Baldock, Paul A.; Rogers, Michael J.; Eaton, Colby L.; Vanderkerken, Karin; Pettit, Allison R.; Quinn, Julian M. W.; Zannettino, Andrew C. W.; Phan, Tri Giang; Croucher, Peter I.

2015-01-01

Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and reactivation. In this study, we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state that is switched ‘on' by engagement with bone-lining cells or osteoblasts, and switched ‘off' by osteoclasts remodelling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy that targets dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse. PMID:26632274

Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

ClinicalTrials.gov

2017-12-26

B-Cell Prolymphocytic Leukemia; Hypodiploidy; Loss of Chromosome 17p; Plasma Cell Leukemia; Progression of Multiple Myeloma or Plasma Cell Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Non-Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; t(14;16); t(4;14); T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

Prophylactic broad spectrum antibiotics as a new anti-myeloma therapy.

PubMed

Valkovic, Toni; Nacinovic, Antica Duletic; Petranovic, Duska

2013-12-01

Multiple myeloma is a common, yet incurable, haematological neoplasm. The reciprocal communication between malignant plasma cells, other cell types, and the extracellular matrix in the bone marrow micro-eco system is mediated by cell-cell and cell-matrix adhesion, as well as the production of different soluble factors, and is crucial for tumour growth and drug resistance. Inflammation and pro-inflammatory cytokines contribute to the clonal expansion of neoplastic plasmacytes. This extremely complex pathogenesis of multiple myeloma gives us the opportunity to promote numerous novel drugs and approaches based on the paradigm of targeted therapy. Immune dysfunction is a hallmark of multiple myeloma. Intrinsic and therapy-related immunosuppression leads to an increased risk of recurrent infection, the major cause of mortality. However, little data is available regarding the possible influence of infection on the biology and progression of multiple myeloma. Some authors have shown that pathogenic microorganisms can activate tool-like receptors on myeloma cells, as well as the robust production of pro-inflammatory cytokines; together these factors can contribute to myeloma growth, survival, and progression. Therefore, we proposed a simple, inexpensive, and new approach for anti-myeloma therapy that, to the best of our knowledge, is the first one concerning the prophylactic, long-term use of broad-spectrum antibiotics during the course of disease regardless of the chosen concomitant regimens. Prophylactic treatment with antibiotics should suppress the pro-inflammatory milieu produced during recurrent bacterial infections and prevent the activation of tool-like receptors on tumour cells, which are important factors responsible for tumour growth and survival in patients with multiple myeloma. Copyright © 2013 Elsevier Ltd. All rights reserved.

Multiple myeloma in the very elderly patient: challenges and solutions

PubMed Central

Willan, John; Eyre, Toby A; Sharpley, Faye; Watson, Caroline; King, Andrew J; Ramasamy, Karthik

2016-01-01

Diagnosis and management of myeloma in the very elderly patient is challenging. Treatment options have vastly improved for elderly myeloma patients but still require the clinician to personalize therapy. In this paper, we offer evidence-based, pragmatic advice on how to overcome six of the main challenges likely to arise: 1) diagnosis of myeloma in this age group, 2) assessment of the need for treatment, and the fitness for combination chemotherapy, 3) provision of the best quality of supportive care, 4) choice of combination chemotherapy in those fit enough for it, 5) treatment of relapsed myeloma, and 6) provision of end of life care. With an increased burden of comorbidities and a reduced resilience to treatment and its associated toxicities, the management of myeloma in this age group requires a different approach to that in younger patients to maximize both quality and length of life. PMID:27143866

Managing renal complications in multiple myeloma.

PubMed

Fotiou, Despoina; Dimopoulos, Meletios A; Kastritis, Efstathios

2016-09-01

About 20-40% of patients with multiple myeloma (MM) will present with some degree of renal impairment (RI) and about 25% of patients will experience RI at later disease stages. Patients with MM and RI have poorer overall survival and are at higher risk of early death. The mechanisms of acute renal damage in MM are covered and the issues around diagnosis and renal evaluation response are discussed. The importance of optimal supportive care is stressed and the role and effectiveness of different anti-myeloma agents covered including the role of high cut-off hemodialysis, autologous stem cell transplantation and kidney transplant. Expert commentary: Outcomes of patients with RI and rates of renal recovery have improved with the use of novel anti-myeloma agents. Bortezomib-dexamethasone backbone regimes (±third agent) are the current first choice in newly diagnosed patients. In relapsed/refractory disease additional treatment options include newer novel agents.

Immunoglobulin M myeloma: evaluation of molecular features and cytokine expression.

PubMed

Konduri, Kartik; Sahota, Surinder S; Babbage, Gavin; Tong, Alex W; Kumar, Padmasini; Newman, Joseph T; Stone, Marvin J

2005-03-01

Immunoglobulin (Ig) M myeloma is a distinct entity with features of multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM). The malignant cells in IgM myeloma have a distinctive chromosomal translocation that differentiates them from WM. These cells are postgerminal-center in origin with isotype-switch transcripts. They appear to be arrested at a point of maturation between that of WM and MM. Preliminary data indicate that a pattern of osteoclast-activating factor and osteoprotegerin expression similar to that observed in classic MM is present in IgM myeloma. Additional studies on patients with this rare tumor may provide further insight into the pathogenesis of bone disease in plasma cell dyscrasias.

Consensus in the Management of Multiple Myeloma in India at Myeloma State of the Art 2016 Conference.

PubMed

Yanamandra, Uday; Khattry, Navin; Kumar, Shaji; Raje, Noopur; Jain, Arihant; Jagannath, Sundar; Menon, Hari; Kumar, Lalit; Varma, Neelam; Varma, Subhash; Saikia, Tapan; Malhotra, Pankaj

2017-03-01

The science of multiple myeloma (MM) and related plasma cell disorders is rapidly evolving with increased understanding of the disease biology and recent approval of the newer drugs widening the therapeutic armamentarium. Despite multiple international guidelines regarding the management of this disease, the practice of managing MM is not uniform amongst Indian physicians. There are challenges in management which are unique to the Indian patients. This review discusses these challenges and the consensus of the nation-wide experts in dealing with the same. We also briefly highlighted the perspective of international experts as discussed in the Myeloma State of the Art conference held in September 2016 at PGI, Chandigarh. An I ndian M yeloma A cademic G roup e (IMAGe) group was formed to strengthen the research, create awareness about myeloma and related disorders and form consensus guidelines/ recommendations that can be adapted to the Indian Scenario.

Induction of myeloma-specific cytotoxic T lymphocytes responses by natural killer cells stimulated-dendritic cells in patients with multiple myeloma.

PubMed

Nguyen-Pham, Thanh-Nhan; Im, Chang-Min; Nguyen, Truc-Anh Thi; Lim, Mi-Seon; Hong, Cheol Yi; Kim, Mi-Hyun; Lee, Hyun Ju; Lee, Youn-Kyung; Cho, Duck; Ahn, Jae-Sook; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Chung, Ik-Joo; Kim, Hyeoung-Joon; Lee, Je-Jung

2011-09-01

The interaction between dendritic cells (DCs) and natural killer (NK) cells plays a key role in inducing DC maturation for subsequent T-cell priming. We investigated to generate potent DCs by stimulated with NK cells to induce myeloma-specific cytotoxic T lymphocytes (CTLs). NK cells-stimulated-DCs exhibited high expression of costimulatory molecules and high production of IL-12p70. These DCs induce high potency of Th1 polarization and exhibit a high ability to generate myeloma-specific CTLs responses. These results suggest that functionally potent DCs can be generated by stimulation with NK cells and may provide an effective source of DC-based immunotherapy in multiple myeloma. Copyright © 2011 Elsevier Ltd. All rights reserved.

Guidelines for supportive care in multiple myeloma 2011.

PubMed

Snowden, John A; Ahmedzai, Sam H; Ashcroft, John; D'Sa, Shirley; Littlewood, Timothy; Low, Eric; Lucraft, Helen; Maclean, Rhona; Feyler, Sylvia; Pratt, Guy; Bird, Jennifer M

2011-07-01

Supportive care plays an increasingly important role in the modern management of multiple myeloma. While modern treatments have significantly prolonged overall and progression free survival through improved disease control, the vast majority of patients remain incurable, and live with the burden of the disease itself and the cumulative side effects of treatments. Maintenance of quality of life presents challenges at all stages of the disease from diagnosis through the multiple phases of active treatment to the end of life. Written on behalf of the British Committee for Standards in Haematology (BCSH) and the UK Myeloma Forum (UKMF), these evidence based guidelines summarize the current national consensus for supportive and symptomatic care in multiple myeloma in the following areas; pain management, peripheral neuropathy, skeletal complications, infection, anaemia, haemostasis and thrombosis, sedation, fatigue, nausea, vomiting, anorexia, constipation, diarrhoea, mucositis, bisphosphonate-induced osteonecrosis of the jaw, complementary therapies, holistic needs assessment and end of life care. Although most aspects of supportive care can be supervised by haematology teams primarily responsible for patients with multiple myeloma, multidisciplinary collaboration involving specialists in palliative medicine, pain management, radiotherapy and surgical specialities is essential, and guidance is provided for appropriate interdisciplinary referral. These guidelines should be read in conjunction with the BCSH/UKMF Guidelines for the Diagnosis and Management of Multiple Myeloma 2011. © 2011 Blackwell Publishing Ltd.

[Association of Kaposi sarcoma--multiple myeloma. A new case].

PubMed

Cohen, J D; Thomas, E; Garnier, N; Hellier, I; Durand, L; Guilhou, J J; Baldet, P; Blotman, F

2000-11-01

Kaposi's disease is an angiogenic multifocal cancer process that has several forms, namely Mediterranean, African, HIV-associated, and secondary to a preexisting immunodepressive state (hematological disorder, corticosteroid therapy, immunodepressive treatment). Whatever its form, Kaposi's sarcoma is probably associated with a chronic viral human herpes type 8 infection (HHV8). This virus has been implicated in the pathogenesis of multiple myeloma (17 cases recorded to date). In the present study, a further case of Kaposi's sarcoma associated with multiple myeloma has been reported. However, Epstein-Barr virus, cytomegalovirus, hepatitis B and C, HIV and HHV8 serologies were negative. Radiotherapy on the lower limbs was initiated. It is concluded that HHV8 does not appear to play a pathogenic role in cases of multiple myeloma, given the rarity of the association between Kaposi's sarcoma/multiple myeloma/HHV8.

Maxillary Swelling as the First Evidence of Multiple Myeloma

PubMed Central

Kasamatsu, Atsushi; Kimura, Yasushi; Tsujimura, Hideki; Kanazawa, Harusachi; Koide, Nao; Miyamoto, Isao; Endo-Sakamoto, Yosuke; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

2015-01-01

Multiple myeloma is a malignant neoplasm of plasma cells characterized by proliferation of a single clone of abnormal immunoglobulin-secreting plasma cells. Since the amount of hemopoietic bone marrow is decreased in the maxilla, oral manifestations of multiple myeloma are less common in the maxilla than in the mandible. We report the case of 33-year-old Japanese man who presented with a mass in the right maxillary alveolar region. Computed tomography and magnetic resonance images showed a soft tissue mass in the right maxilla eroding the anterior and lateral walls of the maxillary sinus and extending into the buccal space. The biopsy results, imaging, and laboratory investigations led to the diagnosis of multiple myeloma. This case report suggests that oral surgeons and dentists should properly address oral manifestations as first indications of multiple myeloma. PMID:26640721

The synthetic parasite-derived peptide GK1 increases survival in a preclinical mouse melanoma model.

PubMed

Pérez-Torres, Armando; Vera-Aguilera, Jesús; Hernaiz-Leonardo, Juan Carlos; Moreno-Aguilera, Eduardo; Monteverde-Suarez, Diego; Vera-Aguilera, Carlos; Estrada-Bárcenas, Daniel

2013-11-01

The therapeutic efficacy of a synthetic parasite-derived peptide GK1, an immune response booster, was evaluated in a mouse melanoma model. This melanoma model correlates with human stage IIb melanoma, which is treated with wide surgical excision; a parallel study employing a surgical treatment was carried out as an instructive goal. C57BL/6 mice were injected subcutaneously in the flank with 2×10(5) B16-F10 murine melanoma cells. When the tumors reached 20 mm3, mice were separated into two different groups; the GK1 group, treated weekly with peritumoral injections of GK1 (10 μg/100 μL of sterile saline solution) and the control group, treated weekly with an antiseptic peritumoral injection of 100 μL of sterile saline solution without further intervention. All mice were monitored daily for clinical appearance, tumor size, and survival. Surgical treatment was performed in parallel when the tumor size was 20 mm3 (group A), 500 mm3 (group B), and >500 mm3 (group C). The GK1 peptide effectively increased the mean survival time by 9.05 days, corresponding to an increase of 42.58%, and significantly delayed tumor growth from day 3 to 12 of treatment. In addition, tumor necrosis was significantly increased (p<0.05) in the treated mice. The overall survival rates obtained with surgical treatment at 6 months were 83.33% for group A, 40% for group B, and 0% for group C, with significant differences (p<0.05) among the groups. The GK1 peptide demonstrated therapeutic properties in a mouse melanoma model, as treatment resulted in a significant increase in the mean survival time of the treated animals (42.58%). The potential for GK1 to be used as a primary or adjuvant component of chemotherapeutic cocktails for the treatment of experimental and human cancers remains to be determined, and surgical removal remains a challenge for any new experimental treatment of melanoma in mouse models.

Large registry analysis to accurately define second malignancy rates and risks in a well-characterized cohort of 744 consecutive multiple myeloma patients followed-up for 25 years

PubMed Central

Engelhardt, Monika; Ihorst, Gabriele; Landgren, Ola; Pantic, Milena; Reinhardt, Heike; Waldschmidt, Johannes; May, Annette M.; Schumacher, Martin; Kleber, Martina; Wäsch, Ralph

2015-01-01

Additional malignancies in multiple myeloma patients after first-line and maintenance treatment have been observed, questioning whether specific risks exist. Second primary malignancies have also gained attention since randomized data showed associations to newer drugs. We have conducted this large registry analysis in 744 consecutive patients and analyzed: 1) frequency and onset of additional malignancies; and 2) second primary malignancy- and myeloma-specific risks. We assessed the frequency of additional malignancies in terms of host-, myeloma- and treatment-specific characteristics. To compare these risks, we estimated cumulative incidence rates for second malignancies and myeloma with Fine and Gray regression models taking into account competing risks. Additional malignancies were found in 118 patients: prior or synchronous malignancies in 63% and subsequent in 37%. Cumulative incidence rates for second malignancies were increased in IgG-myeloma and decreased in bortezomib-treated patients (P<0.05). Cumulative incidence rates for myeloma death were increased with higher stage and age, but decreased in IgG-subtypes and due to anti-myeloma treatment (P<0.05). Cytogenetics in patients acquiring second primary malignancies were predominantly favorable, suggesting that indolent myeloma and long disease latency may allow the manifestation of additional malignancies. An assessment of the Surveillance, Epidemiology, and End Result Program of the National Cancer Institute and our data with long-term follow up of 25 years confirmed a prevalence of second malignancy of 10% at 25 years, whereas death from myeloma decreased from 90% to 83%, respectively. Our important findings widen our knowledge of second malignancies and show that they are of increasing relevance as the prognosis in myeloma improves and mortality rates decrease. PMID:26160877

Otogenic pneumocephalus as a complication of multiple myeloma.

PubMed

Maguire, Melissa J; Nath, Uma; Bignardi, Guiseppe E

2012-09-01

We report a case of otogenic pneumocephalus in an 80-year-old woman with multiple myeloma. The pneumocephalus was associated with Haemophilus influenzae otitis media and reactive meningitis in the absence of an intracranial brain abscess. Myeloma causes thinning of bone trabeculae and destructive lytic bone lesions. This can predispose to a risk of pathologic fractures and, in patients with skull vault involvement, to the rare complication of pneumocephalus. Therefore, pneumocephalus should be considered in the differential diagnosis of acute headache in patients with multiple myeloma, especially those with skull vault involvement. Prompt computed tomography and liaison between the otolaryngology and neurology teams may assist in making an early diagnosis and preventing life-threatening intracranial complications.

Association between intracranial plasmacytoma and multiple myeloma: clinicopathological outcome study.

PubMed

Schwartz, T H; Rhiew, R; Isaacson, S R; Orazi, A; Bruce, J N

2001-11-01

Intracranial plasmacytomas are rare lesions that can arise from the calvarium, dura, or cranial base and exhibit a benign course unless associated with myeloma. Attention has recently been focused on the role of the cell adhesion molecules CD56 and CD31 in the pathogenesis of myeloma. No such information is available for intracranial plasmacytomas and myeloma-associated lesions. We investigated the relationship between CD56 and CD31 expression, intracranial location, and progression to myeloma for a series of nine intracranial plasmacytomas (three dural, one calvarial, and five cranial base lesions). These parameters were also correlated with proliferation indices, as assessed by MIB-1 immunostaining of the histological sections. A single pathologist (AO) performed immunohistochemical analyses and reviewed all slides. Intracranial plasmacytomas presented more commonly in female patients (89%). The three dural lesions were CD56- and CD31-negative and exhibited MIB-1 staining of less than 10%; no patient developed myeloma or recurrence. Of the five cranial base lesions, three were CD56-positive, none was CD31-positive, and two exhibited MIB-1 labeling of more than 45%, with plasmablastic morphological features. Compared with other intracranial plasmacytomas, five of five patients with cranial base lesions developed bone marrow biopsy-proven myeloma (P < 0.05) within 8 months. The calvarial lesion was CD56- and CD31-positive, and the patient developed myeloma soon after diagnosis. Both of the two highly proliferative plasmablastic lesions recurred, one after gross total resection without radiotherapy and the other after a biopsy and 2000-cGy radiotherapy. Among intracranial plasmacytomas, cranial base location was the strongest predictor of the development of multiple myeloma. Expression of the cell adhesion molecules CD31 and CD56 was not predictive of outcome. Extramedullary dural-based lesions were CD56-negative and were not associated with myeloma. A high

Ex-vivo dynamic 3-D culture of human tissues in the RCCS™ bioreactor allows the study of Multiple Myeloma biology and response to therapy.

PubMed

Ferrarini, Marina; Steimberg, Nathalie; Ponzoni, Maurilio; Belloni, Daniela; Berenzi, Angiola; Girlanda, Stefania; Caligaris-Cappio, Federico; Mazzoleni, Giovanna; Ferrero, Elisabetta

2013-01-01

Three-dimensional (3-D) culture models are emerging as invaluable tools in tumor biology, since they reproduce tissue-specific structural features and cell-cell interactions more accurately than conventional 2-D cultures. Multiple Myeloma, which depends on myeloma cell-Bone Marrow microenvironment interactions for development and response to drugs, may particularly benefit from such an approach. An innovative 3-D dynamic culture model based on the use of the RCCS™ Bioreactor was developed to allow long-term culture of myeloma tissue explants. This model was first validated with normal and pathological explants, then applied to tissues from myeloma patients. In all cases, histological examination demonstrated maintenance of viable myeloma cells inside their native microenvironment, with an overall well preserved histo-architecture including bone lamellae and vessels. This system was then successfully applied to evaluate the cytotoxic effects exerted by the proteasome inhibitor Bortezomib not only on myeloma cells but also on angiogenic vessels. Moreover, as surrogate markers of specialized functions expressed by myeloma cells and microenvironment, β2 microglobulin, VEGF and Angiopoietin-2 levels, as well as Matrix Metalloproteases activity, were evaluated in supernatants from 3D cultures and their levels reflected the effects of Bortezomib treatment. Notably, determination of β2 microglobulin levels in supernatants from Bortezomib-treated samples and in patients'sera following Bortezomib-based therapies disclosed an overall concordance in the response to the drug ex vivo and in vivo. Our findings indicate, as a proof of principle, that 3-D, RCCS™ bioreactor-based culture of tissue explants can be exploited for studying myeloma biology and for a pre-clinical approach to patient-targeted therapy.

Ex-Vivo Dynamic 3-D Culture of Human Tissues in the RCCS™ Bioreactor Allows the Study of Multiple Myeloma Biology and Response to Therapy

PubMed Central

Ponzoni, Maurilio; Belloni, Daniela; Berenzi, Angiola; Girlanda, Stefania; Caligaris-Cappio, Federico; Mazzoleni, Giovanna; Ferrero, Elisabetta

2013-01-01

Three-dimensional (3-D) culture models are emerging as invaluable tools in tumor biology, since they reproduce tissue-specific structural features and cell-cell interactions more accurately than conventional 2-D cultures. Multiple Myeloma, which depends on myeloma cell-Bone Marrow microenvironment interactions for development and response to drugs, may particularly benefit from such an approach. An innovative 3-D dynamic culture model based on the use of the RCCS™ Bioreactor was developed to allow long-term culture of myeloma tissue explants. This model was first validated with normal and pathological explants, then applied to tissues from myeloma patients. In all cases, histological examination demonstrated maintenance of viable myeloma cells inside their native microenvironment, with an overall well preserved histo-architecture including bone lamellae and vessels. This system was then successfully applied to evaluate the cytotoxic effects exerted by the proteasome inhibitor Bortezomib not only on myeloma cells but also on angiogenic vessels. Moreover, as surrogate markers of specialized functions expressed by myeloma cells and microenvironment, β2 microglobulin, VEGF and Angiopoietin-2 levels, as well as Matrix Metalloproteases activity, were evaluated in supernatants from 3D cultures and their levels reflected the effects of Bortezomib treatment. Notably, determination of β2 microglobulin levels in supernatants from Bortezomib-treated samples and in patients'sera following Bortezomib-based therapies disclosed an overall concordance in the response to the drug ex vivo and in vivo. Our findings indicate, as a proof of principle, that 3-D, RCCS™ bioreactor-based culture of tissue explants can be exploited for studying myeloma biology and for a pre-clinical approach to patient-targeted therapy. PMID:23990965

Therapy of myeloma in vivo using marine phospholipid in combination with Agaricus blazei Murill as an immune respond activator.

PubMed

Murakawa, Kentaro; Fukunaga, Kenji; Tanouchi, Masatoshi; Hosokawa, Masashi; Hossain, Zakir; Takahashi, Koretaro

2007-01-01

Mushroom (Agaricus blazei Murill) extract has been reported to possess antitumor effects through immune activation. Here, we investigated the beneficial effects of combining A. blazei extract with marine phospholipids in comparison to A. blazei extract alone on myeloma sp2 tumor suppression when orally administrated. The experimental groups designed for sp2 tumor bearing BALB/c nu/nu mice were drinks of: (1)control; (2)1.0 mg/mL squid phospholipid liposome alone; (3)0.5 mg/mL A. blazei Murill water extract alone; (4)1.0 mg/mL squid phospholipid liposome with 0.5 mg/mL A. blazei Murill water extract in the form of those simple mixture; and (5)1.0 mg/mL squid phospholipid liposome with 0.5 mg/mL A. blazei Murill water extract partially encapsulated. Orally administrated volumes amounted to approximately 5 mL per day per mouse for all groups. A. blazei Murill water extract alone and squid phospholipid alone served groups show moderate tumor suppression with total administrations of approximately 105 mg/mouse for squid phospholipid through out the experimental term. When both A. blazei Murill water extract and squid phospholipid were administrated simultaneously in a simple mixture form, promotional effect on cancer tumor suppression was observed. And when A. blazei Murill water extract was partially encapsulated in the squid phospholipid liposomes with total administrations being 105 mg/mouse for squid phospholipid, effect on cancer tumor suppression was more pronounced. Though there was no statistically significant difference in tumor sizes between the simple mixture form administrated group i.e. group (4) and the partially encapsulated form administrated group i.e. group (5), the tumor vanished mouse was seen in the partially encapsulated form administrated group. Thus it was concluded that combinational administration of the A. blazei Murill water extract and the marine phospholipid may be useful in myeloma sp2 therapy.

Role of Bruton’s tyrosine kinase in myeloma cell migration and induction of bone disease

PubMed Central

Bam, Rakesh; Ling, Wen; Khan, Sharmin; Pennisi, Angela; Venkateshaiah, Sathisha Upparahalli; Li, Xin; van Rhee, Frits; Usmani, Saad; Barlogie, Bart; Shaughnessy, John; Epstein, Joshua; Yaccoby, Shmuel

2014-01-01

Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Bruton’s tyrosine kinase (BTK), of the TEC family, is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. We demonstrated BTK expression in clinical myeloma plasma cells, interleukin (IL) –6– or stroma–dependent cell lines and osteoclasts. SDF-1 induced BTK activation in myeloma cells and BTK inhibition by small hairpin RNA or the small molecule inhibitor, LFM-A13, reduced their migration toward stromal cell-derived factor-1 (SDF-1). Pretreatment with LFM-A13 also reduced in vivo homing of myeloma cells to bone using bioluminescence imaging in the SCID-rab model. Enforced expression of BTK in myeloma cell line enhanced cell migration toward SDF-1 but had no effect on short-term growth. BTK expression was correlated with cell-surface CXCR4 expression in myeloma cells (n = 33, r = 0.81, P < 0.0001), and BTK gene and protein expression was more profound in cell-surface CXCR4-expressing myeloma cells. BTK was not upregulated by IL-6 while its inhibition had no effect on IL-6 signaling in myeloma cells. Human osteoclast precursors also expressed BTK and cell-surface CXCR4 and migrated toward SDF-1. LFM-A13 suppressed migration and differentiation of osteoclast precursors as well as bone-resorbing activity of mature osteoclasts. In primary myeloma-bearing SCID-rab mice, LFM-A13 inhibited osteoclast activity, prevented myeloma-induced bone resorption and moderately suppressed myeloma growth. These data demonstrate BTK and cell-surface CXCR4 association in myeloma cells and that BTK plays a role in myeloma cell homing to bone and myeloma-induced bone disease. PMID:23456977

Plasma cell morphology in multiple myeloma and related disorders.

PubMed

Ribourtout, B; Zandecki, M

2015-06-01

Normal and reactive plasma cells (PC) are easy to ascertain on human bone marrow films, due to their small mature-appearing nucleus and large cytoplasm, the latter usually deep blue after Giemsa staining. Cytoplasm is filled with long strands of rough endoplasmic reticulum and one large Golgi apparatus (paranuclear hof), demonstrating that PC are dedicated mainly to protein synthesis and excretion (immunoglobulin). Deregulation of the genome may induce clonal expansion of one PC that will lead to immunoglobulin overproduction and eventually to one among the so-called PC neoplasms. In multiple myeloma (MM), the number of PC is over 10% in most patients studied. Changes in the morphology of myeloma PC may be inconspicuous as compared to normal PC (30-50% patients). In other instances PC show one or several morphological changes. One is related to low amount of cytoplasm, defining lymphoplasmacytoid myeloma (10-15% patients). In other cases (40-50% patients), named immature myeloma cases, nuclear-cytoplasmic asynchrony is observed: presence of one nucleolus, finely dispersed chromatin and/or irregular nuclear contour contrast with a still large and blue (mature) cytoplasm. A peculiar morphological change, corresponding to the presence of very immature PC named plasmablasts, is observed in 10-15% cases. Several prognostic morphological classifications have been published, as mature myeloma is related to favorable outcome and immature myeloma, peculiarly plasmablastic myeloma, is related to dismal prognosis. However, such classifications are no longer included in current prognostic schemes. Changes related to the nucleus are very rare in monoclonal gammopathy of unknown significance (MGUS). In contrast, anomalies related to the cytoplasm of PC, including color (flaming cells), round inclusions (Mott cells, Russell bodies), Auer rod-like or crystalline inclusions, are reported in myeloma cases as well as in MGUS and at times in reactive disorders. They do not correspond

Pomalidomide for Multiple Myeloma

Cancer.gov

A summary of results from a phase III trial that compared the combination of pomalidomide (Pomalyst®) and low-dose dexamethasone versus high-dose dexamethasone alone in patients with multiple myeloma that has progressed despite other treatments.

Spotlight on elotuzumab in the treatment of multiple myeloma: the evidence to date

PubMed Central

Weisel, Katja

2016-01-01

Despite advances in the treatment of multiple myeloma, it remains an incurable disease, with relapses and resistances frequently observed. Recently, immunotherapies, in particular, monoclonal antibodies, have become important treatment options in anticancer therapies. Elotuzumab is a humanized monoclonal antibody to signaling lymphocytic activation molecule F7, which is highly expressed on myeloma cells and, to a lower extent, on selected leukocyte subsets such as natural killer cells. By directly activating natural killer cells and by antibody-dependent cell-mediated cytotoxicity, elotuzumab exhibits a dual mechanism of action leading to myeloma cell death with minimal effects on normal tissue. In several nonclinical models of multiple myeloma, elotuzumab was effective as a single agent and in combination with standard myeloma treatments, supporting the use of elotuzumab in patients. In combination with lenalidomide and dexamethasone, elotuzumab showed a significant increase in tumor response rates and progression-free survival in patients with relapsed and/or refractory multiple myeloma. This review summarizes the nonclinical and clinical development of elotuzumab as a single agent and in combination with established therapies for the treatment of multiple myeloma. PMID:27785050

Role of Bruton's tyrosine kinase (BTK) in growth and metastasis of INA6 myeloma cells

PubMed Central

Bam, R; Venkateshaiah, S U; Khan, S; Ling, W; Randal, S S; Li, X; Zhang, Q; van Rhee, F; Barlogie, B; Epstein, J; Yaccoby, S

2014-01-01

Bruton's tyrosine kinase (BTK) and the chemokine receptor CXCR4 are linked in various hematologic malignancies. The aim of the study was to understand the role of BTK in myeloma cell growth and metastasis using the stably BTK knockdown luciferase-expressing INA6 myeloma line. BTK knockdown had reduced adhesion to stroma and migration of myeloma cells toward stromal cell-derived factor-1. BTK knockdown had no effect on short-term in vitro growth of myeloma cells, although clonogenicity was inhibited and myeloma cell growth was promoted in coculture with osteoclasts. In severe combined immunodeficient-rab mice with contralaterally implanted pieces of bones, BTK knockdown in myeloma cells promoted their proliferation and growth in the primary bone but suppressed metastasis to the contralateral bone. BTK knockdown myeloma cells had altered the expression of genes associated with adhesion and proliferation and increased mammalian target of rapamycin signaling. In 176 paired clinical samples, BTK and CXCR4 expression was lower in myeloma cells purified from a focal lesion than from a random site. BTK expression in random-site samples was correlated with proportions of myeloma cells expressing cell surface CXCR4. Our findings highlight intratumoral heterogeneity of myeloma cells in the bone marrow microenvironment and suggest that BTK is involved in determining proliferative, quiescent or metastatic phenotypes of myeloma cells. PMID:25083818

How we manage autologous stem cell transplantation for patients with multiple myeloma

PubMed Central

Dingli, David

2014-01-01

An estimated 22 350 patients had multiple myeloma diagnosed in 2013, representing 1.3% of all new cancers; 10 710 deaths are projected, representing 1.8% of cancer deaths. Approximately 0.7% of US men and women will have a myeloma diagnosis in their lifetime, and with advances in therapy, 77 600 US patients are living with myeloma. The 5-year survival rate was 25.6% in 1989 and was 44.9% in 2005. The median age at diagnosis is 69 years, with 62.4% of patients aged 65 or older at diagnosis. Median age at death is 75 years. The rate of new myeloma cases has been rising 0.7% per year during the past decade. The most common indication for autologous stem cell transplantation in the United States is multiple myeloma, and this article is designed to provide the specifics of organizing a transplant program for multiple myeloma. We review the data justifying use of stem cell transplantation as initial management in myeloma patients. We provide selection criteria that minimize the risks of transplantation. Specific guidelines on mobilization and supportive care through the transplant course, as done at Mayo Clinic, are given. A review of the data on tandem vs sequential autologous transplants is provided. PMID:24973360

New pharmacotherapy options for multiple myeloma.

PubMed

Mina, Roberto; Cerrato, Chiara; Bernardini, Annalisa; Aghemo, Elena; Palumbo, Antonio

2016-01-01

Novel agents and the availability of autologous stem-cell transplantation have revolutionized the treatment of patients with multiple myeloma. First-generation novel agents namely thalidomide, lenalidomide, and bortezomib have significantly improved response and survival of patients. Second-generation novel agents such as pomalidomide, carfilzomib, and monoclonal antibodies are being tested both in the newly diagnosed and relapse settings, and results are promising. In this review article, the main results derived from Phase III trials with thalidomide, lenalidomide, and bortezomib for the treatment of myeloma patients, both at diagnosis and at relapse, are summarized. Data about second-generation novel agents such as pomalidomide and carfilzomib are also reported. Newer effective drugs currently under investigation and the promising results with monoclonal antibodies are described. The availability of new effective drugs has considerably increased the treatment options for myeloma patients. A sequential approach including induction, transplantation (when possible), consolidation, and maintenance is an optimal strategy to achieve disease control and prolong survival. Despite these improvements, the best combination, the optimal sequence, and the proper target of newer drugs need to be defined.

Gynaecomastia complicating the treatment of myeloma.

PubMed Central

Large, D. M.; Jones, J. M.; Shalet, S. M.; Scarffe, J. H.; Gibbs, A. C.

1983-01-01

The hormonal mechanisms involved in the development of gynaecomastia accompanying the treatment of multiple myeloma in adult men have been investigated by studying levels of circulating testosterone (T), oestrone (EI), oestradiol (E2), sex-hormone binding globulin (SHBG), prolactin (PRL) and the gonadotrophins LH and FSH, before, during and after development of gynaecomastia in 4 men. These have been compared with 5 closely matched men who did not develop gynaecomastia during similar treatment for myeloma. Levels of circulating T fell, and levels of E1 and E2 rose during treatment periods in all subjects, and the changes were statistically significant in subjects developing gynaecomastia, which resolved as levels of sex steroid returned towards normal following cessation of treatment. We conclude that treatment of adult men for myeloma results in testicular dysfunction with a reduction in circulating T and a rise in circulating oestrogens. These changes are most marked in subjects developing gynaecomastia in whom the normal breast tissue is stimulated by a subtle, transient oestrogen:androgen imbalance in favour of oestrogens. PMID:6409138

Perceived benefits and barriers to exercise for recently treated patients with multiple myeloma: a qualitative study.

PubMed

Craike, Melinda J; Hose, Kaye; Courneya, Kerry S; Harrison, Simon J; Livingston, Patricia M

2013-07-01

Understanding the physical activity experiences of patients with multiple myeloma (MM) is essential to inform the development of evidence-based interventions and to quantify the benefits of physical activity. The aim of this study was to gain an in-depth understanding of the physical activity experiences and perceived benefits and barriers to physical activity for patients with MM. This was a qualitative study that used a grounded theory approach. Semi-structured interviews were conducted in Victoria, Australia by telephone from December 2011-February 2012 with patients who had been treated for MM within the preceding 2-12 months. Interviews were transcribed and analysed using the constant comparison coding method to reduce the data to themes. Gender differences and differences between treatment groups were explored. Twenty-four interviews were completed. The sample comprised 13 females (54%), with a mean age of 62 years (SD = 8.8). Sixteen (67%) participants had received an autologous stem cell transplant (ASCT). All participants currently engaged in a range of light to moderate intensity physical activity; walking and gardening were the most common activities. Recovery from the symptoms of MM and side effects of therapy, psychological benefits, social factors and enjoyment were important benefits of physical activity. Barriers to physical activity predominately related to the symptoms of MM and side effects of therapy, including pain, fatigue, and fear of infection. Low self- motivation was also a barrier. Women participated in a more diverse range of physical activities than men and there were gender differences in preferred type of physical activity. Women were more likely to report psychological and social benefits; whereas men reported physical activity as a way to keep busy and self-motivation was a barrier. Patients treated with an ASCT more often reported affective benefits of participation in physical activity and fatigue as a barrier. Patients

Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders

PubMed Central

Ross, Fiona M.; Avet-Loiseau, Hervé; Ameye, Geneviève; Gutiérrez, Norma C.; Liebisch, Peter; O’Connor, Sheila; Dalva, Klara; Fabris, Sonia; Testi, Adele M.; Jarosova, Marie; Hodkinson, Clare; Collin, Anna; Kerndrup, Gitte; Kuglik, Petr; Ladon, Dariusz; Bernasconi, Paolo; Maes, Brigitte; Zemanova, Zuzana; Michalova, Kyra; Michau, Lucienne; Neben, Kai; Hermansen, N. Emil U.; Rack, Katrina; Rocci, Alberto; Protheroe, Rebecca; Chiecchio, Laura; Poirel, Hélène A; Sonneveld, Pieter; Nyegaard, Mette; Johnsen, Hans E.

2012-01-01

The European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approaches of current practice. A second workshop followed a quality control exercise in which 21 laboratories analyzed diagnostic cases of purified plasma cells for recurrent abnormalities. The summary report was discussed at the EHA Myeloma Scientific Working Group Meeting 2010. During the quality control exercise, there was acceptable agreement on more than 1,000 tests. The conclusions from the exercise were that the primary clinical applications for FISH analysis were for newly diagnosed cases of MM or frank relapse cases. A range of technical recommendations included: 1) material should be part of the first draw of the aspirate; 2) samples should be sent at suitable times to allow for the lengthy processing procedure; 3) most importantly, PCs must be purified or specifically identified; 4) positive cut-off levels should be relatively conservative: 10% for fusion or break-apart probes, 20% for numerical abnormalities; 5) informative probes should be combined to best effect; 6) in specialist laboratories, a single experienced analyst is considered adequate; 7) at least 100 PC should be scored; 8) essential abnormalities to test for are t(4;14), t(14;16) and 17p13 deletions; 9) suitable commercial probes should be available for clinically relevant abnormalities; 10) the clinical report should be expressed clearly and must state the percentage of PC involved and the method used for identification; 11) a retrospective European based FISH data bank linked to clinical data should be generated; and 12) prospective analysis should be centralized for upcoming trials based on the recommendations made. The European Myeloma Network aims to build on these recommendations to establish standards for a common European data base to define subgroups with prognostic significance. PMID:22371180

Fundamentals in the management of multiple myeloma.

PubMed

Fadilah, S A W

2010-09-01

Progress in our understanding of multiple myeloma and its treatment has resulted in a more tailored approach to patient management, with different therapeutics regimens for different patient populations. The decision to initiate therapy depends primarily on the presence of symptoms which has to balance the chance of tumor clearance and against the risks of treatment related mortality. Selection of appropriate initial treatment should be based primarily on patient's characteristics (biologic age, co-morbidities), the disease characteristics (tumor burden and genetic risk profile) and the expected toxicity profile of the different regimens. When treatment begins, in younger transplant eligible patients the goal is to achieve high quality responses with intensive therapies as the quality of response appears to be important surrogates for long-term outcome. In the majority of myeloma patients in whom intensive treatment is not an option due to advanced age and co-morbidities, treatment should emphasize on optimal disease control to obtain symptomatic relief and to maintain a satisfactory quality of life. The introduction of novel agents has substantially changed the treatment paradigm of this otherwise incurable disease. The utilization of these drugs has moved from relapse setting to the front line setting and has benefited all patient groups. Because of these rapid developments and many treatment options we need good quality clinical studies to guide clinical practice in the management of patients with multiple myeloma. This review presents an update on current concepts of diagnosis and treatment of patients with multiple myeloma and provides recommendations on tailored therapies with particular reference to the local practice. The information presented herein may be used by the health care providers caring for myeloma patients as a guideline to counsel patients to understand their disease and the treatment better.

Epidemiology of Multiple Myeloma in the Czech Republic.

PubMed

Maluskova, D; Svobodová, I; Kucerova, M; Brozova, L; Muzik, J; Jarkovský, J; Hájek, R; Maisnar, V; Dusek, L

2017-01-01

Multiple myeloma (MM) is a cancer of plasma cells with an incidence of 4.8 cases per 100,000 population in the Czech Republic in 2014; the burden of MM in the Czech Republic is moderate when compared to other European countries. This work brings the latest information on MM epidemiology in the Czech population. The Czech National Cancer Registry is the basic source of data for the population-based evaluation of MM epidemiology. This database also makes it possible to assess patient survival and to predict probable short-term as well as long-term trends in the treatment burden of the entire population. According to the latest Czech National Cancer Registry data, there were 504 new cases of MM and 376 deaths from MM in 2014. Since 2004, there has been a 26.9% increase in MM incidence and an 8.3% increase in MM mortality. In 2014, there were 1,982 persons living with MM or a history of MM, corresponding to a 74.4% increase when compared to MM prevalence in 2004. The 5-year survival of patients treated in the period 2010-2014 was nearly 40%. The available data make it possible to analyse long-term trends in MM epidemiology and to predict the future treatment burden as well as treatment results.Key words: multiple myeloma - epidemiology - Czech National Cancer Registry - Registry of Monoclonal Gammopathies - Czech Republic.

Next-generation multiple myeloma treatment: a pharmacoeconomic perspective

PubMed Central

Harousseau, Jean Luc

2016-01-01

Advances in the diagnosis and treatment of multiple myeloma have come at a rapid pace, especially with several new drugs entering the market in the last few years. However, access to and affordability of new treatments poses a major challenge, both in the United States and around the world. High costs of life-saving drugs are detrimental to both the personal finances of the individual patient, as well as society which must bear the increasing costs in terms of increased health insurance premiums, taxes, or both. The challenges are not unique to myeloma, but are commonly encountered in several other cancers as well. But to some extent these pharmacoeconomic concerns are amplified in myeloma due to the need for multidrug regimens that combine 2 or more expensive new drugs, continuous therapy, and the prolonged disease course in most patients. We examine current myeloma therapy from a pharmacoeconomic perspective, and discuss the costs involved. We outline the underlying reasons why cancer drugs are so expensive, the measures that are required to lower cost, and propose potential ways in which costs can be reduced while still delivering high-quality care. PMID:27742709

Adhesive interactions of human multiple myeloma cell lines with different extracellular matrix molecules.

PubMed

Kibler, C; Schermutzki, F; Waller, H D; Timpl, R; Müller, C A; Klein, G

1998-06-01

Multiple myeloma represents a human B cell malignancy which is characterized by a predominant localization of the malignant cell clone within the bone marrow. With the exception of the terminal stage of the disease the myeloma tumor cells do not circulate in the peripheral blood. The bone marrow microenvironment is believed to play an important role in homing, proliferation and terminal differentiation of myeloma cells. Here we have studied the expression of several extracellular matrix (ECM) molecules in the bone marrow of multiple myeloma patients and analyzed their adhesive capacities with four different human myeloma-derived cell lines. All ECM molecules analyzed (tenascin, laminin, fibronectin, collagen types I, III, V and VI) could be detected in bone marrow cryostat sections of multiple myeloma patients. Adhesion assays showed that only laminin, the microfibrillar collagen type VI and fibronectin were strong adhesive components for the myeloma cell lines U266, IM-9, OPM-2 and NCI-H929. Tenascin and collagen type I were only weak adhesive substrates for these myeloma cells. Adhesion to laminin and fibronectin was beta 1-integrin-mediated since addition of anti-beta 1-integrin antibodies could inhibit the binding of the four different cell types to both matrix molecules. In contrast, integrins do not seem to be involved in binding of the myeloma cells to collagen type VI. Instead, inhibition of binding by heparin suggested that membrane-bound heparan sulfate proteoglycans are responsible ligands for binding to collagen type VI. Adhesion assays with several B-cell lines resembling earlier differentiation stages revealed only weak interactions with tenascin and no interactions with collagen type VI, laminin or fibronectin. In summary, the interactions of human myeloma cells with the extracellular matrix may explain the specific retention of the plasma cells within the bone marrow.

Smoldering multiple myeloma

PubMed Central

Landgren, Ola; Mateos, María-Victoria

2015-01-01

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM. PMID:25838344

Comprehensive evaluation of the revised international staging system in multiple myeloma patients treated with novel agents as a primary therapy.

PubMed

Cho, Hyungwoo; Yoon, Dok Hyun; Lee, Jung Bok; Kim, Sung-Yong; Moon, Joon Ho; Do, Young Rok; Lee, Jae Hoon; Park, Yong; Lee, Ho Sup; Eom, Hyeon Seok; Shin, Ho-Jin; Min, Chang-Ki; Kim, Jin Seok; Jo, Jae-Cheol; Kang, Hye Jin; Mun, Yeung-Chul; Lee, Won Sik; Lee, Je-Jung; Suh, Cheolwon; Kim, Kihyun

2017-12-01

The revised International Staging System (R-ISS) has recently been developed to improve the risk stratification of multiple myeloma (MM) patients over the ISS. We assessed the R-ISS in MM patients who were treated with novel agents as a primary therapy and evaluated its discriminative power and ability to reclassify patients from the ISS. A total of 514 newly diagnosed MM patients treated with novel agents including thalidomide, bortezomib, and lenalidomide as a primary therapy were included in this retrospective analysis. With a median follow-up duration of 42.3 months (range, 40.5-44.1), the median overall survival (OS) was 61.0 months. There was a significant difference in median OS (not reached, 60.9, and 50.1 months for stages 1, 2, and 3, respectively, P < 0.001) among the three stages of R-ISS. The C-statistic was significantly greater for R-ISS than for ISS (0.769 vs. 0.696, P < 0.001). The event NRI was -0.08 (95% confidence interval [CI], -0.18-0.01) and the non-event NRI was 0.05 (95% CI, -0.03-0.10), resulting in a total NRI of -0.03 (95% CI, -0.14-0.08, P = 0.602). The R-ISS performs well and has significantly better discriminative power than the ISS in MM patients treated with novel agents as a primary therapy. However, it does not better reclassify patients from the ISS, suggesting that there is still room to improve the staging system. Moreover, new statistical measures for assessing and quantifying the risk prediction of new prognostic models are necessary in future studies. © 2017 Wiley Periodicals, Inc.

Salinity effect of irrigation with treated wastewater in basal soil respiration in SE of Spain

NASA Astrophysics Data System (ADS)

Morugan, A.; Garcia-Orenes, F.; Mataix-Solera, J.

2012-04-01

The use of treated wastewater for the irrigation of agricultural soils is an alternative to utilizing better-quality water, especially in semiarid regions where water shortage is a very serious problem. Wastewater use in agriculture is not a new practice, all over the world this reuse has been common practice for a long time, but the concept is of greater importance currently because of the global water crisis. Replacement of freshwater by treated wastewater is seen as an important conservation strategy contributing to agricultural production, substantial benefits can derive from using this nutrient-rich waste water but there can also be a negative impact. For this reason it is necessary to know precisely the composition of water before applying it to the soil in order to guarantee minimal impact in terms of contamination and salinization. In this work we have been studying, for more than three years, different parameters in calcareous soils irrigated with treated wastewater in an agricultural Mediterranean area located at Biar (Alicante, SE Spain), with a crop of grape (Vitis labrusca). Three types of waters were used for the irrigation of the soil: fresh water (control) (TC), and treated wastewater from secondary (T2) and tertiary treatment (T3). Three different doses of irrigation have been applied to fit the efficiency of the irrigation to the crop and soil type during the study period. A soil sampling was carried out every four months. We show the results of the evolution of basal soil respiration (BSR), and its relationship with other parameters. We observed a similar pattern of behavior for BSR between treatments, a decrease at the first eighteen months of irrigation and an increase at the end of study. In our study case, the variations of BSR obtained for all the treatments seem to be closely related to the dose and frequency of irrigation and the related soil wetting and drying cycles. However, the results showed a negative correlation between BSR and

Immunologic Approaches for the Treatment of Multiple Myeloma

PubMed Central

Rasche, Leo; Weinhold, Niels; Morgan, Gareth J; van Rhee, Frits; Davies, Faith E

2017-01-01

The FDA approval of two monoclonal antibodies in 2015 has heralded a new era of targeted immunotherapies for multiple myeloma (MM). In this review we discuss the recent approaches using different immunological components to treat MM. In particular, we review current monoclonal antibody based therapies, engineered T- and NK cell products, ‘off-target’ immunomodulation, and strategies utilizing allogeneic cell transplantation in MM. We discuss how an immunologic approach offers promise for the treatment of this genetically heterogeneous disease, and how patients with acquired drug resistance may particularly benefit from these therapies. We also describe some of the limitations of the current strategies and speculate on the future of personalized immunotherapies for MM. PMID:28431262

Agricultural Exposures, Multiple Myeloma Etiology: Profile of Jonathan Hofmann

Cancer.gov

Tenure-track investigator Jonathan Hofmann, Ph.D., M.P.H., has established a research program in the Occupational and Environmental Epidemiology Branch focused on the role of agricultural exposures in the etiology of multiple myeloma and other cancers, and on understanding the biological mechanisms that influence the development and progression of multiple myeloma.

Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation

USDA-ARS?s Scientific Manuscript database

A major problem in patients with multiple myeloma is chemotherapy resistance, which develops in myeloma cells upon interaction with bone marrow stromal cells. However, few studies have determined the role of bone marrow adipocytes, a major component of stromal cells in the bone marrow, in myeloma ch...

Intravenous hypertonic saline solution (7.5%) and oral electrolytes to treat of calves with noninfectious diarrhea and metabolic acidosis.

PubMed

Leal, M L R; Fialho, S S; Cyrillo, F C; Bertagnon, H G; Ortolani, E L; Benesi, F J

2012-01-01

The aim of this study was to compare the efficacy of treating osmotic diarrhea and dehydration in calves with hypertonic saline solution (HSS) IV, isotonic electrolyte solution (IES) PO, and a combination of these 2 solutions (HSS + IES). Eighteen male calves 8-30 days of age were used to evaluate the efficacy of 3 methods of fluid therapy after induction of osmotic diarrhea and dehydration. The diarrhea and dehydration were induced by administration of saccharose, spironolactone, and hydrochlorothiazide for 48 hours. The animals were randomly divided into 3 experimental groups: Group 1: 7.2% hypertonic saline solution-HSS (5 mL/kg IV); Group 2: oral isotonic electrolyte solution IES (60 mL/kg PO); or Group 3: HSS+IES. Clinical signs and laboratory finding observed 48 hours post-induction (Time 0) included diarrhea, dehydration, lethargy, and metabolic acidosis. Calves treated with HSS + IES experienced decreases in hematocrit, total protein concentration, albumin concentration, urea nitrogen concentration, and plasma volume as well as increases in blood pH, blood bicarbonate concentration, and central venous pressure between 1 and 3 hours post-treatment. These findings also were observed in animals treated with IES, however, at a slower rate than in the HSS + IES-treated animals. Animals treated with HSS continued to display signs of dehydration, lethargy, and metabolic acidosis 24 hours post-treatment. Treatment with a combination of HSS and IES produced rapid and sustainable correction of hypovolemia and metabolic acidosis in calves with noninfections diarrhea and dehydration. Copyright © 2012 by the American College of Veterinary Internal Medicine.

Data from SILAC-based quantitative analysis of lysates from mouse microglial cells treated with Withaferin A (WA).

PubMed

Narayan, Malathi; Seeley, Kent W; Jinwal, Umesh K

2016-06-01

Mass spectrometry data collected in a study analyzing the effect of withaferin A (WA) on a mouse microglial (N9) cell line is presented in this article. Data was collected from SILAC-based quantitative analysis of lysates from mouse microglial cells treated with either WA or DMSO vehicle control. This article reports all the proteins that were identified in this analysis. The data presented here is related to the published research article on the effect of WA on the differential regulation of proteins in mouse microglial cells [1]. Mass spectrometry data has also been deposited in the ProteomeXchange with the identifier PXD003032.

Non Secretory Multiple Myeloma With Extensive Extramedullary Plasmacytoma: A Diagnostic Dilemma

PubMed Central

Low, Soo Fin; Mohd Tap, Nor Hanani; Kew, Thean Yean; Ngiu, Chai Soon; Sridharan, Radhika

2015-01-01

Multiple myeloma (MM) is characterized by progressive proliferation of malignant plasma cells, usually initiating in the bone marrow. MM can affect any organ; a total of 7 - 18% of patients with MM demonstrate extramedullary involvement at diagnosis. Non-secretory multiple myeloma (NSMM) is a rare variant that accounts for 1 - 5% of all cases of multiple myeloma. The disease is characterized by the absence of monoclonal gammopathy in serum and urine electrophoresis. Our case report highlights the diagnostic challenge of a case of NSMM with extensive extramedullary involvement in a young female patient who initially presented with right shoulder pain and bilateral breasts lumps. Skeletal survey showed multiple lytic bony lesions. The initial diagnosis was primary breast carcinoma with osseous metastases. No monoclonal gammopathy was found in the serum or urine electrophoresis. Bone marrow and breast biopsies revealed marked plasmacytosis. The diagnosis was delayed for a month in view of the lack of clinical suspicion of multiple myeloma in a young patient and scant biochemical expression of non-secretory type of multiple myeloma. PMID:26528383

A Rare Case of Multiple Myeloma with Biclonal Gammopathy.

PubMed

Banerjee, Abhik; Pimpalgaonkar, Kshama; Christy, Alap Lukiyas

2016-12-01

Multiple myeloma is a debilitating malignancy arising from plasma cells. These malignant plasma cells called myeloma cells proliferate and infiltrate the bone marrow. The disease is characterized by the presence of a monoclonal protein in plasma and/or the urine. In this report, we present a case of biclonal multiple myeloma which showed two M bands on serum protein electrophoresis. The patient had elevated serum IgA and IgG levels. To reveal the nature of M bands or clonality, serum Immunofixation study was performed which revealed IgA with Lambda and IgG with Kappa light chains. Such pattern is very rare if we consider the various immunofixation patterns observed in different gammopathies.

A Rare Case of Multiple Myeloma with Biclonal Gammopathy

PubMed Central

Banerjee, Abhik; Christy, Alap Lukiyas

2016-01-01

Multiple myeloma is a debilitating malignancy arising from plasma cells. These malignant plasma cells called myeloma cells proliferate and infiltrate the bone marrow. The disease is characterized by the presence of a monoclonal protein in plasma and/or the urine. In this report, we present a case of biclonal multiple myeloma which showed two M bands on serum protein electrophoresis. The patient had elevated serum IgA and IgG levels. To reveal the nature of M bands or clonality, serum Immunofixation study was performed which revealed IgA with Lambda and IgG with Kappa light chains. Such pattern is very rare if we consider the various immunofixation patterns observed in different gammopathies. PMID:28208846

Abnormal Notochord Branching Is Associated with Foregut Malformations in the Adriamycin Treated Mouse Model

PubMed Central

Hajduk, Piotr; Sato, Hideaki; Puri, Prem; Murphy, Paula

2011-01-01

Oesophageal atresia (OA) and tracheooesophageal fistula (TOF) are relatively common human congenital malformations of the foregut where the oesophagus does not connect with the stomach and there is an abnormal connection between the stomach and the respiratory tract. They require immediate corrective surgery and have an impact on the future health of the individual. These abnormalities are mimicked by exposure of rat and mouse embryos in utero to the drug adriamycin. The causes of OA/TOF during human development are not known, however a number of mouse mutants where different signalling pathways are directly affected, show similar abnormalities, implicating multiple and complex signalling mechanisms. The similarities in developmental outcome seen in human infants and in the adriamycin treated mouse model underline the potential of this model to unravel the early embryological events and further our understanding of the processes disturbed, leading to such abnormalities. Here we report a systematic study of the foregut and adjacent tissues in embryos treated with adriamycin at E7 and E8 and analysed between E9 and E12, comparing morphology in 3D in 149 specimens. We describe a spectrum of 8 defects, the most common of which is ventral displacement and branching of the notochord (in 94% of embryos at E10) and a close spatial correspondence between the site of notochord branching and defects of the foregut. In addition gene expression analysis shows altered dorso-ventral foregut patterning in the vicinity of notochord branches. This study shows a number of features of the adriamycin mouse model not previously reported, implicates the notochord as a primary site of disturbance in such abnormalities and underlines the importance of the model to further address the mechanistic basis of foregut congenital abnormalities. PMID:22132119

Abnormal notochord branching is associated with foregut malformations in the adriamycin treated mouse model.

PubMed

Hajduk, Piotr; Sato, Hideaki; Puri, Prem; Murphy, Paula

2011-01-01

Oesophageal atresia (OA) and tracheooesophageal fistula (TOF) are relatively common human congenital malformations of the foregut where the oesophagus does not connect with the stomach and there is an abnormal connection between the stomach and the respiratory tract. They require immediate corrective surgery and have an impact on the future health of the individual. These abnormalities are mimicked by exposure of rat and mouse embryos in utero to the drug adriamycin. The causes of OA/TOF during human development are not known, however a number of mouse mutants where different signalling pathways are directly affected, show similar abnormalities, implicating multiple and complex signalling mechanisms. The similarities in developmental outcome seen in human infants and in the adriamycin treated mouse model underline the potential of this model to unravel the early embryological events and further our understanding of the processes disturbed, leading to such abnormalities. Here we report a systematic study of the foregut and adjacent tissues in embryos treated with adriamycin at E7 and E8 and analysed between E9 and E12, comparing morphology in 3D in 149 specimens. We describe a spectrum of 8 defects, the most common of which is ventral displacement and branching of the notochord (in 94% of embryos at E10) and a close spatial correspondence between the site of notochord branching and defects of the foregut. In addition gene expression analysis shows altered dorso-ventral foregut patterning in the vicinity of notochord branches. This study shows a number of features of the adriamycin mouse model not previously reported, implicates the notochord as a primary site of disturbance in such abnormalities and underlines the importance of the model to further address the mechanistic basis of foregut congenital abnormalities.

Durum wheat seedlings in saline conditions: Salt spray versus root-zone salinity

NASA Astrophysics Data System (ADS)

Spanò, Carmelina; Bottega, Stefania

2016-02-01

Salinity is an increasingly serious problem with a strong negative impact on plant productivity. Though many studies have been made on salt stress induced by high NaCl concentrations in the root-zone, few data concern the response of plants to saline aerosol, one of the main constraints in coastal areas. In order to study more in depth wheat salinity tolerance and to evaluate damage and antioxidant response induced by various modes of salt application, seedlings of Triticum turgidum ssp. durum, cv. Cappelli were treated for 2 and 7 days with salt in the root-zone (0, 50 and 200 mM NaCl) or with salt spray (400 mM NaCl + 0 or 200 mM NaCl in the root-zone). Seedlings accumulated Na+ in their leaves and therefore part of their ability to tolerate high salinity seems to be due to Na+ leaf tissue tolerance. Durum wheat, confirmed as a partially tolerant plant, shows a higher damage under airborne salinity, when both an increase in TBA-reactive material (indicative of lipid peroxidation) and a decrease in root growth were recorded. A different antioxidant response was activated, depending on the type of salt supply. Salt treatment induced a depletion of the reducing power of both ascorbate and glutathione while the highest contents of proline were detected under salt spray conditions. In the short term catalase and ascorbate peroxidase co-operated with glutathione peroxidase in the scavenging of hydrogen peroxide, in particular in salt spray-treated plants. From our data, the durum wheat cultivar Cappelli seems to be sensitive to airborne salinity.

Double hemibody irradiation (DHBI) in the management of relapsed and primary chemoresistant multiple myeloma.

PubMed

McSweeney, E N; Tobias, J S; Blackman, G; Goldstone, A H; Richards, J D

1993-01-01

In view of increasing controversy regarding the role of double hemibody irradiation (DHBI) in the treatment of multiple myeloma, we have analysed the use of this technique at our institution over a 6-year period. Fifty-five patients with multiple myeloma were treated with both upper and lower hemibody irradiation between January 1985 and January 1991; 42 had relapsed post-plateau and 13 were chemoresistant to initial therapy. Fifteen patients received alpha IFN-2b maintenance therapy post-DHBI, at a dose of 3 Mu three times per week, as part of a randomized trial. Ninety-five per cent of patients experienced symptomatic improvement in bone pain post-DHBI, 21% of whom discontinued opiate analgesics altogether; 63% had a minor biochemical response and 38% had a partial biochemical response. The overall survival (OS) and progression free survivals (PFS) in all patients were 11 months and 8 months respectively. No significant difference was noted in either OS or PFS, according to whether patients were chemoresistant or had relapsed post-plateau. alpha IFN did not appear to prolong survival (OS or PFS) post-DHBI. Cytopenia was a significant problem, such that only 60% of patients had counts adequate enough to be eligible for alpha IFN. We conclude that DHBI is an effective treatment in patients with relapsed multiple myeloma and in those who are chemoresistant to initial therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Fetal DNA does not induce preeclampsia-like symptoms when delivered in late pregnancy in the mouse.

PubMed

Čonka, Jozef; Konečná, Barbora; Lauková, Lucia; Vlková, Barbora; Celec, Peter

2017-04-01

The etiology of preeclampsia is unclear. Fetal DNA is present in higher concentrations in the plasma of pregnant women suffering from preeclampsia than in the plasma of healthy pregnant women. A previously published study has shown that human fetal DNA injected into pregnant mice induces preeclampsia-like symptoms when administered between gestation days 10-14. The aim of our experiment was to determine whether or not similar effects would be induced by administration of human and mouse fetal DNA, as well as mouse adult DNA and lipopolysaccharide during late pregnancy in the mouse. Experimental animals were injected daily intraperitoneally during gestation days 14-18 with either saline - negative control, lipopolysaccharide - positive control, or various types of DNA. On gestation day 19, blood pressure and proteinuria were measured, and placental and fetal weights were recorded. Fetal and placental hypotrophy were induced only by lipopolysaccharide (p < 0.001). Neither fetal nor adult DNA induced changes in fetal/placental weight. None of the experimental groups had higher blood pressure or urinary protein in comparison to saline treated animals. In our experiment, we found that there was no effect from intraperitoneally injected human fetal DNA, mouse fetal DNA, or mouse adult DNA on pregnant mice. Additionally, relatively high doses of various types of DNA did not induce preeclampsia-like symptoms in mice when administered in late pregnancy. Our negative results support the hypothesis that the increase of fetal DNA circulating in maternal circulation during the third trimester is rather a consequence than a cause of preeclampsia. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safe adalimumab therapy for rheumatoid arthritis in a patient with pre-existing multiple myeloma.

PubMed

Mielke, Frank; Schweigert, Marcus

2008-04-01

We report on a patient with rheumatoid arthritis (RA) who was treated with adalimumab and retrospectively diagnosed as having a multiple myeloma. In addition to the determination of clinical symptoms, investigations included radiography of the thorax, spine, hands and feet, arthrosonography, determination of laboratory parameters (including C-reactive protein levels and presence of antibodies against cyclic citrullinated peptide), cytogenetics and electrocardiography. RA was initially diagnosed in 1988. Stage II and stage III RA were diagnosed for the left and right foot, respectively, in 1996. Joints of both hands were diagnosed with stage I RA; both wrists and some finger joints showed signs of synovitis. Plasmocytoma was diagnosed in 2004; however, investigation of medical records revealed evidence of multiple myeloma 8 years earlier, in 1996. RA was originally treated with gold, sulfasalazine, azathioprin and glucocorticoid. Methotrexate was later used in addition to cortisone and then in combination with a selective cyclo-oxygenase-2 inhibitor. A combination therapy consisting of adalimumab (40 mg every 2 weeks), methotrexate (15 mg weekly) and a cyclo-oxygenase-2 inhibitor (rofecoxib 25 mg daily until July 2004, etoricoxib 90 mg daily from October 2004) was started in November 2003. Adalimumab therapy was interrupted for 6 months owing to safety concerns, but was resumed after a careful risk-benefit assessment.

Multiple myeloma phosphotyrosine proteomic profile associated with FGFR3 expression, ligand activation, and drug inhibition

PubMed Central

St-Germain, Jonathan R.; Taylor, Paul; Tong, Jiefei; Jin, Lily L.; Nikolic, Ana; Stewart, Ian I.; Ewing, Robert M.; Dharsee, Moyez; Li, Zhihua; Trudel, Suzanne; Moran, Michael F.

2009-01-01

Signaling by growth factor receptor tyrosine kinases is manifest through networks of proteins that are substrates and/or bind to the activated receptors. FGF receptor-3 (FGFR3) is a drug target in a subset of human multiple myelomas (MM) and is mutationally activated in some cervical and colon and many bladder cancers and in certain skeletal dysplasias. To define the FGFR3 network in multiple myeloma, mass spectrometry was used to identify and quantify phosphotyrosine (pY) sites modulated by FGFR3 activation and inhibition in myeloma-derived KMS11 cells. Label-free quantification of peptide ion currents indicated the activation of FGFR3 by phosphorylation of tandem tyrosines in the kinase domain activation loop when cellular pY phosphatases were inhibited by pervanadate. Among the 175 proteins that accumulated pY in response to pervanadate was a subset of 52 including FGFR3 that contained a total of 61 pY sites that were sensitive to inhibition by the FGFR3 inhibitor PD173074. The FGFR3 isoform containing the tandem pY motif in its activation loop was targeted by PD173074. Forty of the drug-sensitive pY sites, including two located within the 35-residue cytoplasmic domain of the transmembrane growth factor binding proteoglycan (and multiple myeloma biomarker) Syndecan-1/CD138, were also stimulated in cells treated with the ligand FGF1, providing additional validation of their link to FGFR3. The identification of these overlapping sets of co-modulated tyrosine phosphorylations presents an outline of an FGFR3 network in the MM model and demonstrates the potential for pharmacodynamic monitoring by label-free quantitative phospho-proteomics. PMID:19901323

Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results

PubMed Central

Morgan, Gareth J.; Davies, Faith E.; Gregory, Walter M.; Bell, Sue E.; Szubert, Alexander J.; Navarro Coy, Nuria; Cook, Gordon; Feyler, Sylvia; Johnson, Peter R.E.; Rudin, Claudius; Drayson, Mark T.; Owen, Roger G.; Ross, Fiona M.; Russell, Nigel H.; Jackson, Graham H.; Child, J. Anthony

2012-01-01

Background Thalidomide is active in multiple myeloma and is associated with minimal myelosuppression, making it a good candidate for induction therapy prior to high-dose therapy with autologous stem-cell transplantation. Design and Methods Oral cyclophosphamide, thalidomide, and dexamethasone was compared with infusional cyclophosphamide, vincristine, doxorubicin, and dexamethasone in patients with newly diagnosed multiple myeloma. Results The post-induction overall response rate (≥ partial response) for the intent-to-treat population was significantly higher with cyclophosphamide-thalidomide-dexamethasone (n=555) versus cyclophosphamide-vincristine-doxorubicin-dexamethasone (n=556); 82.5% versus 71.2%; odds ratio 1.91; 95% confidence interval 1.44–2.55; P<0.0001. The complete response rates were 13.0% with cyclophosphamide-thalidomide-dexamethasone and 8.1% with cyclophos-phamide-vincristine-doxorubicin-dexamethasone (P=0.0083), with this differential response being maintained in patients who received autologous stem-cell transplantation (post-transplant complete response 50.0% versus 37.2%, respectively; P=0.00052). Cyclophosphamide-thalidomide-dexamethasone was non-inferior to cyclophosphamide-vincristine-doxorubicin-dexamethasone for progression-free and overall survival, and there was a trend toward a late survival benefit with cyclophosphamide-thalidomide-dexamethasone in responders. A trend toward an overall survival advantage for cyclophosphamide-thalidomide-dexamethasone over cyclophosphamide-vincristine-doxorubicin-dexamethasone was also observed in a subgroup of patients with favorable interphase fluorescence in situ hybridization. Compared with cyclophosphamide-vincristine-doxorubicin-dexamethasone, cyclophosphamide-thalidomide-dexamethasone was associated with more constipation and somnolence, but a lower incidence of cytopenias. Conclusions The cyclophosphamide-thalidomide-dexamethasone regimen showed improved response rates and was not inferior

Smoldering Multiple Myeloma

PubMed Central

Gao, Minjie; Yang, Guang; Kong, Yuanyuan; Wu, Xiaosong; Shi, Jumei

2015-01-01

Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage of multiple myeloma (MM) characterized by clonal bone marrow plasma cells (BMPC) ≥ 10% and/or M protein level ≥ 30 g/L in the absence of end organ damage. It represents an intermediate stage between monoclonal gammopathy of undetermined significance (MGUS) and symptomatic MM. The risk of progression to symptomatic MM is not uniform, and several parameters have been reported to predict the risk of progression. These include the level of M protein and the percentage of BMPC, the proportion of immunophenotypically aberrant plasma cells, and the presence of immunoparesis, free light-chain (FLC) ratio, peripheral blood plasma cells (PBPC), pattern of serum M protein evolution, abnormal magnetic resonance imaging (MRI), cytogenetic abnormalities, IgA isotype, and Bence Jones proteinuria. So far treatment is still not recommended for SMM, because several trials suggested that patients with SMM do not benefit from early treatment. However, the Mateos et al. trial showed a survival benefit after early treatment with lenalidomide plus dexamethasone in patients with high-risk SMM. This trial has prompted a reevaluation of early treatment in an asymptomatic patient population. PMID:26000300

Hypothalamic digoxin, hemispheric chemical dominance, and oncogenesis: evidence from multiple myeloma.

PubMed

Kurup, Ravi Kumar; Kurup, Paramesware Achutha

2003-12-01

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol, and ubiquinone in multiple myeloma. The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find out the rote of cerebral dominance in the genesis of multiple myeloma and neoplasms. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition, and free radical metabolism--in multiple myeloma, as well as in individuals of differing hemispheric dominance. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol, and a reduction in RBC membrane Na(+)-K+ ATPase activity, serum ubiquinone, and magnesium levels. Serum tryptophan, serotonin, nicotine, strychnine, and quinolinic acid were elevated, while tyrosine, dopamine, noradrenaline, and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins, cholesterol, and phospholipids were reduced. The activity of all free-radical scavenging enzymes, concentration of glutathione, iron binding capacity, and ceruloplasmin decreased significantly, while the concentration of lipid peroxidation products and nitric oxide increased. Hyperdigoxinemia-related altered intracellular Ca++/Mg++ ratios mediated oncogene activation, dolichol-induced altered glycoconjugate metabolism, and ubiquinone deficiency-related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical patterns obtained in multiple myeloma are similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. But all the patients with

Ibrutinib targets microRNA-21 in multiple myeloma cells by inhibiting NF-κB and STAT3.

PubMed

Ma, Jing; Gong, Wei; Liu, Su; Li, Qian; Guo, Mengzheng; Wang, Jinhan; Wang, Suying; Chen, Naiyao; Wang, Yafei; Liu, Qiang; Zhao, Hui

2018-01-01

The oncogenic microRNA-21 contributes to the pathogenesis of multiple myeloma. Ibrutinib (also referred to as PCI-32765), an inhibitor of Bruton's tyrosine kinase, while its effects on multiple myeloma have not been well described. Here, we show that microRNA-21 is an oncogenic marker closely linked with progression of multiple myeloma. Moreover, ibrutinib attenuates microRNA-21 expression in multiple myeloma cells by inhibiting nuclear factor-κB and signal transducer and activator of transcription 3 signaling pathways. Taken together, our results suggest that ibrutinib is a promising potential treatment for multiple myeloma. Further investigation of mechanisms of ibrutinib function in multiple myeloma will be necessary to evaluate its use as a novel multiple myeloma treatment.

FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells

PubMed Central

Suvannasankha, Attaya; Tompkins, Douglas R.; Edwards, Daniel F.; Petyaykina, Katarina V.; Crean, Colin D.; Fournier, Pierrick G.; Parker, Jamie M.; Sandusky, George E.; Ichikawa, Shoji; Imel, Erik A.; Chirgwin, John M.

2015-01-01

Multiply myeloma (MM) grows in and destroys bone, where osteocytes secrete FGF23, a hormone which affects phosphate homeostasis and aging. We report that multiple myeloma (MM) cells express receptors for and respond to FGF23. FGF23 increased mRNA for EGR1 and its target heparanase, a pro-osteolytic factor in MM. FGF23 signals through a complex of klotho and a classical FGF receptor (FGFR); both were expressed by MM cell lines and patient samples. Bone marrow plasma cells from 42 MM patients stained positively for klotho, while plasma cells from 8 patients with monoclonal gammopathy of undetermined significance (MGUS) and 6 controls were negative. Intact, active FGF23 was increased 2.9X in sera of MM patients compared to controls. FGF23 was not expressed by human MM cells, but co-culture with mouse bone increased its mRNA. The FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23. NVP-BGJ398 did not inhibit 8226 growth in vitro but significantly suppressed growth in bone and induction of the osteoclast regulator RANK ligand, while decreasing heparanase mRNA. The bone microenvironment provides resistance to some anti-tumor drugs but increased the activity of NVP-BGJ398 against 8226 cells. The FGF23/klotho/heparanase signaling axis may offer targets for treatment of MM in bone. PMID:25944690

Late diagnosis of multiple myeloma: a case report

NASA Astrophysics Data System (ADS)

Syahreza, A.; Gatot, D.; Mardia, A. I.

2018-03-01

Multiple myeloma is a challenging hematologic case to handle. Sometimes the disease is diagnosed too late for the patient and doctor. Therefore, careful approaches are needed to manage the patient. A 66-year-old mansuffersfrom low back pain since one year before he came to the hospital. He was diagnosed multiple compression fractures by orthopedic and had undergone two surgeries in one year. Punched out lesions werein skull radiology and lumbar compression in lumbar MRI. After further investigation, plasmacytoma and M protein in urine electrophoresis were founded. Significant improvement found after bortezomib and dexamethasone were given.Diagnosis and management of multiple myeloma is a challenge for a doctor. Systematically approach is needed for a patient with a recurrent fracture. Even a novel therapies are not widely available in our country.We reported a late diagnosis of multiple myeloma and had a significant improvement after bortezomib and dexamethasone therapy.

A look at treatment strategies for relapsed multiple myeloma.

PubMed

Cetani, Giusy; Boccadoro, Mario; Oliva, Stefania

2018-05-16

Multiple myeloma treatment considerably improved during the past decade, thanks to novel effective drugs, a better understanding of myeloma biology and clonal heterogeneity, and an improved management of toxicities. The choice of regimen at relapse is usually based on prior response, toxicities, age and comorbidities of relapsed patients. Areas covered: A review was performed of the most recent and effective therapeutic strategies for the relapsed myeloma setting, by documenting the latest clinical evidence from phase II and III clinical trials. Of note, new drugs, such as carfilzomib, ixazomib, pomalidomide, daratumumab and elotuzumab, alone or in combinations in doublet or triplet regimens, have greatly increased the treatment armamentarium against myeloma. Expert Commentary: Impressive results have been obtained with new drugs in relapsed patients. Besides number of prior therapies and previous response, other factors play a crucial role in the selection of therapy. Re-challenge with previous drugs can be adopted if previous responses lasted at least 6 months and therapy had induced low toxicity. Patients' risk status can further help to appropriately select therapy at relapse, and clinical trials will allow physicians to use newer targeted therapies and immune-therapies, thus delaying palliative approaches to later relapse stages.

Roles of Macrophages and Neutrophils in the Early Host Response to Bacillus anthracis Spores in a Mouse Model of Infection

PubMed Central

Cote, Christopher K.; Van Rooijen, Nico; Welkos, Susan L.

2006-01-01

The development of new approaches to combat anthrax requires that the pathogenesis and host response to Bacillus anthracis spores be better understood. We investigated the roles that macrophages and neutrophils play in the progression of infection by B. anthracis in a mouse model. Mice were treated with a macrophage depletion agent (liposome-encapsulated clodronate) or with a neutrophil depletion agent (cyclophosphamide or the rat anti-mouse granulocyte monoclonal antibody RB6-8C5), and the animals were then infected intraperitoneally or by aerosol challenge with fully virulent, ungerminated B. anthracis strain Ames spores. The macrophage-depleted mice were significantly more susceptible to the ensuing infection than the saline-pretreated mice, whereas the differences observed between the neutropenic mice and the saline-pretreated controls were generally not significant. We also found that augmenting peritoneal neutrophil populations before spore challenge did not increase resistance of the mice to infection. In addition, the bacterial load in macrophage-depleted mice was significantly greater and appeared significantly sooner than that observed with the saline-pretreated mice. However, the bacterial load in the neutropenic mice was comparable to that of the saline-pretreated mice. These data suggest that, in our model, neutrophils play a relatively minor role in the early host response to spores, whereas macrophages play a more dominant role in early host defenses against infection by B. anthracis spores. PMID:16369003

Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling

PubMed Central

Accardi, Fabrizio; Toscani, Denise; Dalla Palma, Benedetta; Aversa, Franco; Giuliani, Nicola

2015-01-01

Multiple myeloma (MM) is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI) bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease. PMID:26579531

[Effect of thalidomide combined with dexamethasone on multiple myeloma KM3 cells].

PubMed

He, Bin; Zhang, Yu; Zhou, Wei; Gao, Na; Gao, Bo; Gu, Jian; Li, Jian-Yong

2009-08-01

The purpose of this study was to investigate the effect of thalidomide (THD) combined with dexamethasone (Dx) on multiple myeloma KM3 cells and its mechanism. The effect of the different concentrations and treatment time of THD or THD + Dx on KM3 cells was assayed by cytotoxicity test (MTT method), the inhibitory ratio of THD or THD + Dx on the KM3 cell growth was detected for choosing the best intervention condition. The expression levels of IL-6, TNF-alpha, VEGF, ES, survivin in supernatant of cells treated with best intervention condition were measured by indirect ELISA. The results indicated that an enhancement of cell growth inhibition was observed in treated KM3 cells along with increasing of drug concentrations and prolonging of treatment times, at the same time the THD combined with Dx could significantly inhibit the KM3 cell growth. The combination of THD in concentration of 80 or 100 microg/ml with Dx in concentration of 4 microg/ml decreased the expression of IL-6, TNF-alpha and survivin, increased the expression of ES, while no influence on VEGF expression was found. It is concluded that THD combined with Dx shows the synergistic inhibitory effect on KM3 cells, they bring the effect resistant to multiple myeloma probably through down-regulating the expression of IL-6, TNF-alpha and survivin, and up-regulating the expression of ES in KM3 cell.

Endothelial stress products and coagulation markers in patients with multiple myeloma treated with lenalidomide plus dexamethasone: an observational study

PubMed Central

Rosovsky, Rachel; Hong, Fangxin; Tocco, Deanna; Connell, Brendan; Mitsiades, Constantine; Schlossman, Robert; Ghobrial, Irene; Lockridge, Leslie; Warren, Diane; Bradwin, Gary; Doyle, Mary; Munshi, Nikhil; Soiffer, Robert J.; Anderson, Kenneth C.; Weller, Edie; Richardson, Paul

2014-01-01

Summary In this prospective study of patients with relapsed and/or refractory multiple myeloma (MM) treated with lenalidomide and dexamethasone, relationships between markers of endothelial stress and drug administration and incidence of venous thromboembolism (VTE) were assessed. Of 33 enrolled patients, laboratory and treatment data were available for 32 patients. Of these, 23 received pulsed dexamethasone (40 mg/day on days 1–4, 9–12, and 17–21 of each 28-day cycle) and 9 received weekly dexamethasone (40 mg/day on days 1, 8, 15, and 21 of each cycle). The overall incidence of VTE was 9%. A decreasing trend in markers values was observed with intercellular adhesion molecule (P = 0·05), fibrinogen (P = 0·008), plasminogen activator inhibitor-1 (P < 0·001), homocysteine (P = 0·002), and P-selectin (P < 0·001) during therapy. Compared with weekly dexamethasone, pulsed dexamethasone was associated with significantly greater variation in mean adjusted relative values of fibrinogen, P-selectin, and vascular endothelial growth factor (P < 0·001 for all comparisons), although there was no apparent association with VTE incidence. Lenalidomide plus dexamethasone affects endothelial stress marker levels in patients with advanced MM. The higher variation seen with pulsed dexamethasone suggests greater endothelial stress with this approach. PMID:23240658

Multiple Myeloma Index for Risk of Infection.

PubMed

T, Valkovic; V, Gacic; A, Nacinovic-Duletic

2018-01-01

Based on our earlier research into the main characteristics and risk factors for infections in hospitalized patients with multiple myeloma, we created the numerical Multiple Myeloma Index for Risk of Infection (MMIRI) to predict infection in myeloma patients. The included factors that could influence the pathogenesis and incidence of infections were sex, performance status, Durie Salmon stage of disease, International Staging System, serum creatinine level, immune paresis, neutropenia, serum ferritin level, the presence of any catheters, disease duration, stable/progressive disease, and type of therapy. For each of these parameters, the strength of association with infection was statistically estimated and specific number of points was assigned to each of these parameters, proportional to the strength of the association. When designing the MMIRI, we included only those parameters that we determined were pathophysiologically associated with the infection. After further statistical analysis, we identified an optimal cutoff score of 6 or above as indicating a significant risk for infection, with a sensitivity of 93.2% and specificity of 80.2%. The scoring system in the retrospective receiver operating characteristic analysis showed an area under the curve of 0.918. The potential value of the MMIRI is the possibility of identifying those patients who would benefit from the prophylactic administration of antibiotics and other anti-infective measures while minimizing the contribution to antibiotic resistance related to the overuse of these drugs. As far as we know, this index represents the first attempt to create such an instrument for predicting the occurrence of infections in myeloma patients.

Bone marrow invasion in multiple myeloma and metastatic disease.

PubMed

Vilanova, J C; Luna, A

2016-04-01

Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases. Copyright © 2015 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Cold physical plasma treated buffered saline solution as effective agent against pancreatic cancer cells.

PubMed

Bekeschus, Sander; Kading, Andre; Schroder, Tim; Wende, Kristian; Hackbarth, Christine; Liedtke, Kim Rouven; van der Linde, Julia; von Woedtke, Thomas; Heidecke, Claus-Dieter; Partecke, Lars-Ivo

2018-05-07

Cold physical plasma has been suggested as a new anticancer tool recently. However, direct use of plasma is limited to visible tumors and in some clinical situations not feasible. This includes repetitive treatment of peritoneal metastases which commonly occur in advanced gastrointestinal cancer and in pancreatic cancer in particular. In case of diffuse intraperitoneal metastatic spread Hyperthermic Intraperitoneal Intraoperative Chemotherapy (HIPEC) is used as therapeutic approach. Plasma treated solutions may combine their suspected systemic non-toxic characteristics with the anticancer effects of HIPEC. Previous work has provided evidence for an anti-cancer efficacy of plasma treated cell culture medium but the clinical relevance of such an approach is low due to its complex formulation and lack of medical accreditation. Therefore, plasma treated phosphate-buffered saline (PBS) which closely resembles medically certified solutions was investigated for its cytotoxic effect on 2D monolayer murine pancreatic cancer cells in vitro. It significantly decreased cancer cell metabolisms and proliferation whereas plasma treated Dulbecco's Modified Eagle Medium had no effect. Moreover, tumor cell growth attenuation was significantly higher when compared to syngeneic primary murine fibroblasts. Both results were confirmed in a human pancreatic cancer cell line. Finally, plasma treated PBS also decreased tumor sizes of pancreatic tumors in the TUM-CAM model in a three-dimensional manner, and induction of apoptosis was found to be responsible for all anticancer effects identified. Altogether, plasma treated PBS inhibited cell growth in 2D and 3D models of cancer. These results may help facilitating the development of new plasma derived anticancer agent with clinical relevance in the future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Hypertonic saline or mannitol for treating elevated intracranial pressure in traumatic brain injury: a meta-analysis of randomized controlled trials.

PubMed

Gu, Jiajie; Huang, Haoping; Huang, Yuejun; Sun, Haitao; Xu, Hongwu

2018-06-15

Hyperosmolar therapy is regarded as the mainstay for treatment of elevated intracranial pressure (ICP) in traumatic brain injury (TBI). This still has been disputed as application of hypertonic saline (HS) or mannitol for treating patients with severe TBI. Thus, this meta-analysis was performed to further compare the advantages and disadvantages of mannitol with HS for treating elevated ICP after TBI. We conducted a systematic search on PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Wan Fang Data, VIP Data, SinoMed, and China National Knowledge Infrastructure (CNKI) databases. Studies were included or not based on the quality assessment by the Jadad scale and selection criteria. Twelve RCTs with 438 patients were enrolled for the meta-analysis. The comparison of HS and mannitol indicated that they were close in field of improving function outcome (RR = 1.17, 95% CI 0.89 to 1.54, p = 0.258) and reducing intracranial pressure (MD = - 0.16, 95% CI: - 0.59 to 0.27, p = 0.473) and mortality (RR = 0.78, 95% CI 0.53 to 1.16, p = 0.216). The pooled relative risk of successful ICP control was 1.06 (95% CI: 1.00 to 1.13, p = 0.044), demonstrating that HS was more effective than mannitol in ICP management. Both serum sodium (WMD = 5.30, 95% CI: 4.37 to 6.22, p < 0.001) and osmolality (WMD = 3.03, 95% CI: 0.18 to 5.88, p = 0.037) were increased after injection of hypertonic saline. The results do not lend a specific recommendation to select hypertonic saline or mannitol as a first-line for the patients with elevated ICP caused by TBI. However, for the refractory intracranial hypertension, hypertonic saline seems to be preferred.

Comparison of embryo development between intracytoplasmic and Piezo-assisted sperm injection after treating mouse sperms by Ca2+ ionophore.

PubMed

Shahverdi, Abdolhossein; Movahedin, Mansoureh; Rezazadeh Valojerdi, Mojtaba; Kazemi Ashtiani, Saeid

2007-10-01

The purpose of this study was to evaluate the efficiency of intracytoplasmic sperm injection (ICSI) and Piezo-assisted sperm injection after pretreatment with calcium ionophore (CaI) on the mouse embryo development. In this study, the conventional ICSI and Piezo-ICSI procedures were used. The efficacy of the methods was examined after mouse matured oocytes were fertilized with or without CaI-treated sperms. Piezo-ICSI demonstrated significantly more favorable results, with a fertilization rate of 64% (conventional ICSI: 42%, P<0.001) and a cleavage rate of 73% (conventional ICSI: 58%, P<0.05). When the Piezo-ICSI procedure was performed with CaI-pretreated sperms, the cleavage rate significantly increased (92% vs. 73%, P<0.05). However, the fertilization rate did not change significantly (64% vs. 56%). The Piezo-ICSI accompanies with CaI-treated sperms is more efficient than the conventional ICSI method for fertilizing and thus obtaining more mouse embryos.

Propensity score matching analysis to evaluate the comparative effectiveness of daratumumab versus real-world standard of care therapies for patients with heavily pretreated and refractory multiple myeloma.

PubMed

Kumar, Shaji; Durie, Brian; Nahi, Hareth; Vij, Ravi; Dimopoulos, Meletios A; Kastritis, Efstathios; Terpos, Evangelos; Leleu, Xavier; Beksac, Meral; Goldschmidt, Hartmut; Hillengass, Jens; Su, Zhuo; Hutton, Brian; Cameron, Chris; Khan, Imran; Lam, Annette

2018-05-09

Daratumumab is a CD38-directed monoclonal antibody approved for treating multiple myeloma (MM). Propensity score matching (PSM) based on individual patient data (IPD) was conducted to compare overall survival (OS) and progression-free survival (PFS) for daratumumab versus real-world standard of care (SOC). IPD for patients with relapsed and refractory (RR) MM treated with daratumumab monotherapy were from the GEN501 and SIRIUS studies; IPD for patients treated with SOC were from an International Myeloma Working Group (IMWG) chart review of patients with RRMM. Prior to PSM, patients treated with daratumumab had significantly longer OS (median 20.1 vs. 10.1 months, hazard ratio [HR] = 0.51 [0.39-0.67]) and PFS (median 4.0 vs. 2.8 months, HR = 0.73 [0.58-0.92]) than patients treated with SOC therapies. After PSM, daratumumab maintained a significantly prolonged OS (19.9 vs. 9.2 months, HR = 0.44 [0.31-0.63]) and PFS (3.9 vs. 1.6 months, HR = 0.56 [0.42-0.74]) compared with SOC.

Evaluation of Revised International Staging System (R-ISS) for transplant-eligible multiple myeloma patients.

PubMed

González-Calle, Verónica; Slack, Abigail; Keane, Niamh; Luft, Susan; Pearce, Kathryn E; Ketterling, Rhett P; Jain, Tania; Chirackal, Sintosebastian; Reeder, Craig; Mikhael, Joseph; Noel, Pierre; Mayo, Angela; Adams, Roberta H; Ahmann, Gregory; Braggio, Esteban; Stewart, A Keith; Bergsagel, P Leif; Van Wier, Scott A; Fonseca, Rafael

2018-04-06

The International Myeloma Working Group has proposed the Revised International Staging System (R-ISS) for risk stratification of multiple myeloma (MM) patients. There are a limited number of studies that have validated this risk model in the autologous stem cell transplant (ASCT) setting. In this retrospective study, we evaluated the applicability and value for predicting survival of the R-ISS model in 134 MM patients treated with new agents and ASCT at the Mayo Clinic in Arizona and the University Hospital of Salamanca in Spain. The patients were reclassified at diagnosis according to the R-ISS: 44 patients (33%) had stage I, 75 (56%) had stage II, and 15 (11%) had stage III. After a median follow-up of 60 months, R-ISS assessed at diagnosis was an independent predictor for overall survival (OS) after ASCT, with median OS not reached, 111 and 37 months for R-ISS I, II and III, respectively (P < 0.001). We also found that patients belonging to R-ISS II and having high-risk chromosomal abnormalities (CA) had a significant shorter median OS than those with R-ISS II without CA: 70 vs. 111 months, respectively. Therefore, this study lends further support for the R-ISS as a reliable prognostic tool for estimating survival in transplant myeloma patients and suggests the importance of high-risk CA in the R-ISS II group.

Cold atmospheric plasma as a potential tool for multiple myeloma treatment.

PubMed

Xu, Dehui; Xu, Yujing; Cui, Qingjie; Liu, Dingxin; Liu, Zhijie; Wang, Xiaohua; Yang, Yanjie; Feng, Miaojuan; Liang, Rong; Chen, Hailan; Ye, Kai; Kong, Michael G

2018-04-06

Multiple myeloma (MM) is a fatal and incurable hematological malignancy thus new therapy need to be developed. Cold atmospheric plasma, a new technology that could generate various active species, could efficiently induce various tumor cells apoptosis. More details about the interaction of plasma and tumor cells need to be addressed before the application of gas plasma in clinical cancer treatment. In this study, we demonstrate that He+O 2 plasma could efficiently induce myeloma cell apoptosis through the activation of CD95 and downstream caspase cascades. Extracellular and intracellular reactive oxygen species (ROS) accumulation is essential for CD95-mediated cell apoptosis in response to plasma treatment. Furthermore, p53 is shown to be a key transcription factor in activating CD95 and caspase cascades. More importantly, we demonstrate that CD95 expression is higher in tumor cells than in normal cells in both MM cell lines and MM clinical samples, which suggests that CD95 could be a favorable target for plasma treatment as it could selectively inactivate myeloma tumor cells. Our results illustrate the molecular details of plasma induced myeloma cell apoptosis and it shows that gas plasma could be a potential tool for myeloma therapy in the future.

[Current approaches in multiple myeloma and other cancer-related bone diseases].

PubMed

Engelhardt, M; Kleber, M; Udi, J; Wäsch, R

2012-05-01

Multiple myeloma (MM) ranges second of all hematological malignancies and occurs most commonly in elderly patients. Almost all MM patients develop bone lesions in the course of their disease or have evidence of bone loss at initial diagnosis. Whole-body conventional radiography remains the gold standard in the diagnostic evaluation, albeit computed tomography (CT) and magnetic resonance imaging (MRI) are increasingly used as complementary techniques in the more sensitive detection of osteolytic processes. Bisphosphonates like zoledronate or pamidronate represent the cornerstone therapeutics in osteolytic disease, and are effective supportives to potent anti-myeloma therapies, including novel agents such as the proteasome inhibitor bortezomib or immunomodulatory drugs (IMIDs, e. g. thalidomide or lenalidomide). Several studies are ongoing to investigate the effects of alternative bone-seeking agents and their therapeutic potential for the management of myeloma bone disease, such as denosumab (RANKL-neutralizing antibody), anti-sclerostin (monoclonal antibody, generated against sclerostin) or sotatercept (potent activin-A inhibitor). This review summarizes the most prominent data on myeloma bone disease pathogenesis, the role of imaging techniques as well as therapy and prevention of lytic complications in myeloma which may similarly or equally be true for other bone metastases-inducing solid tumors. © Georg Thieme Verlag KG Stuttgart · New York.

Cold atmospheric plasma as a potential tool for multiple myeloma treatment

PubMed Central

Cui, Qingjie; Liu, Dingxin; Liu, Zhijie; Wang, Xiaohua; Yang, Yanjie; Feng, Miaojuan; Liang, Rong; Chen, Hailan; Ye, Kai; Kong, Michael G.

2018-01-01

Multiple myeloma (MM) is a fatal and incurable hematological malignancy thus new therapy need to be developed. Cold atmospheric plasma, a new technology that could generate various active species, could efficiently induce various tumor cells apoptosis. More details about the interaction of plasma and tumor cells need to be addressed before the application of gas plasma in clinical cancer treatment. In this study, we demonstrate that He+O2 plasma could efficiently induce myeloma cell apoptosis through the activation of CD95 and downstream caspase cascades. Extracellular and intracellular reactive oxygen species (ROS) accumulation is essential for CD95-mediated cell apoptosis in response to plasma treatment. Furthermore, p53 is shown to be a key transcription factor in activating CD95 and caspase cascades. More importantly, we demonstrate that CD95 expression is higher in tumor cells than in normal cells in both MM cell lines and MM clinical samples, which suggests that CD95 could be a favorable target for plasma treatment as it could selectively inactivate myeloma tumor cells. Our results illustrate the molecular details of plasma induced myeloma cell apoptosis and it shows that gas plasma could be a potential tool for myeloma therapy in the future. PMID:29719586

Combination therapy with carfilzomib, lenalidomide and dexamethasone (KRd) results in an unprecedented purity of the stem cell graft in newly diagnosed patients with myeloma.

PubMed

Tageja, Nishant; Korde, Neha; Kazandjian, Dickran; Panch, Sandhya; Manasanch, Elisabet; Bhutani, Manisha; Kwok, Mary; Mailankody, Sham; Yuan, Constance; Stetler-Stevenson, Maryalice; Leitman, Susan F; Sportes, Claude; Landgren, Ola

2018-05-04

Still, many physicians give 4 cycles of combination therapy to multiple myeloma patients prior to collection of stem cells for autologous bone marrow transplant. This tradition originates from older doxorubicin-containing regiments which limited the number of cycles due to cumulative cardiotoxicity. Using older regiments, most patients had residual myeloma cells in their autologous stem-cell grafts during collection. Emerging data show that newly diagnosed multiple myeloma patients treated with modern carfilzomib/lenalidomide/dexamethasone (KRd) therapy, on average, take 6 cycles until reaching minimal residual disease (MRD) negativity. We assessed newly diagnosed patients treated with KRd focusing MRD status both in the individual patient's bone marrow, and the corresponding autologous hematopoietic progenitor cell grafts during collection. Per protocol, stem-cell collection was allowed after 4 to 8 cycles of KRd. We found similar stem-cell yield independent of the number of cycles of KRd. At stem-cell collection, 11/30 patients (36.6%) were MRD negative in their bone marrow; all 11 patients had MRD negative hematopoietic progenitor cell grafts. Furthermore, 18/19 patients who were MRD positive in their bone marrows also had MRD negative hematopoietic progenitor cell grafts. These observations support 6 cycles of KRd as an efficacious and safe induction strategy prior to stem-cell collection.

Epibulbar Plasmacytoma Masquerading as Subconjunctival Hemorrhage in a Patient With Multiple Myeloma.

PubMed

Bradley, Amanda; Estes, Amy; Ulrich, Lane; Thomas, Dilip; Gay, David

2017-02-01

We report a 75-year-old woman with a history of multiple myeloma immunoglobulin D (IgD) variant, who presented with an epibulbar plasmacytoma masquerading as a subconjunctival hemorrhage. Magnetic resonance imaging of the brain and orbits with and without contrast was obtained and surgical biopsy of the subconjunctival lesion was performed; histopathology confirmed the diagnosis of plasmacytoma. Subconjunctival biopsy revealed a plasma cell neoplasm infiltrate in the episcleral layer. The subconjunctival biopsy stained positive for CD138 and lambda-immunohistochemistry in the majority of plasma cells. Histologic findings were consistent with involvement by known IgD plasma cell myeloma where previous bone marrow biopsy demonstrated myeloma cells which stained monoclonally for IgD-lambda light chains. Although plasma cell neoplasms seldom present with ocular manifestations, it is crucial to recognize that these tumors may be associated with multiple myeloma. In patients with known multiple myeloma who present with subconjunctival hemorrhage, close follow-up is highly recommended, as this may be the initial presentation of an ocular plasmacytoma. Although a plasmacytoma is a rare subconjunctival lesion, it should not be immediately excluded from the differential diagnosis of such lesions.

Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias.

PubMed

Mitsiades, Constantine S; Rouleau, Cecile; Echart, Cinara; Menon, Krishna; Teicher, Beverly; Distaso, Maria; Palumbo, Antonio; Boccadoro, Mario; Anderson, Kenneth C; Iacobelli, Massimo; Richardson, Paul G

2009-02-15

Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation-related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further, given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma cells by bone marrow stromal cells. Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma cells with bone marrow stromal cells in vitro, defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myeloma-bone marrow stromal cell adhesion and its sequelae, including nuclear factor-kappaB activation in multiple myeloma and bone marrow stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines, and adhesion molecules. Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in

Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group.

PubMed

Laubach, J; Garderet, L; Mahindra, A; Gahrton, G; Caers, J; Sezer, O; Voorhees, P; Leleu, X; Johnsen, H E; Streetly, M; Jurczyszyn, A; Ludwig, H; Mellqvist, U-H; Chng, W-J; Pilarski, L; Einsele, H; Hou, J; Turesson, I; Zamagni, E; Chim, C S; Mazumder, A; Westin, J; Lu, J; Reiman, T; Kristinsson, S; Joshua, D; Roussel, M; O'Gorman, P; Terpos, E; McCarthy, P; Dimopoulos, M; Moreau, P; Orlowski, R Z; Miguel, J S; Anderson, K C; Palumbo, A; Kumar, S; Rajkumar, V; Durie, B; Richardson, P G

2016-05-01

The prognosis for patients multiple myeloma (MM) has improved substantially over the past decade with the development of new, more effective chemotherapeutic agents and regimens that possess a high level of anti-tumor activity. In spite of this important progress, however, nearly all MM patients ultimately relapse, even those who experience a complete response to initial therapy. Management of relapsed MM thus represents a vital aspect of the overall care for patients with MM and a critical area of ongoing scientific and clinical research. This comprehensive manuscript from the International Myeloma Working Group provides detailed recommendations on management of relapsed disease, with sections dedicated to diagnostic evaluation, determinants of therapy, and general approach to patients with specific disease characteristics. In addition, the manuscript provides a summary of evidence from clinical trials that have significantly impacted the field, including those evaluating conventional dose therapies, as well as both autologous and allogeneic stem cell transplantation. Specific recommendations are offered for management of first and second relapse, relapsed and refractory disease, and both autologous and allogeneic transplant. Finally, perspective is provided regarding new agents and promising directions in management of relapsed MM.

Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1.

PubMed

Gong, Jia-Nan; Khong, Tiffany; Segal, David; Yao, Yuan; Riffkin, Chris D; Garnier, Jean-Marc; Khaw, Seong Lin; Lessene, Guillaume; Spencer, Andrew; Herold, Marco J; Roberts, Andrew W; Huang, David C S

2016-10-06

New therapeutic targets are needed to address the poor prognosis of patients with high-risk multiple myeloma. Myeloma cells usually express a range of the prosurvival BCL2 proteins. To define the hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines, using pharmacological inhibitors or gene editing or by peptide-based approaches, alone or in combination. The majority of well-established immortalized cell lines (17/25) or low-passage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized subset of myeloma that is highly BCLXL-dependent, and has the potential for cotargeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high-quality, validated inhibitors become available. © 2016 by The American Society of Hematology.

Interpretation Difficulties of Serum Immunofixation Test in Immunoglobulin D Multiple Myeloma with Hidden Lambda Light Chains.

PubMed

Biaz, A; Uwingabiye, J; Rachid, A; Dami, A; Bouhsain, S; Ouzzif, Z; Idrissi, S El Machtani

2018-06-01

We report a case of immunoglobulin (Ig) D myeloma with hidden lambda light chains in a patient whose immunofixation test was very difficult to interpret: the IgD reacts with the anti-δ heavy chain antiserum but does not react with anti-lambda antiserum. The band in the D heavy chain lane is unmatched in light chain lanes and the band in lambda light chain lane migrates higher. To distinguish between heavy chain disease and immunoglobulin with "hidden" light chains, the sample was exposed to a very high concentration of anti-lambda and anti-kappa antisera for 48 hours. The serum immunofixation test of the sample treated with anti-lambda showed a decrease in the intensity of the band corresponding to D heavy chain lane as well as the modification of its mobility confirming the presence of IgD with the hidden lambda light chains. The IgD myeloma with hidden light chains remains a rare entity, hence the interest of sensitizing health professionals to be vigilant and ensure a good diagnosis. The proposed technique is useful, simple, reliable, and less laborious than those previous reported in the literature. Medical laboratories using Sebia-Hydrasys® system should be aware of the described phenomenon in order to avoid identifying an IgD myeloma as a delta heavy chain disease.

Phosphoinositide protein kinase PDPK1 is a crucial cell signaling mediator in multiple myeloma.

PubMed

Chinen, Yoshiaki; Kuroda, Junya; Shimura, Yuji; Nagoshi, Hisao; Kiyota, Miki; Yamamoto-Sugitani, Mio; Mizutani, Shinsuke; Sakamoto, Natsumi; Ri, Masaki; Kawata, Eri; Kobayashi, Tsutomu; Matsumoto, Yosuke; Horiike, Shigeo; Iida, Shinsuke; Taniwaki, Masafumi

2014-12-15

Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles. ©2014 American Association for Cancer Research.

A phase I trial of Flavopiridol in relapsed multiple myeloma

PubMed Central

Hofmeister, Craig C.; Poi, Ming; Bowers, Mindy A.; Zhao, Weiqiang; Phelps, Mitch A.; Benson, Don M.; Kraut, Eric H.; Farag, Sherif; Efebera, Yvonne A.; Sexton, Jennifer; Lin, Thomas S.; Grever, Michael; Byrd, John C.

2014-01-01

Purpose Flavopiridol is primarily a cyclin-dependent kinase (CDK)-9 inhibitor and we performed a dose escalation trial to determine the maximum tolerated dose, safety, and generate a pharmacokinetic profile. Methods Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus then continuous infusion weekly for 4 weeks in a 6 week cycle. Results Fifteen patients were treated at three dose levels (30 mg/m2 bolus, 30 mg/m2 CIV to 50 mg/m2 bolus, 50 mg/m2 CIV). Cytopenias were significant and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients, grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein greater than 50% percent that did not persist. Pharmacokinetic properties were similar to prior publications and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response. Conclusions Flavopiridol as a single agent given by bolus then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myeloma (ClinicalTrials.gov identifier NCT00112723). PMID:24241210

Advancements in Nanomedicine for Multiple Myeloma.

PubMed

Detappe, Alexandre; Bustoros, Mark; Mouhieddine, Tarek H; Ghoroghchian, P Peter

2018-06-01

In the past decades, considerable progress has been made in our understanding and treatment of multiple myeloma. Several challenges remain including our abilities to longitudinally image tumor responses to treatment, to combine various therapeutic agents with different mechanisms of action but with overlapping toxicities, and to efficiently harness the power of the immune system to augment remission and/or to induce permanent cures. Nanomedicine may help to address many of these outstanding issues, affording novel diagnostic capabilities and offering disruptive technologies that promise to revolutionize treatment. Here, we review recent developments and the future of nanomedicine for multiple myeloma, highlighting new considerations in nanoparticle designs that may help to augment active targeting, to facilitate longitudinal imaging, and to improve drug delivery. Copyright © 2018 Elsevier Ltd. All rights reserved.

Acquired dysfibrinogenemia secondary to multiple myeloma.

PubMed

Kotlín, Roman; Sobotková, Alzbeta; Riedel, Tomás; Salaj, Peter; Suttnar, Jirí; Reicheltová, Zuzana; Májek, Pavel; Khaznadar, Tarek; Dyr, Jan E

2008-01-01

Abnormal coagulation properties indicative of a dysfibrinogen were found in the plasma of a 72-year-old male with multiple myeloma (IgGkappa, stage IIIA). The patient had high paraprotein concentration (85.75 g/l) and prolonged thrombin time (76.8 s), activated partial thromboplastin time (39.5 s), prothrombin time (23.5 s) and reptilase time (72.0 s). The fibrinogen level was increased. The fibrin polymerization induced by both thrombin and reptilase was impaired. Scanning electron microscopy revealed abnormal clot morphology. After six months of treatment, the paraprotein level decreased (19.48 g/l) and coagulation normalized as well as fibrin polymerization and fibrin clot morphology. It was found that the paraprotein interacts with the gamma-chain of fibrinogen. Acquired dysfibrinogenemia associated with multiple myeloma was diagnosed in the 72-year-old patient.

Permeation of antigen protein-conjugated nanoparticles and live bacteria through microneedle-treated mouse skin

PubMed Central

Kumar, Amit; Li, Xinran; Sandoval, Michael A; Rodriguez, B Leticia; Sloat, Brian R; Cui, Zhengrong

2011-01-01

Background: The present study was designed to evaluate the extent to which pretreatment with microneedles can enhance skin permeation of nanoparticles in vitro and in vivo. Permeation of live bacteria, which are physically nanoparticles or microparticles, through mouse skin pretreated with microneedles was also studied to evaluate the potential risk of microbial infection. Methods and results: It was found that pretreatment of mouse skin with microneedles allowed permeation of solid lipid nanoparticles, size 230 nm, with ovalbumin conjugated on their surface. Transcutaneous immunization in a mouse skin area pretreated with microneedles with ovalbumin nanoparticles induced a stronger antiovalbumin antibody response than using ovalbumin alone. The dose of ovalbumin antigen determined whether microneedle-mediated transcutaneous immunization with ovalbumin nanoparticles induced a stronger immune response than subcutaneous injection of the same ovalbumin nanoparticles. Microneedle treatment permitted skin permeation of live Escherichia coli, but the extent of the permeation was not greater than that enabled by hypodermic injection. Conclusion: Transcutaneous immunization on a microneedle-treated skin area with antigens carried by nanoparticles can potentially induce a strong immune response, and the risk of bacterial infection associated with microneedle treatment is no greater than that with a hypodermic injection. PMID:21753877

Incidence and Risk of Cardiac Events in Patients With Previously Treated Multiple Myeloma Versus Matched Patients Without Multiple Myeloma: An Observational, Retrospective, Cohort Study.

PubMed

Kistler, Kristin D; Kalman, Jill; Sahni, Gagan; Murphy, Brian; Werther, Winifred; Rajangam, Kanya; Chari, Ajai

2017-02-01

Multiple myeloma (MM) patients have age-, disease-, and treatment-related risk factors for cardiac events. We analyzed the 2006 to 2011 MarketScan database to determine whether the risk of cardiac events is greater in MM patients than in non-MM patients. Included were 1723 MM patients treated with corticosteroids and ≥ 3 drugs (bortezomib, immunomodulatory derivatives, and alkylating agents or anthracyclines). The index date (ID) was the date on which the 3-drug exposure criterion was met. Also included were 8615 age- and gender-matched non-MM patients (5:1). The distribution of non-MM patients' IDs matched that of the MM patients' IDs. Baseline was 6 months before the ID. The follow-up duration was from the ID to study end (ie, 2011 or end of enrollment or prescription drug coverage). Hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for baseline variables when the univariate analyses showed a 10% difference. The median duration of observation was 9 months (range, 0-60 months) for MM patients and 19 months (range, 0-66 months) for non-MM patients. The risk of any cardiac event (HR, 2.2; 95% CI, 1.9-2.5), dysrhythmia (HR, 4.1; 95% CI, 3.5-4.8), congestive heart failure (HR, 2.9; 95% CI, 2.2-3.7), cardiomyopathy (HR, 2.6; 95% CI, 1.8-3.8), and conduction disorders (HR, 1.7; 95% CI, 1.2-2.5) was significantly greater for MM than for non-MM patients. The incidence of hypertensive or arterial events and ischemic heart disease was similar between the 2 groups. The present study provides the first known comparison of cardiac event risk in patients with MM versus age- and gender-matched patients without MM. The cardiac event risk was greater in MM patients with ≥ 3 previous drugs for any cardiac event, dysrhythmias, congestive heart failure, cardiomyopathy, and conduction disorders compared with patients without MM. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Expression of c-Kit isoforms in multiple myeloma: differences in signaling and drug sensitivity.

PubMed

Montero, Juan Carlos; López-Pérez, Ricardo; San Miguel, Jesús F; Pandiella, Atanasio

2008-06-01

c-Kit is expressed in the plasma cells from 30% of patients with multiple myeloma. Two different isoforms of c-Kit, characterized by the presence or absence of the tetrapeptide sequence GNNK in the extracellular domain, have been described. However, their expression and function in myeloma cells are unknown. We explored the function and expression of these c-Kit isoforms in myeloma cells. Expression of c-Kit isoforms was investigated by reverse transcriptase polymerase chain reaction in fresh plasma cells from patients and cell lines. The function of these c-Kit isoforms was analyzed upon expression in myeloma cells. Signaling was investigated by western blotting using antibodies specific for activated forms of several signaling proteins. The impact of c-Kit on the action of drugs commonly used in the treatment of multiple myeloma was investigated by MTT proliferation assays. Fresh plasma cells from patients as well as myeloma cell lines expressed the two isoforms of c-Kit. Retroviral infection of myeloma cells with vectors that code for c-Kit-GNNK+ or c-Kit-GNNK- forms demonstrated differences in the kinetics of phosphorylation between these isoforms. Stem cell factor-induced activation of the GNNK- form was faster and more pronounced than that of the GNNK+ form, whose activation, however, lasted for longer. The c-Kit receptors weakly activated the Erk1/2 and Erk5 pathways. Both receptors, however, efficiently coupled to the PI3K/Akt pathway, and stimulated p70S6K activation. The latter was sensitive to the mTOR inhibitor, rapamycin. Studies of drug sensitivity indicated that cells expressing the GNNK- form were more resistant to the anti-myeloma action of bortezomib and melphalan. Our data indicate that c-Kit expression in multiple myeloma cells is functional, and coupled to survival pathways that may modulate cell death in response to therapeutic compounds used in the treatment of this disease.

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions.

PubMed

Purushothaman, Anurag; Bandari, Shyam Kumar; Liu, Jian; Mobley, James A; Brown, Elizabeth E; Sanderson, Ralph D

2016-01-22

Exosomes regulate cell behavior by binding to and delivering their cargo to target cells; however, the mechanisms mediating exosome-cell interactions are poorly understood. Heparan sulfates on target cell surfaces can act as receptors for exosome uptake, but the ligand for heparan sulfate on exosomes has not been identified. Using exosomes isolated from myeloma cell lines and from myeloma patients, we identify exosomal fibronectin as a key heparan sulfate-binding ligand and mediator of exosome-cell interactions. We discovered that heparan sulfate plays a dual role in exosome-cell interaction; heparan sulfate on exosomes captures fibronectin, and on target cells it acts as a receptor for fibronectin. Removal of heparan sulfate from the exosome surface releases fibronectin and dramatically inhibits exosome-target cell interaction. Antibody specific for the Hep-II heparin-binding domain of fibronectin blocks exosome interaction with tumor cells or with marrow stromal cells. Regarding exosome function, fibronectin-mediated binding of exosomes to myeloma cells activated p38 and pERK signaling and expression of downstream target genes DKK1 and MMP-9, two molecules that promote myeloma progression. Antibody against fibronectin inhibited the ability of myeloma-derived exosomes to stimulate endothelial cell invasion. Heparin or heparin mimetics including Roneparstat, a modified heparin in phase I trials in myeloma patients, significantly inhibited exosome-cell interactions. These studies provide the first evidence that fibronectin binding to heparan sulfate mediates exosome-cell interactions, revealing a fundamental mechanism important for exosome-mediated cross-talk within tumor microenvironments. Moreover, these results imply that therapeutic disruption of fibronectin-heparan sulfate interactions will negatively impact myeloma tumor growth and progression. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions*

PubMed Central

Purushothaman, Anurag; Bandari, Shyam Kumar; Liu, Jian; Mobley, James A.; Brown, Elizabeth E.; Sanderson, Ralph D.

2016-01-01

Exosomes regulate cell behavior by binding to and delivering their cargo to target cells; however, the mechanisms mediating exosome-cell interactions are poorly understood. Heparan sulfates on target cell surfaces can act as receptors for exosome uptake, but the ligand for heparan sulfate on exosomes has not been identified. Using exosomes isolated from myeloma cell lines and from myeloma patients, we identify exosomal fibronectin as a key heparan sulfate-binding ligand and mediator of exosome-cell interactions. We discovered that heparan sulfate plays a dual role in exosome-cell interaction; heparan sulfate on exosomes captures fibronectin, and on target cells it acts as a receptor for fibronectin. Removal of heparan sulfate from the exosome surface releases fibronectin and dramatically inhibits exosome-target cell interaction. Antibody specific for the Hep-II heparin-binding domain of fibronectin blocks exosome interaction with tumor cells or with marrow stromal cells. Regarding exosome function, fibronectin-mediated binding of exosomes to myeloma cells activated p38 and pERK signaling and expression of downstream target genes DKK1 and MMP-9, two molecules that promote myeloma progression. Antibody against fibronectin inhibited the ability of myeloma-derived exosomes to stimulate endothelial cell invasion. Heparin or heparin mimetics including Roneparstat, a modified heparin in phase I trials in myeloma patients, significantly inhibited exosome-cell interactions. These studies provide the first evidence that fibronectin binding to heparan sulfate mediates exosome-cell interactions, revealing a fundamental mechanism important for exosome-mediated cross-talk within tumor microenvironments. Moreover, these results imply that therapeutic disruption of fibronectin-heparan sulfate interactions will negatively impact myeloma tumor growth and progression. PMID:26601950

Ex Vivo Induction of Multiple Myeloma-specific Immune Responses by Monocyte-derived Dendritic Cells Following Stimulation by Whole-tumor Antigen of Autologous Myeloma Cells.

PubMed

Vasileiou, Spyridoula; Baltadakis, Ioannis; Delimpasi, Sosanna; Karatza, Maria-Helena; Liapis, Konstantinos; Garofalaki, Maria; Tziotziou, Eirini; Poulopoulou, Zoe; Karakasis, Dimitri; Harhalakis, Nicholas

2017-09-01

The introduction of novel agents has significantly expanded treatment options for multiple myeloma (MM), albeit long-term disease control cannot be achieved in the majority of patients. Vaccination with MM antigen-loaded dendritic cells (DCs) represents an alternative strategy that is currently being explored. The aim of this study was to assess the immunogenic potential of ex vivo-generated monocyte-derived DCs (moDCs), following stimulation with the whole-antigen array of autologous myeloma cells (AMC). MoDCs were loaded with antigens of myeloma cells by 2 different methods: phagocytosis of apoptotic bodies from γ-irradiated AMC, or transfection with AMC total RNA by square-wave electroporation. Twenty patients with MM were enrolled in the study. Following stimulation and maturation, moDCs were tested for their capacity to induce T-helper 1 and cytotoxic T lymphocyte responses in vitro. Both strategies were effective in the induction of myeloma-specific cytotoxic T lymphocyte and T-helper 1 cells, as demonstrated by cytotoxicity and ELISpot assays. On the whole, T-cell responses were observed in 18 cases by either method of DC pulsing. We conclude that both whole-tumor antigen approaches are efficient in priming autologous antimyeloma T-cell responses and warrant further study aiming at the development of individualized DC vaccines for MM patients.

Apoptosis and gene expression in the developing mouse brain of fusarenon-X-treated pregnant mice.

PubMed

Sutjarit, Samak; Nakayama, Shota M M; Ikenaka, Yoshinori; Ishizuka, Mayumi; Banlunara, Wijit; Rerkamnuaychoke, Worawut; Kumagai, Susumu; Poapolathep, Amnart

2014-08-17

Fusarenon-X (FX), a type B trichothecene mycotoxin, is mainly produced by Fusarium crookwellense, which occurs naturally in agricultural commodities, such as wheat and barley. FX has been shown to exert a variety of toxic effects on multiple targets in vitro. However, the embryonic toxicity of FX in vivo remains unclear. In the present study, we investigated FX-induced apoptosis and the relationship between the genetic regulatory mechanisms and FX-induced apoptosis in the developing mouse brain of FX-treated pregnant mice. Pregnant mice were orally administered FX (3.5 mg/kg b.w.) and were assessed at 0, 12, 24 and 48 h after treatment (HAT). Apoptosis in the fetal brain was determined using hematoxylin and eosin staining, the TUNEL method, immunohistochemistry for PCNA and electron microscopy. Gene expressions were evaluated using microarray and real time-reverse transcription polymerase chain reaction (qRT-PCR). Histopathological changes showed that the number of apoptotic cells in the telencephalon of the mouse fetus peaked at 12 HAT and decreased at 24 and 48 HAT. FX induced the up-regulation of Bax, Trp53 and Casp9 and down-regulated Bcl2 but the expression levels of Fas and Casp8 mRNA remained unchanged. These data suggested that FX induces apoptosis in the developing mouse brain in FX-treated dams. Moreover, the genetic regulatory mechanisms of FX-induced apoptosis are regulated by Bax, Bcl2, Trp53 and Casp9 or can be defined via an intrinsic apoptotic pathway. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Clinical and biological features of multiple myeloma involving the gastrointestinal system.

PubMed

Talamo, Giampaolo; Cavallo, Federica; Zangari, Maurizio; Barlogie, Bart; Lee, Choon-Kee; Pineda-Roman, Mauricio; Kiwan, Elias; Krishna, Somashekar; Tricot, Guido

2006-07-01

We report 24 cases of multiple myeloma (MM) with involvement of the gastrointestinal (GI) system. We found a strong association with high A lactate dehydrogenase levels, plasmablastic morphology, and A unfavorable karyotype. GI involvement at the time of initial diagnosis was much rarer than later in the course of the disease. The A median survival after diagnosis of GI involvement was 7 months. Among 13 patients treated with stem cell transplantation, the response rate was 92%, and median progression-free survival was 4 months. We conclude that MM involving the GI system is associated with adverse biological features and with short-lasting remissions, even after A high-dose chemotherapy.

Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)—Patient Version

Cancer.gov

Plasma cell neoplasms occur when abnormal plasma cells or myeloma cells form tumors in the bones or soft tissues of the body. Multiple myeloma, plasmacytoma, lymphoplasmacytic lymphoma, and monoclonal gammopathy of undetermined significance (MGUS) are different types of plasma cell neoplasms. Find out about risk factors, symptoms, diagnostic tests, prognosis, and treatment for these diseases.

A pilot study of direct delivery of hydroxypropyl-beta-cyclodextrin to the lung by the nasal route in a mouse model of Niemann-Pick C1 disease: motor performance is unaltered and lung disease is worsened.

PubMed

Erickson, Robert P; Deutsch, Gail; Patil, Ruturaj

2018-05-01

We have tested the efficacy of hydroxypropyl-beta-cyclodextrin (HPBCD) delivered by the nasal route in the mouse model of juvenile Niemann-Pick C1 disease (NPC1), as pulmonary disease has not responded to systemic therapy with this drug. Since mice have no gag reflex, coating of the nasal cavity, with possible access to the brain, would be followed by delivery of HPBCD to the lung. While foamy macrophages, containing stored cholesterol, were found in the Npc1 nmf164 homozygous mice, a marked inflammatory response was found with inhaled HPBCD, both in mutant and wild-type animals. Slight inflammation also occasionally occurred with saline inhalation. There was no difference between the saline-treated, HPBCD-treated, and untreated Npc1 nmf164 homozygous mice for weight, balance beam performance, or coat hanger performance. Interestingly, there was a trend to longer survival in the HPBCD-treated Npc1 nmf164 homozygous mice, which, when combined with the survival times of the saline-treated survivals (each of which was not different), became significant.

The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma.

PubMed

Evans, Robert P; Naber, Claudia; Steffler, Tara; Checkland, Tamara; Maxwell, Christopher A; Keats, Jonathan J; Belch, Andrew R; Pilarski, Linda M; Lai, Raymond; Reiman, Tony

2008-02-01

Aurora kinases are potential targets for cancer therapy. Previous studies have validated Aurora kinase A as a therapeutic target in multiple myeloma (MM), and have demonstrated in vitro anti-myeloma effects of small molecule Aurora kinase inhibitors that inhibit both Aurora A and B. This study demonstrated that Aurora B kinase was strongly expressed in myeloma cell lines and primary plasma cells. The selective Aurora B inhibitor AZD1152-induced apoptotic death in myeloma cell lines at nanomolar concentrations, with a cell cycle phenotype consistent with that reported previously for Aurora B inhibition. In some cases, AZD1152 in combination with dexamethasone showed increased anti-myeloma activity compared with the use of either agent alone. AZD1152 was active against sorted CD138(+) BM plasma cells from myeloma patients but also, as expected, was toxic to CD138(-) marrow cells from the same patients. In a murine myeloma xenograft model, AZD1152-inhibited tumour growth at well-tolerated doses and induced cell death in established tumours, with associated mild, transient leucopenia. AZD1152 shows promise in these preclinical studies as a novel treatment for MM.

Drugs Approved for Multiple Myeloma

Cancer.gov

This page lists cancer drugs approved by the Food and Drug Administration (FDA) for multiple myeloma and other plasma cell neoplasms. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

Role of 18F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group.

PubMed

Cavo, Michele; Terpos, Evangelos; Nanni, Cristina; Moreau, Philippe; Lentzsch, Suzanne; Zweegman, Sonja; Hillengass, Jens; Engelhardt, Monika; Usmani, Saad Z; Vesole, David H; San-Miguel, Jesus; Kumar, Shaji K; Richardson, Paul G; Mikhael, Joseph R; da Costa, Fernando Leal; Dimopoulos, Meletios-Athanassios; Zingaretti, Chiara; Abildgaard, Niels; Goldschmidt, Hartmut; Orlowski, Robert Z; Chng, Wee Joo; Einsele, Hermann; Lonial, Sagar; Barlogie, Bart; Anderson, Kenneth C; Rajkumar, S Vincent; Durie, Brian G M; Zamagni, Elena

2017-04-01

The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of 18 fluorodeoxyglucose ( 18 F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. 18 F-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of 18 F-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of 18 F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. 18 F-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Multiple Myeloma and Epidural Spinal Cord Compression : Case Presentation and a Spine Surgeon's Perspective

PubMed Central

Ha, Kee-Yong; Kim, Hyun-Woo

2013-01-01

Multiple myeloma, a multicentric hematological malignancy, is the most common primary tumor of the spine. As epidural myeloma causing spinal cord compression is a rare condition, its therapeutic approach and clinical results have been reported to be diverse, and no clear guidelines for therapeutic decision have been established. Three patients presented with progressive paraplegia and sensory disturbance. Image and serological studies revealed multiple myeloma and spinal cord compression caused by epidural myeloma. Emergency radiotherapy and steroid therapy were performed in all three cases. However, their clinical courses and results were distinctly different. Following review of our cases and the related literature, we suggest a systematic therapeutic approach for these patients to achieve better clinical results. PMID:24175035

Usefulness and safety of oral cryotherapy in the prevention of oral mucositis after conditioning regimens with high-dose melphalan for autologous stem cell transplantation for lymphoma and myeloma.

PubMed

Batlle, Montserrat; Morgades, Mireia; Vives, Susana; Ferrà, Christelle; Oriol, Albert; Sancho, Juan-Manuel; Xicoy, Blanca; Moreno, Miriam; Magallón, Laura; Ribera, Josep-Maria

2014-12-01

Oral mucositis (OM) is a common complication of conditioning regimens with high-dose melphalan (HDmel). This retrospective cohort study analyzes the impact of oral cryotherapy (OC) or room temperature saline rinses on the prevention of OM in patients with multiple myeloma (MM) or lymphoid neoplasias submitted to autologous stem cell transplantation (ASCT) in a single center. From August 2006 to July 2011, 134 consecutive patients were enrolled. Two consecutive groups were included: Non-OC (August 2006 to April 2009, 68 patients) and OC (May 2009 to July 2011, 66 cases). MM cases (78, 58%) received HDmel as the conditioning regimen and 56 patients (42%) with lymphoma received BEAM. The non-OC and OC groups were comparable for the main clinicobiologic features and type of neoplasia. OM was more frequent and severe in patients receiving BEAM as the conditioning therapy. The group of OC showed less frequent and less severe mucositis and fewer days on antibiotics. No differences were observed in the duration of OM, need for parenteral nutrition and narcotics, and the length of hospital stay on comparison with the OC and non-OC groups. By multivariate analyses, OC was an independent favorable prognostic factor for OM development. This study shows that OC is more effective than saline rinses in the prevention of OM in patients with lymphoma and myeloma receiving conditioning regimens with HDmel for ASCT. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Avascular necrosis of femoral and/or humeral heads in multiple myeloma: results of a prospective study of patients treated with dexamethasone-based regimens and high-dose chemotherapy.

PubMed

Talamo, Giampaolo; Angtuaco, Edgardo; Walker, Ronald C; Dong, Li; Miceli, Marisa H; Zangari, Maurizio; Tricot, Guido; Barlogie, Bart; Anaissie, Elias

2005-08-01

To assess the prevalence, time of onset, risk factors, and outcome of avascular necrosis (AVN) of bone in patients with multiple myeloma undergoing antineoplastic therapy. A total of 553 consecutive assessable patients were enrolled onto a treatment protocol consisting of dexamethasone-containing induction chemotherapy, autologous stem-cell transplantation, consolidation chemotherapy, and maintenance with interferon alfa. Patients were randomly assigned to receive thalidomide (269 patients) or no thalidomide (284 patients) throughout the study period. With a median follow-up of 33 months (range, 5 to 114 months), AVN of the femoral head(s) developed in 49 patients (9%). Median time to onset of AVN was 12 months (range, 2 to 41 months). Three risk factors for AVN were identified by multivariate analysis: cumulative dexamethasone dose (odds ratio [OR], 1.028; 95% CI, 1.012 to 1.044; P = .0006 [per 40 mg dexamethasone]), male sex (OR, 0.390; 95% CI, 0.192 to 0.790; P = .009), and younger age (OR, 0.961; 95% CI, 0.934 to 0.991 per year; P = .0122). Thalidomide-treated patients had a prevalence of AVN similar to that of the control group (8% v 10%, respectively; P = .58). AVN-related pain and limited range of motion of the affected joint were present in only nine and four patients, respectively, and four patients underwent hip replacement because of AVN. Fluorine-18 fluorodeoxyglucose positron emission tomography failed to detect abnormal uptake in the AVN-affected bones. AVN is a rare and usually asymptomatic complication during myeloma therapy. Cumulative dexamethasone dose, male sex, and younger age, but not thalidomide, increase the risk of AVN.

Multiple Myeloma and Its Precursor Disease Among Firefighters Exposed to the World Trade Center Disaster.

PubMed

Landgren, Ola; Zeig-Owens, Rachel; Giricz, Orsolya; Goldfarb, David; Murata, Kaznouri; Thoren, Katie; Ramanathan, Lakshmi; Hultcrantz, Malin; Dogan, Ahmet; Nwankwo, George; Steidl, Ulrich; Pradhan, Kith; Hall, Charles B; Cohen, Hillel W; Jaber, Nadia; Schwartz, Theresa; Crowley, Laura; Crane, Michael; Irby, Shani; Webber, Mayris P; Verma, Amit; Prezant, David J

2018-06-01

The World Trade Center (WTC) attacks on September 11, 2001, created an unprecedented environmental exposure to known and suspected carcinogens suggested to increase the risk of multiple myeloma. Multiple myeloma is consistently preceded by the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS, detectable in peripheral blood. To characterize WTC-exposed firefighters with a diagnosis of multiple myeloma and to conduct a screening study for MGUS and light-chain MGUS. Case series of multiple myeloma in firefighters diagnosed between September 11, 2001, and July 1, 2017, together with a seroprevalence study of MGUS in serum samples collected from Fire Department of the City of New York (FDNY) firefighters between December 2013 and October 2015. Participants included all WTC-exposed FDNY white, male firefighters with a confirmed physician diagnosis of multiple myeloma (n = 16) and WTC-exposed FDNY white male firefighters older than 50 years with available serum samples (n = 781). WTC exposure defined as rescue and/or recovery work at the WTC site between September 11, 2001, and July 25, 2002. Multiple myeloma case information, and age-adjusted and age-specific prevalence rates for overall MGUS (ie, MGUS and light-chain MGUS), MGUS, and light-chain MGUS. Sixteen WTC-exposed white male firefighters received a diagnosis of multiple myeloma after September 11, 2001; median age at diagnosis was 57 years (interquartile range, 50-68 years). Serum/urine monoclonal protein isotype/free light-chain data were available for 14 cases; 7 (50%) had light-chain multiple myeloma. In a subset of 7 patients, myeloma cells were assessed for CD20 expression; 5 (71%) were CD20 positive. In the screening study, we assayed peripheral blood from 781 WTC-exposed firefighters. The age-standardized prevalence rate of MGUS and light-chain MGUS combined was 7.63 per 100 persons (95% CI, 5.45-9.81), 1.8-fold higher than rates from the Olmsted

The impact of recent chemotherapy innovation on the longevity of myeloma patients: US and international evidence.

PubMed

Hostenkamp, Gisela; Lichtenberg, Frank R

2015-04-01

The longevity of multiple myeloma patients increased sharply since the late 1990s. This increase coincided with the introduction of several important innovations in chemotherapy for myeloma. In this study, we aim to quantify the impact of recent chemotherapy innovation on the longevity of myeloma patients using both time-series US data and longitudinal data on 38 countries. We estimate that almost two-thirds (0.99 years) of the 1997-2005 increase in the life expectancy of American myeloma patients was due to an increase in the number of chemotherapy regimens now preferred by specialists. Based on a back-of-the-envelope calculation, this means that the cost per US life-year gained from post-1997 chemotherapy innovation is unlikely to have exceeded $46,000. We also investigate the impact of chemotherapy innovation on the myeloma mortality rate using longitudinal country-level data on 38 countries during the period 2002-2012. Countries that had larger increases in the number of chemotherapy regimens now preferred by specialists had larger subsequent declines in myeloma mortality rates, controlling for myeloma incidence. The (marginal) effect on the mortality rate of one additional preferred chemotherapy regimen is similar in other countries to its effect in the US. Non-US prices of two of the three new drugs were lower than US prices, so recent myeloma chemotherapy innovation may have been more cost-effective in other countries than it was in the US. Recent chemotherapy innovation has had a significant positive impact on the longevity of myeloma patients in the countries in which the drugs have been available. Copyright © 2015 Elsevier Ltd. All rights reserved.

Maternal embryonic leucine zipper kinase inhibitor OTSSP167 has preclinical activity on multiple myeloma bone disease.

PubMed

Muller, Joséphine; Bolomsky, Arnold; Dubois, Sophie; Duray, Elodie; Stangelberger, Kathrin; Plougonven, Erwan; Lejeune, Margaux; Léonard, Angélique; Marty, Caroline; Hempel, Ute; Baron, Frédéric; Beguin, Yves; Cohen-Solal, Martine; Ludwig, Heinz; Heusschen, Roy; Caers, Jo

2018-05-10

Multiple myeloma bone disease is characterized by an uncoupling of bone remodeling in the multiple myeloma microenvironment, resulting in the development of lytic bone lesions. Most myeloma patients suffer from these bone lesions, which not only causes morbidity but also negatively impacts survival. The development of novel therapies, ideally with a combined anti-resorptive and bone-anabolic effect, is of great interest because lesions persist with the current standard of care, even in patients in complete remission. We have previously shown that MELK plays a central role in proliferation-associated high-risk multiple myeloma and its inhibition with OTSSP167 resulted in decreased tumor load. MELK inhibition in bone cells has not yet been explored, although some reports suggest factors downstream of MELK stimulate osteoclast activity and inhibit osteoblast activity, which makes MELK inhibition a promising therapeutic approach. Therefore, we assessed the effect of OTSSP167 on bone cell activity and the development of myeloma-induced bone disease. OTSSP167 inhibited osteoclast activity in vitro by decreasing progenitor viability as well as via a direct anti-resorptive effect on mature osteoclasts. In addition, OTSSP167 stimulated matrix deposition and mineralization by osteoblasts in vitro. This combined anti-resorptive and osteoblast-stimulating effect of OTSSP167 resulted in the complete prevention of lytic lesions and bone loss in myeloma-bearing mice. Immunohistomorphometric analyses corroborated our in vitro findings. In conclusion, we show that OTSSP167 has a direct effect on myeloma-induced bone disease in addition to its anti-multiple myeloma effect, which warrants further clinical development of MELK inhibition in multiple myeloma. Copyright © 2018, Ferrata Storti Foundation.

The Role of Apolipoprotein E and Ethanol Exposure in Age-Related Changes in Choline Acetyltransferase and Brain-Derived Neurotrophic Factor Expression in the Mouse Hippocampus.

PubMed

Jamal, Mostofa; Ito, Asuka; Tanaka, Naoko; Miki, Takanori; Takakura, Ayaka; Suzuki, Shingo; Ameno, Kiyoshi; Kinoshita, Hiroshi

2018-05-01

Disruption of apolipoprotein E (APOE) is responsible for age-dependent neurodegeneration and cognitive impairment. Elderly individuals are more sensitive than young individuals to the effects of ethanol (EtOH), particularly those affecting cognition. We investigated the role of APOE deficiency and EtOH exposure on age-dependent alterations in choline acetyltransferase (ChAT) and brain-derived neurotrophic factor (BDNF) mRNA and protein expression in the mouse hippocampus. Three-month-old (young) and 12-month-old (aged) ApoE-knockout (ApoE-KO) and wild-type (WT) mice were treated with saline or 2 g/kg EtOH, and the bilateral hippocampus was collected after 60 min for real-time PCR and western blotting analyses. ChAT (P < 0.01) and BDNF (P < 0.01) expression were significantly decreased in both young and aged saline- and EtOH-treated ApoE-KO mice versus young and aged saline- and EtOH-treated WT mice. Aged saline- and EtOH-treated ApoE-KO mice exhibited greater differences in ChAT and BDNF expression (P < 0.01) than young saline- and EtOH-treated ApoE-KO mice. Aged EtOH-treated WT mice also exhibited larger decreases in BDNF expression (P < 0.01)-but not in ChAT expression-than young EtOH-treated WT mice. EtOH decreased ChAT and BDNF expression in both young (P < 0.01) and aged (P < 0.01) ApoE-KO mice versus EtOH-free ApoE-KO mice of the same age. EtOH also decreased BDNF expression in aged (P < 0.01) WT mice versus EtOH-free aged WT mice. In summary, these results suggest that APOE deficiency and EtOH exposure cause age-dependent decreases in ChAT and BDNF in the hippocampus. Importantly, the decreases in ChAT and BDNF were greater in aged EtOH-treated mice, particularly those lacking APOE, raising the possibility that APOE-deficient individuals who consume alcohol may be at greater risk of memory deficit.

Impact of long-term salinity exposure in anaerobic membrane bioreactors treating phenolic wastewater: Performance robustness and endured microbial community.

PubMed

Muñoz Sierra, Julian D; Oosterkamp, Margreet J; Wang, Wei; Spanjers, Henri; van Lier, Jules B

2018-05-07

Industrial wastewaters are becoming increasingly associated with extreme conditions such as the presence of refractory compounds and high salinity that adversely affect biomass retention or reduce biological activity. Hence, this study evaluated the impact of long-term salinity increase to 20 gNa + .L -1 on the bioconversion performance and microbial community composition in anaerobic membrane bioreactors treating phenolic wastewater. Phenol removal efficiency of up to 99.9% was achieved at 14 gNa + .L -1 . Phenol conversion rates of 5.1 mgPh.gVSS -1 .d -1 , 4.7 mgPh.gVSS -1 .d -1 , and 11.7 mgPh.gVSS -1 .d -1 were obtained at 16 gNa + .L -1 ,18 gNa + .L -1 and 20 gNa + .L -1 , respectively. The AnMBR's performance was not affected by short-term step-wise salinity fluctuations of 2 gNa + .L -1 in the last phase of the experiment. It was also demonstrated in batch tests that the COD removal and methane production rate were higher at a K + :Na + ratio of 0.05, indicating the importance of potassium to maintain the methanogenic activity. The salinity increase adversely affected the transmembrane pressure likely due to a particle size decrease from 185 μm at 14 gNa + .L -1 to 16 μm at 20 gNa + .L -1 . Microbial community was dominated by bacteria belonging to the Clostridium genus and archaea by Methanobacterium and Methanosaeta genus. Syntrophic phenol degraders, such as Pelotomaculum genus were found to be increased when the maximum phenol conversion rate was attained at 20 gNa + .L -1 . Overall, the observed robustness of the AnMBR performance indicated an endured microbial community to salinity changes in the range of the sodium concentrations applied. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Preliminary study on the dynamics of heavy metals in saline wastewater treated in constructed wetland mesocosms or microcosms filled with porous slag.

PubMed

Liang, Yinxiu; Zhu, Hui; Bañuelos, Gary; Xu, Yingying; Yan, Baixing; Cheng, Xianwei

2018-06-07

This study aims to evaluate the practical potential of using constructed wetlands (CWs) for treating saline wastewater containing various heavy metals. The results demonstrated that CWs growing Canna indica with porous slag as substrate could efficiently remove heavy metals (Cu, Zn, Cd, and Pb) from saline wastewater at an electrical conductivity (EC) of 7 mS/cm, especially under low influent load. Salts with salinity level (characterized as EC) of 30 mS/cm suppressed the removal of some heavy metals, dependent on heavy metal species and their influent concentrations. The presence of salts in CWs can improve the accumulation of Cu, Zn, and Pb in plant tissues as compared to control treatment, irrespective of metal concentrations in solution. The influence of salts on Cd accumulation depended on both salinity levels and Cd concentrations in solution. Although more heavy metals were accumulated in roots than in shoots, the harvesting of aboveground plant materials is still efficient addition for heavy metal removal due to the greater biomass and growth rate of aboveground plant material. Furthermore, replacing all plants instead of preserving roots from harvested plants in CWs over a period of time is essential for heavy metal removal, because the continued accumulation by roots can be inhibited by the increasing accumulated heavy metals from saline wastewater.

Treatment of Acute Renal Failure Secondary to Multiple Myeloma with Chemotherapy and Extended High Cut-Off Hemodialysis

PubMed Central

Hutchison, Colin A.; Bradwell, Arthur R.; Cook, Mark; Basnayake, Kolitha; Basu, Supratik; Harding, Stephen; Hattersley, John; Evans, Neil D.; Chappel, Mike J.; Sampson, Paul; Foggensteiner, Lukas; Adu, Dwomoa; Cockwell, Paul

2009-01-01

Background and objectives: Extended hemodialysis using a high cut-off dialyzer (HCO-HD) removes large quantities of free light chains in patients with multiple myeloma. However, the clinical utility of this method is uncertain. This study assessed the combination of chemotherapy and HCO-HD on serum free light chain concentrations and renal recovery in patients with myeloma kidney (cast nephropathy) and dialysis-dependent acute renal failure. Design, setting, participants, & measurements: An open-label study of the relationship between free light chain levels and clinical outcomes in 19 patients treated with standard chemotherapy regimens and HCO-HD. Results: There were sustained early reductions in serum free light chain concentrations (median 85% [range 50 to 97]) in 13 patients. These 13 patients became dialysis independent at a median of 27 d (range 13 to 120). Six patients had chemotherapy interrupted because of early infections and did not achieve sustained early free light chain reductions; one of these patients recovered renal function (at 105 d) the remaining 5 patients did not recover renal function. Patients who recovered renal function had a significantly improved survival (P < 0.012). Conclusion: In dialysis-dependent acute renal failure secondary to myeloma kidney, patients who received uninterrupted chemotherapy and extended HCO-HD had sustained reductions in serum free light chain concentrations and recovered independent renal function. PMID:19339414

Sarcoidosis and multiple myeloma: Concurrent presentation of an unusual association

PubMed Central

Nair, Vidya; Prajapat, Deepak; Talwar, Deepak

2016-01-01

Literature on concurrent association of sarcoidosis with lymphoproliferative malignancies other than lymphoma e.g. multiple myeloma is meager. The rarity of the situation prompted us to report this patient who was a 51-year-old woman with a 2-years history of breathlessness, cough with expectoration, chest pain and backache. Initial evaluation revealed mild anemia, increased alkaline phosphatase with chest skiagram showing both lower zone non homogenous opacities with calcified hilar lymph nodes. CECT chest showed mediastinal with bilateral hilar lymphadenopathy, parenchymal fibrosis, traction bronchiectasis, ground glass opacities, septal and peribronchovascular thickening affecting mid and lower lung zones bilaterally. MRI Dorsolumbar spine was suggestive of marrow infiltrative disorder. EBUS FNA of intrathoracic nodes, EBB and TBLB confirmed sarcoidosis. PET CT revealed hyper metabolic activity in lung, multiple lymph nodes and lytic bone lesions. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin IgG kappa type. Bone marrow biopsy revealed an increase in plasma cells (15%), but no granulomas. Diagnosis of Indolent or multiple myeloma with sarcoidosis was established. 12 cases of sarcoidosis and multiple myeloma have been reported in literature, and mostly preceding the onset of multiple myeloma by many years, in our case both were diagnosed concurrently. PMID:26933313

Heparanase promotes myeloma progression by inducing mesenchymal features and motility of myeloma cells.

PubMed

Li, Juan; Pan, Qianying; Rowan, Patrick D; Trotter, Timothy N; Peker, Deniz; Regal, Kellie M; Javed, Amjad; Suva, Larry J; Yang, Yang

2016-03-08

Bone dissemination and bone disease occur in approximately 80% of patients with multiple myeloma (MM) and are a major cause of patient mortality. We previously demonstrated that MM cell-derived heparanase (HPSE) is a major driver of MM dissemination to and progression in new bone sites. However the mechanism(s) by which HPSE promotes MM progression remains unclear. In the present study, we investigated the involvement of mesenchymal features in HPSE-promoted MM progression in bone. Using a combination of molecular, biochemical, cellular, and in vivo approaches, we demonstrated that (1) HPSE enhanced the expression of mesenchymal markers in both MM and vascular endothelial cells; (2) HPSE expression in patient myeloma cells positively correlated with the expression of the mesenchymal markers vimentin and fibronectin. Additional mechanistic studies revealed that the enhanced mesenchymal-like phenotype induced by HPSE in MM cells is due, at least in part, to the stimulation of the ERK signaling pathway. Finally, knockdown of vimentin in HPSE expressing MM cells resulted in significantly attenuated MM cell dissemination and tumor growth in vivo. Collectively, these data demonstrate that the mesenchymal features induced by HPSE in MM cells contribute to enhanced tumor cell motility and bone-dissemination.

Maternal embryonic leucine zipper kinase is a novel target for proliferation-associated high-risk myeloma

PubMed Central

Bolomsky, Arnold; Heusschen, Roy; Schlangen, Karin; Stangelberger, Kathrin; Muller, Joséphine; Schreiner, Wolfgang; Zojer, Niklas; Caers, Jo; Ludwig, Heinz

2018-01-01

Treatment of high-risk patients is a major challenge in multiple myeloma. This is especially true for patients assigned to the gene expression profiling-defined proliferation subgroup. Although recent efforts have identified some key players of proliferative myeloma, genetic interactions and players that can be targeted with clinically effective drugs have to be identified in order to overcome the poor prognosis of these patients. We therefore examined maternal embryonic leucine zipper kinase (MELK) for its implications in hyper-proliferative myeloma and analyzed the activity of the MELK inhibitor OTSSP167 both in vitro and in vivo. MELK was found to be significantly overexpressed in the proliferative subgroup of myeloma. This finding translated into poor overall survival in patients with high vs. low MELK expression. Enrichment analysis of upregulated genes in myeloma cells of MELKhigh patients confirmed the strong implications in myeloma cell proliferation. Targeting MELK with OTSSP167 impaired the growth and survival of myeloma cells, thereby affecting central survival factors such as MCL-1 and IRF4. This activity was also observed in the 5TGM.1 murine model of myeloma. OTSSP167 reduced bone marrow infiltration and serum paraprotein levels in a dose-dependent manner. In addition, we revealed a strong link between MELK and other proliferation-associated high-risk genes (PLK-1, EZH2, FOXM1, DEPDC1) and MELK inhibition also impaired the expression of those genes. We therefore conclude that MELK is an essential component of a proliferative gene signature and that pharmacological inhibition of MELK represents an attractive novel approach to overcome the poor prognosis of high-risk patients with a proliferative expression pattern. PMID:29122991

A messenger at the door: cytomegalovirus retinitis in myeloma patients with progressive disease.

PubMed

Teh, B W; Khot, A S; Harrison, S J; Prince, H M; Slavin, M A

2013-08-01

Cytomegalovirus (CMV) retinitis is an uncommon manifestation of CMV disease and is a marker of severe and profound immunosuppression in human immunodeficiency virus-positive patients. Here, we describe 2 cases of CMV retinitis in myeloma patients with progressive disease, following autologous stem cell transplantation and immunomodulatory therapy for myeloma. To our knowledge, this is the first report of CMV retinitis in this patient population. This report illustrates the need for close monitoring of relapsed and refractory myeloma patients for new presentations of opportunistic infections secondary to severe immunosuppression. © 2013 John Wiley & Sons A/S.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM): a practical guide to management.

PubMed

Maciocia, Nicola; Wechalekar, Ashutosh; Yong, Kwee

2017-12-01

Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma are precursor conditions of symptomatic multiple myeloma (MM). Diagnostic principles are aimed at excluding MM requiring therapy, other conditions associated with paraproteins that may require different management, and risk stratifying patients for the purposes of tailored follow-up and investigation. The International Myeloma Working Group have recently published a revised definition of MM, which singles out a small group of patients with smoldering multiple myeloma who are at very high risk of progression and organ damage; such patients are now included under the definition of MM and recommended to start anti-myeloma treatment. Furthermore, the recently published National Institute of Health and Care Excellence guideline recommends cross-sectional imaging techniques in place of skeletal survey. These recent recommendations are discussed, and practical guidance for investigation and management are presented. Copyright © 2016 John Wiley & Sons, Ltd.

Osteosclerosis (punctate form) in multiple myeloma.

PubMed

Shin, M S; Mowry, R W; Bodie, F L

1979-02-01

Generalized punctate and nodular osteosclerosis associated with multiple myeloma is reported with review of the literature and differential diagnoses. This patient differs from some others reported earlier in the absence of any recognized osteolytic lesions either during life or at autopsy.

Hypertonic Saline Reduces Vascular Leakage in a Mouse Model of Severe Dengue

PubMed Central

Tan, Kar Wai; Angeli, Veronique; Moochhala, Shabbir; Ooi, Eng Eong; Alonso, Sylvie

2013-01-01

Dengue (DEN) is a mosquito-borne viral disease and represents a serious public health threat and an economical burden throughout the tropics. Dengue clinical manifestations range from mild acute febrile illness to severe DEN hemorrhagic fever/DEN shock syndrome (DHF/DSS). Currently, resuscitation with large volumes of isotonic fluid remains the gold standard of care for DEN patients who develop vascular leakage and shock. Here, we investigated the ability of small volume of hypertonic saline (HTS) suspensions to control vascular permeability in a mouse model of severe DEN associated with vascular leakage. Several HTS treatment regimens were considered and our results indicated that a single bolus of 7.5% NaCl at 4 mL per kg of body weight administered at the onset of detectable vascular leakage rapidly and significantly reduced vascular leak for several days after injection. This transient reduction of vascular leakage correlated with reduced intestine and liver damage with restoration of the hepatic functions, and resulted in delayed death of the infected animals. Mechanistically, we showed that HTS did not directly impact on the viral titers but resulted in lower immune cells counts and decreased systemic levels of soluble mediators involved in vascular permeability. In addition, we demonstrated that neutrophils do not play a critical role in DEN-associated vascular leakage and that the therapeutic effect of HTS is not mediated by its impact on the neutrophil counts. Together our data indicate that HTS treatment can transiently but rapidly reduce dengue-associated vascular leakage, and support the findings of a recent clinical trial which evaluated the efficacy of a hypertonic suspension to impact on vascular permeability in DSS children. PMID:23637867

The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells.

PubMed

Vuckovic, Slavica; Vandyke, Kate; Rickards, David A; McCauley Winter, Padraig; Brown, Simon H J; Mitchell, Todd W; Liu, Jun; Lu, Jun; Askenase, Philip W; Yuriev, Elizabeth; Capuano, Ben; Ramsland, Paul A; Hill, Geoffrey R; Zannettino, Andrew C W; Hutchinson, Andrew T

2017-05-01

We have discovered that a small cationic molecule, GW4869, is cytotoxic to a subset of myeloma cell lines and primary myeloma plasma cells. Biochemical analysis revealed that GW4869 binds to anionic phospholipids such as phosphatidylserine - a lipid normally confined to the intracellular side of the cell membrane. However, interestingly, phosphatidylserine was expressed on the surface of all myeloma cell lines tested (n = 12) and 9/15 primary myeloma samples. Notably, the level of phosphatidylserine expression correlated well with sensitivity to GW4869. Inhibition of cell surface phosphatidylserine exposure with brefeldin A resulted in resistance to GW4869. Finally, GW4869 was shown to delay the growth of phosphatidylserine-high myeloma cells in vivo. To the best of our knowledge, this is the first example of using a small molecule to target phosphatidylserine on malignant cells. This study may provide the rationale for the development of phosphatidylserine-targeting small molecules for the treatment of surface phosphatidylserine-expressing cancers. © 2017 John Wiley & Sons Ltd.

[Clinical and laboratory features and prognostic implications in myeloma with and without renal impairment].

PubMed

Griniūte, Rasa; Bumblyte, Inga Arūne

2003-01-01

Presenting clinical and laboratory features, prognostic implications and survival in 124 multiple myeloma patients were reviewed in a retrospective study based on hospital records. The median age was 65 years. Out of all patients, 2.42% were younger than 40 years and 62.9% were 60 years and older. The main presenting clinical features were bone pain (70.16%), fatigue (31.45%), recurrent infections (9.68%) and weight loss (0.3%). Renal failure was present in 35.48% of patients. The higher means of ionised calcium, uric acid, erythrocyte sedimentation rate, M protein were correlated with the higher mean of serum creatinine. The acturial survival of myeloma patients without renal failure at 1 and 2 years was 95.08% and 89.23% respectively, while acturial survival of myeloma patients with renal failure at 1 and 2 years was 82.5% and 73.35% respectively (p<0.01). One-year survival in myeloma patients maintained on chronic hemodialysis was 68.75% while it is reported as 90.91% for myeloma patients not on dialysis (p<0.006).

Development of doxorubicin-induced chronic cardiotoxicity in the B6C3F{sub 1} mouse model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Desai, Varsha G., E-mail: varsha.desai@fda.hhs.gov; Herman, Eugene H.; Moland, Carrie L.

2013-01-01

Serum levels of cardiac troponins serve as biomarkers of myocardial injury. However, troponins are released into the serum only after damage to cardiac tissue has occurred. Here, we report development of a mouse model of doxorubicin (DOX)-induced chronic cardiotoxicity to aid in the identification of predictive biomarkers of early events of cardiac tissue injury. Male B6C3F{sub 1} mice were administered intravenous DOX at 3 mg/kg body weight, or an equivalent volume of saline, once a week for 4, 6, 8, 10, 12, and 14 weeks, resulting in cumulative DOX doses of 12, 18, 24, 30, 36, and 42 mg/kg, respectively.more » Mice were sacrificed a week following the last dose. A significant reduction in body weight gain was observed in mice following exposure to a weekly DOX dose for 1 week and longer compared to saline-treated controls. DOX treatment also resulted in declines in red blood cell count, hemoglobin level, and hematocrit compared to saline-treated controls after the 2nd weekly dose until the 8th and 9th doses, followed by a modest recovery. All DOX-treated mice had significant elevations in cardiac troponin T concentrations in plasma compared to saline-treated controls, indicating cardiac tissue injury. Also, a dose-related increase in the severity of cardiac lesions was seen in mice exposed to 24 mg/kg DOX and higher cumulative doses. Mice treated with cumulative DOX doses of 30 mg/kg and higher showed a significant decline in heart rate, suggesting drug-induced cardiac dysfunction. Altogether, these findings demonstrate the development of DOX-induced chronic cardiotoxicity in B6C3F{sub 1} mice. -- Highlights: ► 24 mg/kg was a cumulative cardiotoxic dose of doxorubicin in male B6C3F{sub 1} mice. ► Doxorubicin-induced hematological toxicity was in association with splenomegaly. ► Doxorubicin induced severe testicular toxicity in B6C3F{sub 1} male mice.« less

Sorafenib in Treating Patients With Metastatic or Unresectable Solid Tumors, Multiple Myeloma, or Non-Hodgkin's Lymphoma With or Without Impaired Liver or Kidney Function

ClinicalTrials.gov

2013-01-04

Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia

Obesity-induced diabetes in mouse strains treated with gold thioglucose: a novel animal model for studying β-cell dysfunction.

PubMed

Karasawa, Hiroshi; Takaishi, Kiyosumi; Kumagae, Yoshihiro

2011-03-01

An obesity-induced diabetes model using genetically normal mouse strains would be invaluable but remains to be established. One reason is that several normal mouse strains are resistant to high-fat diet-induced obesity. In the present study, we show the effectiveness of gold thioglucose (GTG) in inducing hyperphagia and severe obesity in mice, and demonstrate the development of obesity-induced diabetes in genetically normal mouse strains. GTG treated DBA/2, C57BLKs, and BDF1 mice gained weight rapidly and exhibited significant increases in nonfasting plasma glucose levels 8-12 weeks after GTG treatment. These mice showed significantly impaired insulin secretion, particularly in the early phase after glucose load, and reduced insulin content in pancreatic islets. Interestingly, GTG treated C57BL/6 mice did not become diabetic and retained normal early insulin secretion and islet insulin content despite being as severely obese and insulin resistant as the other mice. These results suggest that the pathogenesis of obesity-induced diabetes in GTG-treated mice is attributable to the inability of their pancreatic β-cells to secrete enough insulin to compensate for insulin resistance. Mice developing obesity-induced diabetes after GTG treatment might be a valuable tool for investigating obesity-induced diabetes. Furthermore, comparing the genetic backgrounds of mice with different susceptibilities to diabetes may lead to the identification of novel genetic factors influencing the ability of pancreatic β-cells to secrete insulin.

White matter injuries induced by MK-801 in a mouse model of schizophrenia based on NMDA antagonism.

PubMed

Xiu, Yun; Kong, Xiang-Ru; Zhang, Lei; Qiu, Xuan; Chao, Feng-Lei; Peng, Chao; Gao, Yuan; Huang, Chun-Xia; Wang, San-Rong; Tang, Yong

2014-08-01

The etiology of schizophrenia (SZ) is complex and largely unknown. Neuroimaging and postmortem studies have suggested white matter disturbances in SZ. In the present study, we tested the white matter deficits hypothesis of SZ using a mouse model of SZ induced by NMDA receptor antagonist MK-801. We found that mice with repeated chronic MK-801 administration showed increased locomotor activity in the open field test, less exploration of a novel environment in the hole-board test, and increased anxiety in the elevated plus maze but no impairments were observed in coordination or motor function on accelerating rota-rod. The total white matter volume and corpus callosum volume in mice treated with MK-801 were significantly decreased compared to control mice treated with saline. Myelin basic protein and 2', 3'-cyclic nucleotide 3'-phosphodiesterase were also significantly decreased in the mouse model of SZ. Furthermore, we observed degenerative changes of myelin sheaths in the mouse model of SZ. These results provide further evidence of white matter deficits in SZ and indicate that the animal model of SZ induced by MK-801 is a useful model to investigate mechanisms underlying white matter abnormalities in SZ. Copyright © 2014 Wiley Periodicals, Inc.

Occupation, exposure to chemicals, sensitizing agents, and risk of multiple myeloma in Sweden.

PubMed

Lope, Virginia; Pérez-Gómez, Beatriz; Aragonés, Nuria; López-Abente, Gonzalo; Gustavsson, Per; Plato, Nils; Zock, Jan-Paul; Pollán, Marina

2008-11-01

This study sought to identify occupations with high incidence of multiple myeloma and to investigate possible excess risk associated with occupational exposure to chemicals and sensitizing agents in Sweden. A historical cohort of 2,992,166 workers was followed up (1971--1989) through record linkage with the National Cancer and Death Registries. For each job category, age and period standardized incidence ratios and age and period adjusted relative risks of multiple myeloma were calculated using Poisson models. Exposure to chemicals and to sensitizing agents was also assessed using two job-exposure matrices. Men and women were analyzed separately. During follow-up, 3,127 and 1,282 myelomas were diagnosed in men and women, respectively. In men, excess risk was detected among working proprietors, agricultural, horticultural and forestry enterprisers, bakers and pastry cooks, dental technicians, stone cutters/carvers, and prison/reformatory officials. In women, this excess was observed among attendants in psychiatric care, metal workers, bakers and pastry cooks, and paper/paperboard product workers. Workers, particularly bakers and pastry cooks, exposed to high molecular weight sensitizing agents registered an excess risk of over 40% across the sexes. Occasional, although intense, exposure to pesticides was also associated with risk of myeloma in our cohort. Our study supports a possible etiologic role for farming and use of pesticides in myeloma risk. The high incidence found in both female and male bakers and pastry cooks has not been described previously. Further research is required to assess the influence of high molecular weight sensitizing agents on risk of multiple myeloma.

Long-term exposure to intranasal oxytocin in a mouse autism model

PubMed Central

Bales, K L; Solomon, M; Jacob, S; Crawley, J N; Silverman, J L; Larke, R H; Sahagun, E; Puhger, K R; Pride, M C; Mendoza, S P

2014-01-01

Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse's chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT. PMID:25386957

Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis Independence Among Patients With Myeloma Cast Nephropathy: A Randomized Clinical Trial.

PubMed

Bridoux, Frank; Carron, Pierre-Louis; Pegourie, Brigitte; Alamartine, Eric; Augeul-Meunier, Karine; Karras, Alexandre; Joly, Bertrand; Peraldi, Marie-Noëlle; Arnulf, Bertrand; Vigneau, Cécile; Lamy, Thierry; Wynckel, Alain; Kolb, Brigitte; Royer, Bruno; Rabot, Nolwenn; Benboubker, Lotfi; Combe, Christian; Jaccard, Arnaud; Moulin, Bruno; Knebelmann, Bertrand; Chevret, Sylvie; Fermand, Jean-Paul

2017-12-05

Cast nephropathy is the main cause of acute kidney injury in multiple myeloma and persistent reduction in kidney function strongly affects prognosis. Strategies to rapidly remove nephrotoxic serum-free light chains combined with novel antimyeloma agents have not been evaluated prospectively. To compare the hemodialysis independence rate among patients newly diagnosed with myeloma cast nephropathy treated with hemodialysis using a high-cutoff dialyzer (with very large membrane pores and high permeability to immunoglobulin light chains) or a conventional high-flux dialyzer (with small pores and lower permeability). Randomized clinical trial involving 98 patients with biopsy-proven myeloma cast nephropathy requiring hemodialysis treated at 48 French centers between July 2011 and June 2016; the final date of follow-up was June 29, 2016. Intensive hemodialysis (eight 5-hour sessions over 10 days) with either a high-cutoff dialyzer (46 patients) or a conventional high-flux dialyzer (48 patients). All patients received the same chemotherapy regimen of bortezomib and dexamethasone. Primary end point was hemodialysis independence at 3 months; secondary end points: hemodialysis independence rates at 6 and 12 months, hemodialysis- and chemotherapy-related adverse events, and death. Among 98 randomized patients, 94 (96%) (median age, 68.8 years [interquartile range, 61.2-75.3 years]; 45% women) were included in the modified intent-to-treat analysis. The hemodialysis independence rate at 3 months was 41.3% (n = 19) in the high-cutoff hemodialysis group vs 33.3% (n = 16) in the conventional hemodialysis group (between-group difference, 8.0% [95% CI, -12.0% to 27.9%], P = .42); at 6 months, the rate was 56.5% (n = 26) vs 35.4% (n = 17), respectively (between-group difference, 21.1% [95% CI, 0.9% to 41.3%], P = .04); and at 12 months, the rate was 60.9% (n = 28) vs 37.5% (n = 18) (between-group difference, 23.4% [95% CI, 3.2% to 43.5%], P = .02

Pathogenesis of renal failure in multiple myeloma: any role of contrast media?

PubMed

Mussap, Michele; Merlini, Giampaolo

2014-01-01

The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis. Multiple myeloma per se cannot be considered a main risk factor for developing acute kidney injury following intravascular administration of iodinated contrast media. The risk is increased by comorbidities such as chronic kidney disease, diabetes, hypercalcemia, dehydration, and use of nephrotoxic drugs. Before the administration of contrast media, the current recommended laboratory tests for assessing kidney function are serum creatinine measurement and the estimation of glomerular filtration rate by using the CKD-EPI equation. The assessment of Bence Jones proteinuria is unnecessary for evaluating the risk of kidney failure in patients with multiple myeloma, since this test cannot be considered a surrogate biomarker of kidney function.

Management of multiple myeloma in older adults: Gaining ground with geriatric assessment.

PubMed

Wildes, Tanya M; Campagnaro, Erica

2017-01-01

Multiple myeloma increases in incidence with age. With the aging of the population, the number of cases of multiple myeloma diagnosed in older adults each year will nearly double in the next 20years. The novel therapeutic agents have significantly improved survival in older adults, but their outcomes remain poorer than in younger patients. Older adults may be more vulnerable to toxicity of therapy, resulting in decreased dose intensity and contributing to poorer outcomes. Data are beginning to emerge to aid in identifying which individuals are at greater risk for toxicity of therapy; comorbidities, functional limitations, and age over 80years are among the factors associated with greater risk. Geriatric assessment holds promise in the care of older adults with multiple myeloma, both to allow modification of treatment to prevent toxicity, and to identify vulnerabilities that may require intervention. Emerging treatments with low toxicity and attention to individualizing therapy based on geriatric assessment may aid in further improving outcomes in older adults with multiple myeloma. Copyright © 2016 Elsevier Inc. All rights reserved.

Pathogenesis of Renal Failure in Multiple Myeloma: Any Role of Contrast Media?

PubMed Central

Mussap, Michele; Merlini, Giampaolo

2014-01-01

The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis. Multiple myeloma per se cannot be considered a main risk factor for developing acute kidney injury following intravascular administration of iodinated contrast media. The risk is increased by comorbidities such as chronic kidney disease, diabetes, hypercalcemia, dehydration, and use of nephrotoxic drugs. Before the administration of contrast media, the current recommended laboratory tests for assessing kidney function are serum creatinine measurement and the estimation of glomerular filtration rate by using the CKD-EPI equation. The assessment of Bence Jones proteinuria is unnecessary for evaluating the risk of kidney failure in patients with multiple myeloma, since this test cannot be considered a surrogate biomarker of kidney function. PMID:24877060

The combination of ionizing radiation and proteasomal inhibition by bortezomib enhances the expression of NKG2D ligands in multiple myeloma cells.

PubMed

Lee, Young Shin; Heo, Woong; Nam, Jiho; Jeung, Young Hwa; Bae, Jaeho

2018-05-01

Bortezomib, which is a potent proteasome inhibitor, has been used as a first-line drugs to treat multiple myeloma for a few decades, and radiotherapy has frequently been applied to manage acute bone lesions in the patients. Therefore, it was necessary to investigate what the benefits might be if the two therapies were applied simultaneously in the treatment of multiple myeloma. Since it was known that radiotherapy and proteasome inhibitors could increase the expression of NKG2D ligands through induction of protein synthesis and suppression of protein degradation of NKG2D ligands, respectively, we supposed that the combined treatment might further enhance the expression of NKG2D ligands. In this study, we analyzed the expression level of NKG2D ligands using multiplex PCR and flow cytometry after treatment of IM-9 and RPMI-8226 myeloma cells with bortezomib and ionizing radiation; we then assayed the susceptibility to NK-92 cells. Although the expression of only some kinds of NKG2D ligands were increased by treatment with bortezomib alone, five kinds of NKG2D ligands that we assayed were further induced at the surface protein level after combined treatment with ionizing radiation and bortezomib. Furthermore, combined treatment made myeloma cells more susceptible to NK-92 cells, compared with treatment with bortezomib alone. In conclusion, the combination therapy of ionizing radiation plus the proteasome inhibitor bortezomib is a promising therapeutical strategy for enhancing NK cell-mediated anticancer immune responses.

Myeloid transformation of plasma cell myeloma: molecular evidence of clonal evolution revealed by next generation sequencing.

PubMed

Gralewski, Jonathon H; Post, Ginell R; van Rhee, Frits; Yuan, Youzhong

2018-02-20

Plasma cell myeloma (PCM) is a neoplasm of terminally differentiated B lymphocytes with molecular heterogeneity. Although therapy-related myeloid neoplasms are common in plasma cell myeloma patients after chemotherapy, transdifferentiation of plasma cell myeloma into myeloid neoplasms has not been reported in literature. Here we report a very rare case of myeloid neoplasm transformed from plasma cell myeloma. A 60-year-old man with a history of plasma cell myeloma with IGH-MAF gene rearrangement and RAS/RAF mutations developed multiple soft tissue lesions one year following melphalan-based chemotherapy and autologous stem cell transplant. Morphological and immunohistochemical characterization of the extramedullary disease demonstrated that the tumor cells were derived from the monocyte-macrophage lineage. Next generation sequencing (NGS) studies detected similar clonal aberrations in the diagnostic plasma cell population and post-therapy neoplastic cells, including IGH-MAF rearrangement, multiple genetic mutations in RAS signaling pathway proteins, and loss of tumor suppressor genes. Molecular genetic analysis also revealed unique genomic alterations in the transformed tumor cells, including gain of NF1 and loss of TRAF3. To our knowledge, this is the first case of myeloid sarcoma transdifferentiated from plasma cell neoplasm. Our findings in this unique case suggest clonal evolution of plasma cell myeloma to myeloma neoplasm and the potential roles of abnormal RAS/RAF signaling pathway in lineage switch or transdifferentiation.

Magnetic resonance appearance of monoclonal gammopathies of unknown significance and multiple myeloma. The GRI Study Group.

PubMed

Bellaïche, L; Laredo, J D; Lioté, F; Koeger, A C; Hamze, B; Ziza, J M; Pertuiset, E; Bardin, T; Tubiana, J M

1997-11-01

A prospective multicenter study. To evaluate the use of magnetic resonance imaging, in the differentiation between monoclonal gammopathies of unknown significance and multiple myeloma. Although multiple myeloma has been studied extensively with magnetic resonance imaging, to the authors' knowledge, no study has evaluated the clinical interest of magnetic resonance imaging in the differentiation between monoclonal gammopathies of unknown significance and multiple myeloma. The magnetic resonance examinations of the thoracolumbar spine in 24 patients with newly diagnosed monoclonal gammopathies of unknown significance were compared with those performed in 44 patients with newly diagnosed nontreated multiple myeloma. All findings on magnetic resonance examination performed in patients with monoclonal gammopathies of unknown significance were normal, whereas findings on 38 (86%) of the 44 magnetic resonance examinations performed in patients with multiple myeloma were abnormal. Magnetic resonance imaging can be considered as an additional diagnostic tool in differentiating between monoclonal gammopathies of unknown significance and multiple myeloma, which may be helpful when routine criteria are not sufficient. An abnormal finding on magnetic resonance examination in a patient with monoclonal gammopathies of unknown significance should suggest the diagnosis of multiple myeloma after other causes of marrow signal abnormalities are excluded. Magnetic resonance imaging also may be proposed in the long-term follow-up of monoclonal gammopathies of unknown significance when a new biologic or clinical event suggests the diagnosis of malignant monoclonal gammopathy.

A novel homologous model for gene therapy of dwarfism by non-viral transfer of the mouse growth hormone gene into immunocompetent dwarf mice.

PubMed

Cecchi, Claudia R; Higuti, Eliza; Oliveira, Nelio A J; Lima, Eliana R; Jakobsen, Maria; Dagnaes-Hansen, Frederick; Gissel, Hanne; Aagaard, Lars; Jensen, Thomas G; Jorge, Alexander A L; Bartolini, Paolo; Peroni, Cibele N

2014-02-01

The possibilities for non-viral GH gene therapy are studied in immunocompetent dwarf mice (lit/lit). As expression vector we used a plasmid previously employed in immunodeficient dwarf mice (pUBI-hGH-gDNA) by replacing the human GH gene with the genomic sequence of mouse-GH DNA (pUBI-mGH-gDNA). HEK-293 human cells transfected with pUBI-mGH-gDNA produced 3.0 µg mGH/10(6) cells/day compared to 3.7 µg hGH/10(6) cells/day for pUBIhGH- gDNA transfected cells. The weight of lit/lit mice treated with the same two plasmids (50 µg DNA/mouse) by electrotransfer into the quadriceps muscle was followed for 3 months. The weight increase up to 15 days for mGH, hGH and saline treated mice were 0.130, 0.112 and 0.027 g/mouse/day. Most sera from hGH-treated mice contained anti-hGH antibodies already on day 15, with the highest titers on day 45, while no significant anti-mGH antibodies were observed in mGH-treated mice. At the end of 3 months, the weight increase for mGH-treated mice was 34.3%, while the nose-to-tail and femur lengths increased 9.5% and 24.3%. Mouse-GH and hGH circulating levels were 4-5 ng/mL 15 days after treatment, versus control levels of ~0.7 ng GH/mL (P<0.001). In mGH-treated mice, mIGF-I determined on days 15, 45 and 94 were 1.5- to 3-fold higher than the control and 1.2- to 1.6-fold higher than hGH-treated mice. The described homologous model represents an important progress forming the basis for preclinical testing of non-viral gene therapy for GH deficiency.

IgM myeloma: A multicenter retrospective study of 134 patients.

PubMed

Castillo, Jorge J; Jurczyszyn, Artur; Brozova, Lucie; Crusoe, Edvan; Czepiel, Jacek; Davila, Julio; Dispenzieri, Angela; Eveillard, Marion; Fiala, Mark A; Ghobrial, Irene M; Gozzetti, Alessandro; Gustine, Joshua N; Hajek, Roman; Hungria, Vania; Jarkovsky, Jiri; Jayabalan, David; Laubach, Jacob P; Lewicka, Barbara; Maisnar, Vladimir; Manasanch, Elisabet E; Moreau, Philippe; Morgan, Elizabeth A; Nahi, Hareth; Niesvizky, Ruben; Paba-Prada, Claudia; Pika, Tomas; Pour, Ludek; Reagan, John L; Richardson, Paul G; Shah, Jatin; Spicka, Ivan; Vij, Ravi; Waszczuk-Gajda, Anna; Gertz, Morie A

2017-08-01

IgM myeloma is a rare hematologic malignancy for which the clinicopathological features and patient outcomes have not been extensively studied. We carried out a multicenter retrospective study in patients with diagnosis of IgM myeloma defined by >10% marrow involvement by monoclonal plasma cells, presence of an IgM monoclonal paraproteinemia of any size, and anemia, renal dysfunction, hypercalcemia, lytic lesions and/or t(11;14) identified by FISH. A total of 134 patients from 20 centers were included in this analysis. The median age at diagnosis was 65.5 years with a male predominance (68%). Anemia, renal dysfunction, elevated calcium and skeletal lytic lesions were found in 37, 43, 19, and 70%, respectively. The median serum IgM level was 2,895 mg dL -1 with 19% of patients presenting with levels >6,000 mg dL -1 . International Staging System (ISS) stages 1, 2, and 3 were seen in 40 (33%), 54 (44%), and 29 (24%) of patients, respectively. The malignant cells expressed CD20 (58%) and cyclin D1 (67%), and t(11;14) was the most common cytogenetic finding (39%). The median overall survival (OS) was 61 months. Higher ISS score was associated with worse survival (P = 0.02). Patients with IgM myeloma present with similar characteristics and outcomes as patients with more common myeloma subtypes. © 2017 Wiley Periodicals, Inc.

Treatment of multiple myeloma.

PubMed

San Miguel, J F; Bladé Creixenti, J; García-Sanz, R

1999-01-01

autotransplantation is not recommended for patients with resistant relapse, patients with primary refractory disease seem to benefit from early myeloablative therapy. Although results from large randomized trials are still pending in order to establish whether early HDT intensification followed by auto-SCT is superior to continuing standard ChT in responding patients, the favorable experience with autotransplantation of the French Myeloma Intergroup supports this approach. However, although the complete response rate is higher with intensive therapy, the median duration of response is relatively short (median, 16 to 36 months), with no survival plateau. There are several ongoing trials comparing conventional ChT with HDT/autoSCT in order to identify the patients who are likely to benefit from one or another approach. With allo-SCT there is a transplant-related mortality ranging from 30 to 50% and also a high relapse rate in patients achieving CR. However, 10 to 20% of patients undergoing allo-SCT are long-term survivors (> 5 years) with no evidence of disease and, consequently, probably cured. The use of allogeneic peripheral blood stem cells (PBSC) in order to speed the engraftment and also the use of partially T-cell depleted PBSC which can decrease the incidence of graft-versus-host disease are promising approaches. In the setting of allo-SCT, donor lymphocyte infusion is an encouraging strategy in order to treat or prevent relapses. Finally, important supportive measures such as the treatment of anemia with erythropoietin, the management of renal failure and the use of bisphosphonates are reviewed.

Three-Drug Combination for Relapsed Multiple Myeloma

Cancer.gov

A summary of Interim results from an international, randomized phase III trial that suggest that adding carfilzomib (Kyprolis®) to a standard treatment improves outcomes for patients with multiple myeloma whose cancer has relapsed.

Improved progression-free and event-free survival in myeloma patients undergoing PBSCH receiving a cyclophosphamide + G-CSF regimen than G-CSF alone.

PubMed

Tanimura, Akira; Hirai, Risen; Nakamura, Miki; Takeshita, Masataka; Hagiwara, Shotaro; Miwa, Akiyoshi

2018-05-01

Two regimens are commonly used for peripheral blood hematopoietic stem cell harvesting (PBSCH) in multiple myeloma: high-dose cyclophosphamide (HD-CY) + granulocyte-colony stimulating factor (G-CSF), and G-CSF alone. The objective of the present study was to evaluate the anti-myeloma effect of the PBSCH regimen including HD-CY. We retrospectively assessed harvesting efficiency, complications, and anti-myeloma effects in 115 patients receiving HD-CY + G-CSF (HD-CY group) and 32 patients receiving G-CSF alone (G-alone group). We collected > 2 × 10 6 CD34-positive cells/kg from 93 and 75% of patients in the HD-CY and G-alone groups, respectively (P = 0.0079). The mean HSC count was also higher in the HD-CY group. No severe complications were observed in the G-alone group, whereas 66% of patients in the HD-CY group were treated with intravenous antibiotics. The median progression-free and event-free survival (PFS and EFS) were longer in the HD-CY group than in the G-alone group (28 vs. 18 months and 25 vs. 13 months, respectively; P = 0.0127 and 0.0139), with no difference in median overall survival. HD-CY showed anti-myeloma effect, as verified by prolonged EFS and PFS, when a vincristine, doxorubicin, and dexamethasone regimen was administered as induction before PBSCH.

Early Application of High Cut-Off Haemodialysis for de-Novo Myeloma Nephropathy is Associated with Long-Term Dialysis-Independency and Renal Recovery

PubMed Central

Khalafallah, Alhossain A.; Loi, Sie Wuong; Love, Sarah; Mohamed, Muhajir; Mace, Rose; Khalil, Ramy; Girgs, Miriam; Raj, Rajesh; Mathew, Mathew

2013-01-01

Background Multiple myeloma (MM) is a haematological malignancy associated with kidney injury resulting from cast nephropathy, which can be caused by monoclonal free light chains (FLC). It has been demonstrated that early reduction of FLC can lead to a higher proportion of patients recovering renal function with a better outcome, especially if high cut-off haemodialysis (HCO-HD) combined with chemotherapy is used. Patients and Methods In this study, four cases with MM nephropathy were treated with HCO-HD and chemotherapy at a single institution during the period from August 2009 to August 2011. All of the patients presented with acute renal failure and high serum FLC. All patients underwent a bone marrow biopsy to confirm the diagnosis of MM, according to the WHO criteria. Three patients had de novo MM and one patient had relapsed light chain myeloma disease. All patients underwent HCO-HD concomitantly with specific myeloma therapy once the diagnosis or relapse of MM was established. Results After a medial follow up of 26 months, (range, 13–36) our data showed that all patients had a significant decrease in serum FLC through HCO-HD, proving the effectiveness of HCO-HD in managing MM. De-novo MM patients restored their renal function and achieved low-level FLC early in the treatment and became dialysis-independent. One patient with relapsed myeloma remained dialysis-dependent. Conclusion In summary, our study suggests that in myeloma nephropathy associated with light-chain MM, HCO-HD should be initiated as early as possible. At the same time a specific MM treatment should be initiated to gain control of the disease and salvage the kidneys in order to achieve dialysis-independency. Further randomized trials to confirm our results are warranted. PMID:23350020

Multiple myeloma associated with acquired cutis laxa.

PubMed

Cho, S Y; Maguire, R F

1980-08-01

Acquired cutis laxa is a rare disorder characterized by diffuse laxity of the skin and loss of connective tissue support with involvement of the lungs, gastrointestinal tract, pelvic organs, and aorta. The case report presented herein describes a forty-six year old woman with multiple myeloma and cutis laxa. Her history included several severe allergic reactions and the gradual development of lax skin, loss of connective tissue support throughout the body, and emphysema. At autopsy, multiple myeloma, diffuse laxity of the skin, and panacinar emphysema were found. The amount of elastic fiber in the skin, lungs, and aorta was decreased and showed abnormal fragmentation. Results of direct immunofluorescence study demonstrated IgG bound to dermal elastic fibers. Speculation regarding an immunologic etiology of the elastic tissue abnormality is presented herein.

Nitrous oxide emissions in a membrane bioreactor treating saline wastewater contaminated by hydrocarbons.

PubMed

Mannina, Giorgio; Cosenza, Alida; Di Trapani, Daniele; Laudicina, Vito Armando; Morici, Claudia; Ødegaard, Hallvard

2016-11-01

The joint effect of wastewater salinity and hydrocarbons on nitrous oxide emission was investigated. The membrane bioreactor pilot plant was operated with two phases: i. biomass acclimation by increasing salinity from 10gNaClL(-1) to 20gNaClL(-1) (Phase I); ii. hydrocarbons dosing at 20mgL(-1) with a constant salt concentration of 20gNaClL(-1) (Phase II). The Phase I revealed a relationship between nitrous oxide emissions and salinity. During the end of the Phase I, the activity of nitrifiers started to recover, indicating a partial acclimatization. During the Phase II, the hydrocarbon shock induced a temporary inhibition of the biomass with the suppression of nitrous oxide emissions. The results revealed that the oxic tank was the major source of nitrous oxide emission, likely due to the gas stripping by aeration. The joint effect of salinity and hydrocarbons was found to be crucial for the production of nitrous oxide. Copyright © 2016 Elsevier Ltd. All rights reserved.

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

PubMed

Stewart, A Keith; Rajkumar, S Vincent; Dimopoulos, Meletios A; Masszi, Tamás; Špička, Ivan; Oriol, Albert; Hájek, Roman; Rosiñol, Laura; Siegel, David S; Mihaylov, Georgi G; Goranova-Marinova, Vesselina; Rajnics, Péter; Suvorov, Aleksandr; Niesvizky, Ruben; Jakubowiak, Andrzej J; San-Miguel, Jesus F; Ludwig, Heinz; Wang, Michael; Maisnar, Vladimír; Minarik, Jiri; Bensinger, William I; Mateos, Maria-Victoria; Ben-Yehuda, Dina; Kukreti, Vishal; Zojwalla, Naseem; Tonda, Margaret E; Yang, Xinqun; Xing, Biao; Moreau, Philippe; Palumbo, Antonio

2015-01-08

Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

[A wrong move in an amateur football player reveals a light chain myeloma].

PubMed

Peyneau, Marine; Nassiri, Shiva; Myara, Anne; Ohana, Salomon; Laplanche, Sophie

2016-01-01

Light chain multiple myeloma is a hematologic malignancy characterized by an excess of tumor plasma cells in the bone marrow and a monoclonal light chain in blood. It is generally diagnosed in patients aged 60-75 years old. Hypercalcemia, anemia, kidney failure, and bone pains are the main clinical and biological signs. Here is an atypical case report about a 30 year-old man who was diagnosed a light chain multiple myeloma. This patient had been suffering from back pain for 5 months. Osteolytic lesions were discovered on X-rays prescribed by the family practitioner. Admitted to the Emergency department, all blood tests showed results within the normal range. The serum protein electrophoresis was also normal. Only the urine analysis showed proteinuria. The urine immunofixation electrophoresis showed a massive κ light chain. The bone marrow aspiration cell count confirmed the myeloma diagnosis with an infiltration of dystrophic plasma cells. The patient was transferred to the hematology ward of Necker Hospital for treatment of light chain myeloma.

Idiotype vaccination in patients with myeloma reduced circulating myeloma cells (CMC).

PubMed

Abdalla, A O; Kokhaei, P; Hansson, L; Mellstedt, H; Osterborg, A

2008-06-01

Circulating myeloma cells (CMC), exhibiting the same immunoglobulin heavy-chain gene rearrangements as the plasma cells, are part of the myeloma clone. In this study, we evaluated the effect of idiotype (Id) vaccination on CMC. Eleven patients were immunized with the autologous Id in combinations with granulocyte-macrophage colony-stimulating factor and interleukin 12, and followed for CMC by quantitative real-time allele-specific PCR. Id-specific T cells were monitored by proliferation assay, enzyme-linked immunospot (interferon-gamma) assay, and quantitative real-time PCR for cytokines. Regulatory T (T(reg)) cells were analyzed by flow cytometry. CMC were detected in 9 of 11 patients at start of vaccination. In four patients, CMC declined and two had a complete molecular remission. Further two patients had stable levels of CMC during follow-up, while in three patients CMC progressively increased. Six patients had a vaccine-induced Id-specific T-cell response. A significant correlation was observed between reduced/stable levels of CMC and the Id-specific T cells (P < 0.02). The frequency of T(reg) cells was decreased in immune responders, but increased in immune nonresponders (P < 0.05). No significant change in the serum M-protein concentration was, however, observed in any patient. Id vaccination reduced CMC, which correlated with vaccine-induced Id-specific T cells. Further studies are warranted to analyze the clinical significance of CMC and clinical effects of Id vaccination.

Allogeneic transplantation for multiple myeloma: late relapse may occur as localised lytic lesion/plasmacytoma despite ongoing molecular remission.

PubMed

Byrne, J L; Fairbairn, J; Davy, B; Carter, I G; Bessell, E M; Russell, N H

2003-02-01

Allogeneic SCT for myeloma may be curative for young patients, but its role remains controversial because of a reported high TRM in some series. Since 1991, we have performed 25 allografts for myeloma using fully matched sibling donors. Of the 18 evaluable patients, 13 achieved CR at a median time of 2.5 months post-transplant. The five patients who were not in CR when assessed at 3 months received a short course of alpha-interferon and four subsequently achieved CR with this approach at a median of 82 days. One patient who failed to respond to IFN went on to achieve CR after four doses of DLI therapy, thus giving an overall CR rate of 72%. Seven patients have relapsed at a median of 4.7 years post-transplant (range 1.38-7.7 years) including two patients who had received IFN therapy. In five of these cases, relapse has been as a localised area of bone disease or isolated plasmacytoma with no evidence of marrow involvement by trephine biopsy or molecular analysis. All patients with localised relapse were treated with local radiotherapy +/-DLI and four are currently disease free despite two patients having had further treatment for a second localised lesion. Six patients died of TRM (24%) and the OS at 8 years is currently 69% with an EFS of 26%. These results suggest that allogeneic SCT for myeloma can be carried out with an acceptable TRM and a high CR rate. However, late relapses as localised disease may be a frequent finding and may represent foci of myeloma not eradicated by the conditioning. The use of pretransplant MRI scanning and top-up radiotherapy to involved areas may be useful in preventing this type of relapse.

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients

PubMed Central

Shah, V; Sherborne, A L; Walker, B A; Johnson, D C; Boyle, E M; Ellis, S; Begum, D B; Proszek, P Z; Jones, J R; Pawlyn, C; Savola, S; Jenner, M W; Drayson, M T; Owen, R G; Houlston, R S; Cairns, D A; Gregory, W M; Cook, G; Davies, F E; Jackson, G H; Morgan, G J; Kaiser, M F

2018-01-01

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10−7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10−14) and 1.68 (P=2.18 × 10−14), respectively. Patients with ‘double-hit’ defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10−27) for all patients and 3.19 (P=1.23 × 10−18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10−15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment. PMID:28584253

Survival of Human Multiple Myeloma Cells Is Dependent on MUC1 C-Terminal Transmembrane Subunit Oncoprotein Function

PubMed Central

Yin, Li; Ahmad, Rehan; Kosugi, Michio; Kufe, Turner; Vasir, Baldev; Avigan, David; Kharbanda, Surender

2010-01-01

The MUC1 C-terminal transmembrane subunit (MUC1-C) oncoprotein is a direct activator of the canonical nuclear factor-κB (NF-κB) RelA/p65 pathway and is aberrantly expressed in human multiple myeloma cells. However, it is not known whether multiple myeloma cells are sensitive to the disruption of MUC1-C function for survival. The present studies demonstrate that peptide inhibitors of MUC1-C oligomerization block growth of human multiple myeloma cells in vitro. Inhibition of MUC1-C function also blocked the interaction between MUC1-C and NF-κB p65 and activation of the NF-κB pathway. In addition, inhibition of MUC1-C in multiple myeloma cells was associated with activation of the intrinsic apoptotic pathway and induction of late apoptosis/necrosis. Primary multiple myeloma cells, but not normal B-cells, were also sensitive to MUC1-C inhibition. Significantly, treatment of established U266 multiple myeloma xenografts growing in nude mice with a lead candidate MUC1-C inhibitor resulted in complete tumor regression and lack of recurrence. These findings indicate that multiple myeloma cells are dependent on intact MUC1-C function for constitutive activation of the canonical NF-κB pathway and for their growth and survival. PMID:20444960

High-risk multiple myeloma: a multifaceted entity, multiple therapeutic challenges.

PubMed

Muchtar, Eli; Magen, Hila; Gertz, Morie A

2017-06-01

The term high-risk multiple myeloma is aimed to identify a heterogeneous group of patients who are more likely to progress and die early of their disease. Therefore, recognition of these patients is crucial. With the increase in the number of treatment options, the outcome for high-risk patients has probably improved, although the true extent of this improvement remains unknown, due to both the heterogeneous components of high-risk disease and its under-representation in clinical trials. In this article, we review the definitions of high-risk disease, emphasizing the fact that no single definition can represent the entire high-risk population. In the second part, we review the treatment options available for the management of high-risk myeloma as well as our general approach for high-risk disease. In light of the poor prognosis associated with high-risk myeloma, even in the current era, new approaches for the management of this subset of patients are needed.

Guidelines for screening and management of late and long-term consequences of myeloma and its treatment.

PubMed

Snowden, John A; Greenfield, Diana M; Bird, Jennifer M; Boland, Elaine; Bowcock, Stella; Fisher, Abigail; Low, Eric; Morris, Monica; Yong, Kwee; Pratt, Guy

2017-03-01

A growing population of long-term survivors of myeloma is now accumulating the 'late effects' not only of myeloma itself, but also of several lines of treatment given throughout the course of the disease. It is thus important to recognise the cumulative burden of the disease and treatment-related toxicity in both the stable and active phases of myeloma, some of which is unlikely to be detected by routine monitoring. We summarise here the evidence for the key late effects in long-term survivors of myeloma, including physical and psychosocial consequences (in Parts 1 and 2 respectively), and recommend the use of late-effects screening protocols in detection and intervention. The early recognition of late effects and effective management strategies should lead to an improvement in the management of myeloma patients, although evidence in this area is currently limited and further research is warranted. © 2017 John Wiley & Sons Ltd.

Maintaining bone health in patients with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board.

PubMed

Miceli, Teresa S; Colson, Kathleen; Faiman, Beth M; Miller, Kena; Tariman, Joseph D

2011-08-01

About 90% of individuals with multiple myeloma will develop osteolytic bone lesions from increased osteoclastic and decreased osteoblastic activity. Severe morbidities from pathologic fractures and other skeletal events can lead to poor circulation, blood clots, muscle wasting, compromised performance status, and overall poor survival. Supportive care targeting bone disease is an essential adjunct to antimyeloma therapy. In addition, the maintenance of bone health in patients with multiple myeloma can significantly improve quality of life. Oncology nurses and other healthcare providers play a central role in the management of bone disease and maintenance throughout the course of treatment. Safe administration of bisphosphonates, promotion of exercise, maintenance of adequate nutrition, vitamin and mineral supplementation, scheduled radiographic examinations, and monitoring of bone complications are among the important functions that oncology nurses and healthcare providers perform in clinical practice.

Effect of potassium channel modulators in mouse forced swimming test

PubMed Central

Galeotti, Nicoletta; Ghelardini, Carla; Caldari, Bernardetta; Bartolini, Alessandro

1999-01-01

The effect of intracerebroventricular (i.c.v.) administration of different potassium channel blockers (tetraethylammonium, apamin, charybdotoxin, gliquidone), potassium channel openers (pinacidil, minoxidil, cromakalim) and aODN to mKv1.1 on immobility time was evaluated in the mouse forced swimming test, an animal model of depression. Tetraethylammonium (TEA; 5 μg per mouse i.c.v.), apamin (3 ng per mouse i.c.v.), charybdotoxin (1 μg per mouse i.c.v.) and gliquidone (6 μg per mouse i.c.v.) administered 20 min before the test produced anti-immobility comparable to that induced by the tricyclic antidepressants amitriptyline (15 mg kg−1 s.c.) and imipramine (30 mg kg−1 s.c.). By contrast pinacidil (10–20 μg per mouse i.c.v.), minoxidil (10–20 μg per mouse i.c.v.) and cromakalim (20–30 μg per mouse i.c.v.) increased immobility time when administered in the same experimental conditions. Repeated administration of an antisense oligonucleotide (aODN) to the mKv1.1 gene (1 and 3 nmol per single i.c.v. injection) produced a dose-dependent increase in immobility time of mice 72 h after the last injection. At day 7, the increasing effect produced by aODN disappeared. A degenerate mKv1.1 oligonucleotide (dODN), used as control, did not produce any effect in comparison with saline- and vector-treated mice. At the highest effective dose, potassium channels modulators and the mKv1.1 aODN did not impair motor coordination, as revealed by the rota rod test, nor did they modify spontaneous motility as revealed by the Animex apparatus. These results suggest that modulation of potassium channels plays an important role in the regulation of immobility time in the mouse forced swimming test. PMID:10323599

A case control study of multiple myeloma at four nuclear facilities.

PubMed

Wing, S; Richardson, D; Wolf, S; Mihlan, G; Crawford-Brown, D; Wood, J

2000-04-01

Reported elevations of multiple myeloma among nuclear workers exposed to external penetrating ionizing radiation, based on small numbers of cases, prompted this multi-facility study of workers at US Department of Energy facilities. Ninety-eight multiple myeloma deaths and 391 age-matched controls were selected from the combined roster of 115,143 workers hired before 1979 at Hanford, Los Alamos National Laboratory, Oak Ridge National Laboratory, and the Savannah River site. These workers were followed for vital status through 1990 (1986 for Hanford). Demographic, work history, and occupational exposure data were derived from personnel, occupational medicine, industrial hygiene, and health physics records. Exposure-disease associations were evaluated using conditional logistic regression. Cases were disproportionately African American, male, and hired prior to 1948. Lifetime cumulative whole body ionizing radiation dose was not associated with multiple myeloma, however, there was a significant effect of age at exposure, with positive associations between multiple myeloma and doses received at older ages. Dose response associations increased in magnitude with exposure age (from 40 to 50) and lag assumption (from 5 to 15 years), while a likelihood ratio goodness of fit test reached the highest value for cumulative doses received at ages above 45 with a 5-year lag (X2=5.43,1 df; relative risk = 6.9% per 10 mSv). Dose response associations persisted with adjustment for potential confounders. Multiple myeloma was associated with low level whole body penetrating ionizing radiation doses at older ages. The exposure age effect is at odds with interpretations of A-bomb survivor studies but in agreement with several studies of cancer among nuclear workers.

Multiple Myeloma, Version 2.2016

PubMed Central

Anderson, Kenneth C.; Alsina, Melissa; Atanackovic, Djordje; Biermann, J. Sybil; Chandler, Jason C.; Costello, Caitlin; Djulbegovic, Benjamin; Fung, Henry C.; Gasparetto, Cristina; Godby, Kelly; Hofmeister, Craig; Holmberg, Leona; Holstein, Sarah; Huff, Carol Ann; Kassim, Adetola; Krishnan, Amrita Y.; Kumar, Shaji K.; Liedtke, Michaela; Lunning, Matthew; Raje, Noopur; Singhal, Seema; Smith, Clayton; Somlo, George; Stockerl-Goldstein, Keith; Treon, Steven P.; Weber, Donna; Yahalom, Joachim; Shead, Dorothy A.; Kumar, Rashmi

2016-01-01

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Recent statistics from the American Cancer Society indicate that the incidence of MM is increasing. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) included in this issue address management of patients with solitary plasmacytoma and newly diagnosed MM. PMID:26553768

Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma

ClinicalTrials.gov

2017-10-23

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Testicular Lymphoma; Waldenström Macroglobulinemia

[Establishment and Management of Multiple Myeloma Specimen Bank Applied for Molecular Biological Researches].

PubMed

Li, Han-Qing; Mei, Jian-Gang; Cao, Hong-Qin; Shao, Liang-Jing; Zhai, Yong-Ping

2017-12-01

To establish a multiple myeloma specimen bank applied for molecular biological researches and to explore the methods of specimen collection, transportation, storage, quality control and the management of specimen bank. Bone marrow and blood samples were collected from multiple myeloma patients, plasma cell sorting were operated after the separation of mononuclear cells from bone marrow specimens. The plasma cells were divided into 2 parts, one was added with proper amount of TRIzol and then kept in -80 °C refrigerator for subsequent RNA extraction, the other was added with proper amount of calf serum cell frozen liquid and then kept in -80 °C refrigerator for subsequent cryopreservation of DNA extraction after numbered respectively. Serum and plasma were separated from peripheral blood, specimens of serum and plasma were then stored at -80 °C refrigerator after registration. Meantime, the myeloma specimen information management system was established, managed and maintained by specially-assigned persons and continuous modification and improvement in the process of use as to facilitate the rapid collection, management, query of the effective samples and clinical data. A total of 244 portions plasma cells, 564 portions of serum, and 1005 portions of plasma were collected, clinical characters were documented. A multiple myeloma specimen bank have been established initially, which can provide quality samples and related clinical information for molecular biological research on multiple myeloma.

NCI collaborates with Multiple Myeloma Research Foundation

Cancer.gov

The National Cancer Institute (NCI) announced a collaboration with the Multiple Myeloma Research Foundation (MMRF) to incorporate MMRF's wealth of genomic and clinical data on the disease into the NCI Genomic Data Commons (GDC), a publicly available datab

Panobinostat and Everolimus in Treating Patients With Recurrent Multiple Myeloma, Non-Hodgkin Lymphoma, or Hodgkin Lymphoma

ClinicalTrials.gov

2018-04-19

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; B-cell Adult Acute Lymphoblastic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Splenic Marginal Zone Lymphoma; T-cell Adult Acute Lymphoblastic Leukemia; Waldenström Macroglobulinemia

Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment.

PubMed

Lam, Christine; Ferguson, Ian D; Mariano, Margarette C; Lin, Yu-Hsiu T; Murnane, Megan; Liu, Hui; Smith, Geoffrey A; Wong, Sandy W; Taunton, Jack; Liu, Jun O; Mitsiades, Constantine S; Hann, Byron C; Aftab, Blake T; Wiita, Arun P

2018-04-05

The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models. Furthermore, tofacitinib strongly synergized with venetoclax in co-culture with marrow stromal cells but not in monoculture. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib reverses the growth-promoting effects of the tumor microenvironment. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients. Copyright © 2018, Ferrata Storti Foundation.

Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy

PubMed Central

Lohr, Jens G.; Stojanov, Petar; Carter, Scott L.; Cruz-Gordillo, Peter; Lawrence, Michael S.; Auclair, Daniel; Sougnez, Carrie; Knoechel, Birgit; Gould, Joshua; Saksena, Gordon; Cibulskis, Kristian; McKenna, Aaron; Chapman, Michael A.; Straussman, Ravid; Levy, Joan; Perkins, Louise M.; Keats, Jonathan J.; Schumacher, Steven E.; Rosenberg, Mara; Getz, Gad

2014-01-01

SUMMARY We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations, and discovered putative tumor suppressor genes by determining homozygous deletions and loss-of-heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53 and DIS3 (particularly in non-hyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g. KRAS, NRAS and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of non-mutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions. PMID:24434212

Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.

PubMed

Lohr, Jens G; Stojanov, Petar; Carter, Scott L; Cruz-Gordillo, Peter; Lawrence, Michael S; Auclair, Daniel; Sougnez, Carrie; Knoechel, Birgit; Gould, Joshua; Saksena, Gordon; Cibulskis, Kristian; McKenna, Aaron; Chapman, Michael A; Straussman, Ravid; Levy, Joan; Perkins, Louise M; Keats, Jonathan J; Schumacher, Steven E; Rosenberg, Mara; Getz, Gad; Golub, Todd R

2014-01-13

We performed massively parallel sequencing of paired tumor/normal samples from 203 multiple myeloma (MM) patients and identified significantly mutated genes and copy number alterations and discovered putative tumor suppressor genes by determining homozygous deletions and loss of heterozygosity. We observed frequent mutations in KRAS (particularly in previously treated patients), NRAS, BRAF, FAM46C, TP53, and DIS3 (particularly in nonhyperdiploid MM). Mutations were often present in subclonal populations, and multiple mutations within the same pathway (e.g., KRAS, NRAS, and BRAF) were observed in the same patient. In vitro modeling predicts only partial treatment efficacy of targeting subclonal mutations, and even growth promotion of nonmutated subclones in some cases. These results emphasize the importance of heterogeneity analysis for treatment decisions. Copyright © 2014 Elsevier Inc. All rights reserved.

Anti-myeloma activity of a multi targeted kinase inhibitor, AT9283, via potent Aurora Kinase and STAT3 inhibition either alone or in combination with lenalidomide

PubMed Central

Santo, Loredana; Hideshima, Teru; Cirstea, Diana; Bandi, Madhavi; Nelson, Erik A.; Gorgun, Gullu; Rodig, Scott; Vallet, Sonia; Pozzi, Samantha; Patel, Kishan; Unitt, Christine; Squires, Matt; Hu, Yiguo; Chauhan, Dharminder; Mahindra, Anuj; Munshi, Nikhil C.; Anderson, Kenneth C.; Raje, Noopur

2014-01-01

Purpose Aurora Kinases, whose expression is linked to genetic instability and cellular proliferation, are under investigation as novel therapeutic targets in multiple myeloma (MM). Here, we investigated the preclinical activity of a small molecule–multi-targeted kinase inhibitor, AT9283, with potent activity against Aurora kinase A (AURKA), Aurora kinase B (AURKB) and Janus Kinase 2/3. Experimental design We evaluated the in vitro anti myeloma activity of AT9283 alone and in combination with lenalidomide and the in vivo efficacy by using a Xenograft mouse model of human MM. Results Our data demonstrated AT9283 induced cell growth inhibition and apoptosis in MM. Studying the apoptosis mechanism of AT9283 in MM, we observed features consistent with both AURKA and AURKB inhibition, e.g increase of cells with polyploid DNA content, decrease in phospho-Histone H3, and decrease of phospho-Aurora A. Importantly, AT9283 also inhibited STAT3 tyrosine phosphorylation in MM cells. Genetic depletion of STAT3, AURKA or AURKB showed growth inhibition of MM cells, suggesting a role of AT9283-induced inhibition of these molecules in the underlying mechanism of MM cell death. In vivo studies demonstrated decreased MM cell growth and prolonged survival in AT9283-treated mice compared to controls. Importantly, combination studies of AT9283 with lenalidomide showed significant synergistic cytotoxicity in MM cells, even in the presence of bone marrow stromal cells (BMSCs). Enhanced cytotoxicity was associated with increased inhibition of pSTAT3 and pERK. Conclusions Demonstration of in vitro and in vivo anti-MM activity of AT9283 provides the rationale for the clinical evaluation of AT9283 as monotherapy and in combination in patients with MM. PMID:21430070

Induction of different activated phenotypes of mouse peritoneal macrophages grown in different tissue culture media.

PubMed

Kawakami, Tomoya; Koike, Atsushi; Amano, Fumio

2017-08-01

The role of activated macrophages in the host defense against pathogens or tumor cells has been investigated extensively. Many researchers have been using various culture media in in vitro experiments using macrophages. We previously reported that J774.1/JA-4 macrophage-like cells showed great differences in their activated macrophage phenotypes, such as production of reactive oxygen, nitric oxide (NO) or cytokines depending on the culture medium used, either F-12 (Ham's F-12 nutrient mixture) or Dulbecco modified Eagle's medium (DMEM). To examine whether a difference in the culture medium would influence the functions of primary macrophages, we used BALB/c mouse peritoneal macrophages in this study. Among the activated macrophage phenotypes, the expression of inducible NO synthase in LPS- and/or IFN-γ-treated peritoneal macrophages showed the most remarkable differences between F-12 and DMEM; i.e., NO production by LPS- and/or IFN-γ-treated cells was far lower in DMEM than in F-12. Similar results were obtained with C57BL mouse peritoneal macrophages. Besides, dilution of F-12 medium with saline resulted in a slight decrease in NO production, whereas that of DMEM with saline resulted in a significant increase, suggesting the possibility that DMEM contained some inhibitory factor(s) for NO production. However, such a difference in NO production was not observed when macrophage-like cell lines were examined. These results suggest that phenotypes of primary macrophages could be changed significantly with respect to host inflammatory responses by the surrounding environment including nutritional factors and that these altered macrophage phenotypes might influence the biological host defense.

Maintaining Bone Health in Patients With Multiple Myeloma: Survivorship Care Plan of the International Myeloma Foundation Nurse Leadership Board

PubMed Central

Miceli, Teresa S.; Colson, Kathleen; Faiman, Beth M.; Miller, Kena; Tariman, Joseph D.

2014-01-01

About 90% of individuals with multiple myeloma will develop osteolytic bone lesions from increased osteoclastic and decreased osteoblastic activity. Severe morbidities from pathologic fractures and other skeletal events can lead to poor circulation, blood clots, muscle wasting, compromised performance status, and overall poor survival. Supportive care targeting bone disease is an essential adjunct to antimyeloma therapy. In addition, the maintenance of bone health in patients with multiple myeloma can significantly improve quality of life. Oncology nurses and other healthcare providers play a central role in the management of bone disease and maintenance throughout the course of treatment. Safe administration of bisphosphonates, promotion of exercise, maintenance of adequate nutrition, vitamin and mineral supplementation, scheduled radiographic examinations, and monitoring of bone complications are among the important functions that oncology nurses and healthcare providers perform in clinical practice. PMID:21816707

MicroRNA Transfer Between Bone Marrow Adipose and Multiple Myeloma Cells.

PubMed

Soley, Luna; Falank, Carolyne; Reagan, Michaela R

2017-06-01

Multiple myeloma remains an incurable disease, largely due to the tumor-supportive role of the bone marrow microenvironment. Bone marrow adipose tissue (BMAT) is one component of the fertile microenvironment which is believed to contribute to myeloma progression and drug resistance, as well as participate in a vicious cycle of osteolysis and tumor growth. MicroRNAs (miRNAs) have recently emerged as instrumental regulators of cellular processes that enable the development and dissemination of cancer. This review highlights the intersection between two emerging research fields and pursues the scientific and clinical implications of miRNA transfer between BMAT and myeloma cells. This review provides a concise and provocative summary of the evidence to support exosome-mediated transfer of tumor-supportive miRNAs. The work may prompt researchers to better elucidate the mechanisms by which this novel means of genetic communication between tumor cells and their environment could someday yield targeted therapeutics.

Stages of Plasma Cell Neoplasms (Including Multiple Myeloma)

MedlinePlus

... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

MYC protein expression is detected in plasma cell myeloma but not in monoclonal gammopathy of undetermined significance (MGUS).

PubMed

Xiao, Ruobing; Cerny, Jan; Devitt, Katherine; Dresser, Karen; Nath, Rajneesh; Ramanathan, Muthalagu; Rodig, Scott J; Chen, Benjamin J; Woda, Bruce A; Yu, Hongbo

2014-06-01

It has been recognized that monoclonal gammopathy of undetermined significance (MGUS) precedes a diagnosis of plasma cell myeloma in most patients. Recent gene expression array analysis has revealed that an MYC activation signature is detected in plasma cell myeloma but not in MGUS. In this study, we performed immunohistochemical studies using membrane CD138 and nuclear MYC double staining on bone marrow biopsies from patients who met the diagnostic criteria of plasma cell myeloma or MGUS. Our study demonstrated nuclear MYC expression in CD138-positive plasma cells in 22 of 26 (84%) plasma cell myeloma samples and in none of the 29 bone marrow samples from patients with MGUS. In addition, our data on the follow-up biopsies from plasma cell myeloma patients with high MYC expression demonstrated that evaluation of MYC expression in plasma cells can be useful in detecting residual disease. We also demonstrated that plasma cells gained MYC expression in 5 of 8 patients (62.5%) when progressing from MGUS to plasma cell myeloma. Analysis of additional lymphomas with plasmacytic differentiation, including lymphoplasmacytic lymphoma, marginal zone lymphoma, and plasmablastic lymphoma, reveals that MYC detection can be a useful tool in the diagnosis of plasma cell myeloma.

Preventing, treating, and predicting barbering: a fundamental role for biomarkers of oxidative stress in a mouse model of trichotillomania

USDA-ARS?s Scientific Manuscript database

Barbering, where a “barber” mouse plucks hair from its cagemates or itself, is both a spontaneously occurring abnormal behavior in mice and a well validated model of Trichotillomania (TTM). N-Acetylcysteine, (NAC) a cysteine derived food additive, is remarkably effective in treating TTM patients, bu...

IgA-kappa type multiple myeloma affecting proximal and distal renal tubules.

PubMed

Minemura, K; Ichikawa, K; Itoh, N; Suzuki, N; Hara, M; Shigematsu, S; Kobayashi, H; Hiramatsu, K; Hashizume, K

2001-09-01

A 45-year-old male was admitted because of chest pain, lumbago, and bilateral ankle pain. Examination disclosed hypophosphatemic osteomalacia, acquired Fanconi syndrome, and abnormalities in distal nephron such as distal renal tubular acidosis and renal diabetes insipidus. Further exploration revealed IgA kappa multiple myeloma excreting urinary Bence Jones protein (kappa-light chain). Renal biopsy revealed thick basement membranes and elec-tron-dense crystals in proximal tubular epithelial cells. Immunofluorescent studies revealed deposition of kappa-light chain in renal tubular epithelial cells that caused the renal tubular damage. Although the osteomalacia was relieved by medical treatment, the urinary Bence Jones protein and the renal tubular defects were not improved by the chemotherapy for the myeloma. The patient died of exacerbation of multiple myeloma at 50 years of age.

Pleural Effusion in Multiple Myeloma.

PubMed

Wang, Zhuo; Xia, Guoguang; Lan, Ling; Liu, Fayong; Wang, Yanxun; Liu, Baoyue; Ding, Yi; Dai, Li; Zhang, Yunjian

2016-01-01

Pleural effusion is rarely observed in patients with multiple myeloma (MM). Myeloma cell infiltration or invasion to the pleura is very rare. This study aimed to investigate the clinical characteristics of pleural effusion in patients with MM. We retrospectively reviewed the medical records of patients diagnosed with pleural effusion, MM, and pleural effusion with MM between 2004 and 2014 at Beijing Jishuitan Hospital. The present study included patients with pleural effusion who underwent cytological, bacteriological, biochemical and other testing. The cytopathology of abnormal pleural effusion cells was not diagnostic, thus flow cytometry was performed. MM was defined using the diagnosis standard of NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) 2014 for MM. This study included 3,480 pleural effusion patients and 319 MM patients. There were 34 patients with both MM and pleural effusion (17 men and 17 women). The average age was 63 years (range, 48-84 years). Pleural effusion with MM was caused by congestive heart disease, chronic renal failure, hypoalbuminemia, pulmonary infarctions, cirrhosis, pulmonary arterial hypertension, parapneumonic effusion, tuberculous pleural effusion, and myelomatous pleural effusion (MPE). The diagnosis of MPE was confirmed by the detection of myeloma cells in the pleural fluid using flow cytometric analyses. There were only 2 MPE cases in our study. The first MPE case was a woman. The first clinical manifestation was pleural effusion, and the diagnosis was non-secretory MM, DSS stage IIIA (Durie-Salmon staging system); ISS stage I (the International Staging System). The second MPE case was a man who was diagnosed with MM IgA-κ, DSS stage IIIA; ISS stage II. The detection rate of MPE was very low. MPE tended to present with yellow exudates and the lack of physical and chemical characteristics. Furthermore, patients with MPE exhibited many yellow nodules on the pleura. These nodules were lobulated and had abundant

Management of Side Effects of Novel Therapies for Multiple Myeloma: Consensus Statements Developed by the International Myeloma Foundation’s Nurse Leadership Board

PubMed Central

Bertolotti, Page; Bilotti, Elizabeth; Colson, Kathleen; Curran, Kathleen; Doss, Deborah; Faiman, Beth; Gavino, Maria; Jenkins, Bonnie; Lilleby, Kathy; Love, Ginger; Mangan, Patricia A.; McCullagh, Emily; Miceli, Teresa; Miller, Kena; Rogers, Kathryn; Rome, Sandra; Sandifer, Stacey; Smith, Lisa C.; Tariman, Joseph D.; Westphal, Jeanne

2014-01-01

Nurses play an essential role in managing the care of patients with multiple myeloma, who require education and support to receive and adhere to optimal therapy. The International Myeloma Foundation created a Nurse Leadership Board comprised of oncology nurses from leading cancer centers and community practices. An assessment survey identified the need for specific recommendations for managing key side effects of novel antimyeloma agents. Myelosuppression, thromboembolic events, peripheral neuropathy, steroid toxicities, and gastrointestinal side effects were selected for the first consensus statements. The board developed recommendations for healthcare providers in any medical setting, including grading of side-effect toxicity and strategies for managing the side effects in general, with specific recommendations pertaining to the novel agents. PMID:18490252

[State of the art treatment of progressive or refractory multiple myeloma].

PubMed

Schmidt-Wolf, I G H; Straka, C; Scheid, C; Einsele, H; Goldschmidt, H; Engelhardt, M

2014-10-01

Multiple myeloma (MM) is with an incidence of 4-6/100 000 inhabitants a fairly frequent malignancy of B cells. The incidence increases markedly with age. In this review changes in the treatment of relapsed / refractory myeloma during the last decade have been analysed. The present standard of care in the progressive or refractory myeloma was elaborated by the working group "Refractory Multiple Myeloma" using an extensive literature search for studies published between 2003 and 2013. Outside of clinical trials, high-dose therapy with stem cell transplantation is recommended in fit patients up to 75 years without significant comorbidities. Ongoing studies address the question about the least toxic and the most effective treatment. Therefore, inclusion of patients in therapeutic trials and use of novel agent combinations is highly recommended, e.g. with 3(rd) generation-IMIDs (pomalidomide), new proteasome inhibitors, such as carfilzomib, ixazomib or oprozomib, antibodies, such as elotuzumab, daratumumab or SAR650984, siltuximab, tabalumab, denosumab, romosozumab, BTK-, HSP-inhibitors and other innovative phase I/II agents. Based on new insights in the pathogenesis of the disease, treatment options for MM have changed significantly in recent years. There is a significantly larger treatment diversity, i.e. more MM-active agents and combinations are available today. Even with relapsed MM, patients with the disease often live longer and have fewer complications. © Georg Thieme Verlag KG Stuttgart · New York.

AR-42 in Treating Patients With Advanced or Relapsed Multiple Myeloma, Chronic Lymphocytic Leukemia, or Lymphoma

ClinicalTrials.gov

2017-02-21

Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large

Efficacy and toxicity of the combination chemotherapy of thalidomide, alkylating agent, and steroid for relapsed/refractory myeloma patients: a report from the Korean Multiple Myeloma Working Party (KMMWP) retrospective study.

PubMed

Kwon, Jihyun; Min, Chang-Ki; Kim, Kihyun; Han, Jae-Joon; Moon, Joon Ho; Kang, Hye Jin; Eom, Hyeon-Seok; Kim, Min Kyoung; Kim, Hyo Jung; Yoon, Dok Hyun; Lee, Jeong-Ok; Lee, Won Sik; Lee, Jae Hoon; Lee, Je-Jung; Choi, Yoon-Seok; Kim, Sung Hyun; Yoon, Sung-Soo

2017-01-01

We analyzed the treatment responses, toxicities, and survival outcomes of patients with relapsed or refractory multiple myeloma who received daily thalidomide, cyclophosphamide, and dexamethasone (CTD) or daily thalidomide, melphalan, and prednisolone (MTP) at 17 medical centers in Korea. Three-hundred and seventy-six patients were enrolled. The combined chemotherapy of thalidomide, corticosteroid, and an alkylating agent (TAS) was second-line chemotherapy in 142 (37.8%) patients, and third-line chemotherapy in 135 (35.9%) patients. The response rate overall was 69.4%. Patients who were not treated with bortezomib and lenalidomide before TAS showed a higher response rate compared to those who were exposed to these agents. The estimated median progression-free survival and overall survival times were 10.4 months and 28.0 months, respectively. The adverse events during TAS were generally tolerable, but 39 (10.4%) patients experienced severe infectious complications. There were no differences in terms of efficacy between CTD and MTP, but infectious complications were more common in CTD group. TAS is an effective treatment regimen which induces a high response rate in relapsed or refractory multiple myeloma patients. Due to the high incidence of grade 3 or 4 infection, proper management of infection is necessary during the TAS treatment, especially the CTD. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Patient-specific 3D microfluidic tissue model for multiple myeloma.

PubMed

Zhang, Wenting; Lee, Woo Y; Siegel, David S; Tolias, Peter; Zilberberg, Jenny

2014-08-01

In vitro culturing of primary multiple myeloma cells (MMC) has been a major challenge as this plasma cell malignancy depends on the bone marrow environment for its survival. Using a microfluidic platform to emulate the dynamic physiology of the bone marrow microenvironment, we report here a new approach for culturing difficult to preserve primary human MMC. The system uses a three-dimensional ossified tissue to mimic the tumor niche and recapitulate interactions between bone marrow cells and osteoblasts (OSB). To this end, the human fetal OSB cell line hFOB 1.19 was cultured in an eight-chamber microfluidic culture device to facilitate the seeding of mononuclear cells from bone marrow aspirates from three multiple myeloma patients. Optical microscopy, used for real-time monitoring of mononuclear cell interactions with the ossified tissue, confirmed that these are drawn toward the OSB layer. After 3 weeks, cocultures were characterized by flow cytometry to evaluate the amount of expansion of primary MMC (with CD138(+) and CD38(+)CD56(+) phenotypes) in this system. For each of the three patients analyzed, bone marrow mononuclear cells underwent, on an average, 2 to 5 expansions; CD38(+)CD56(+) cells underwent 1 to 3 expansions and CD138(+) cells underwent 2.5 to 4.6 expansions. This approach is expected to provide a new avenue that can facilitate: (1) testing of personalized therapeutics for multiple myeloma patients; (2) evaluation of new drugs without the need for costly animal models; and (3) studying the biology of multiple myeloma, and in particular, the mechanisms responsible for drug resistance and relapse.

Multiple myeloma among Danish women: employment history and workplace exposures.

PubMed

Pottern, L M; Heineman, E F; Olsen, J H; Raffn, E; Blair, A

1992-09-01

To investigate the role of employment history and workplace exposures as risk factors for multiple myeloma among women, a population-based case-control study using the Danish Cancer Registry data linkage system was conducted. All cases of myeloma diagnosed in Danish women between 1970 and 1984 (1,010 cases) and 4,040 age-matched women alive at the time of case-diagnosis were identified. Industrial histories from 1964 forward were obtained from the nationwide Pension Fund for 363 cases and 1,517 controls, and the most recent occupation on the tax record was available for 607 cases and 2,596 controls. Using industry/occupational-code combinations for the cases and controls who had industry employment, Danish industrial hygienists assessed the likelihood of exposure to 47 workplace substances. An increased myeloma risk (odds ratio [OR] = 1.2, 95 percent confidence interval [CI] = 1.0-1.5) was seen for women not in the Pension Fund, but who had an occupational title coded as 'Mrs/homemaker.' Nonsignificantly elevated risks of 1.3 or greater were observed for employment in: production of agricultural products; orchards/nurseries; spinning/weaving; other textile and plastics manufacturing; hotel, entertainment, and social services industries. Elevated, but nonsignificant risks were observed for possible and probable exposure to exhaust fumes, formaldehyde, wood dust, animals or animal products, and pesticides. The strongest association with myeloma was employment in the agricultural industry (OR = 1.5, CI = 0.8-2.8), however, the number of women who worked on family farms was unknown and could not be included in this risk estimate.

The streptomycin-treated mouse intestine selects Escherichia coli envZ missense mutants that interact with dense and diverse intestinal microbiota.

PubMed

Leatham-Jensen, Mary P; Frimodt-Møller, Jakob; Adediran, Jimmy; Mokszycki, Matthew E; Banner, Megan E; Caughron, Joyce E; Krogfelt, Karen A; Conway, Tyrrell; Cohen, Paul S

2012-05-01

Previously, we reported that the streptomycin-treated mouse intestine selected nonmotile Escherichia coli MG1655 flhDC deletion mutants of E. coli MG1655 with improved colonizing ability that grow 15% faster in vitro in mouse cecal mucus and 15 to 30% faster on sugars present in mucus (M. P. Leatham et al., Infect. Immun. 73:8039-8049, 2005). Here, we report that the 10 to 20% remaining motile E. coli MG1655 are envZ missense mutants that are also better colonizers of the mouse intestine than E. coli MG1655. One of the flhDC mutants, E. coli MG1655 ΔflhD, and one of the envZ missense mutants, E. coli MG1655 mot-1, were studied further. E. coli MG1655 mot-1 is more resistant to bile salts and colicin V than E. coli MG1655 ΔflhD and grows ca. 15% slower in vitro in mouse cecal mucus and on several sugars present in mucus compared to E. coli MG1655 ΔflhD but grows 30% faster on galactose. Moreover, E. coli MG1655 mot-1 and E. coli MG1655 ΔflhD appear to colonize equally well in one intestinal niche, but E. coli MG1655 mot-1 appears to use galactose to colonize a second, smaller intestinal niche either not colonized or colonized poorly by E. coli MG1655 ΔflhD. Evidence is also presented that E. coli MG1655 is a minority member of mixed bacterial biofilms in the mucus layer of the streptomycin-treated mouse intestine. We offer a hypothesis, which we call the "Restaurant" hypothesis, that explains how nutrient acquisition in different biofilms comprised of different anaerobes can account for our results.

MicroRNA Transfer between Bone Marrow Adipose and Multiple Myeloma Cells

PubMed Central

Soley, Luna; Falank, Carolyne; Reagan, Michaela R.

2017-01-01

Purpose of Review Multiple myeloma remains an incurable disease, largely due to the tumor-supportive role of the bone marrow microenvironment. Bone marrow adipose tissue (BMAT) is one component of the fertile microenvironment which is believed to contribute to myeloma progression and drug resistance, as well as participate in a vicious cycle of osteolysis and tumor growth. Recent Findings MicroRNAs (miRNAs) have recently emerged as instrumental regulators of cellular processes that enable the development and dissemination of cancer. This review highlights the intersection between two emerging research fields and pursues the scientific and clinical implications of miRNA transfer between BMAT and myeloma cells. Summary This review provides a concise and provocative summary of the evidence to support exosome-mediated transfer of tumor-supportive miRNAs. The work may prompt researchers to better elucidate the mechanisms by which this novel means of genetic communication between tumor cells and their environment could someday yield targeted therapeutics. PMID:28432594

Risk of multiple myeloma following medication use and medical conditions: a case-control study in Connecticut women.

PubMed

Landgren, Ola; Zhang, Yawei; Zahm, Sheila Hoar; Inskip, Peter; Zheng, Tongzhang; Baris, Dalsu

2006-12-01

Certain commonly used drugs and medical conditions characterized by chronic immune dysfunction and/or antigen stimulation have been suggested to affect important pathways in multiple myeloma tumor cell growth and survival. We conducted a population-based case-control study to investigate the role of medical history in the etiology of multiple myeloma among Connecticut women. A total of 179 incident multiple myeloma cases (21-84 years, diagnosed 1996-2002) and 691 population-based controls was included in this study. Information on medical conditions, medications, and medical radiation was obtained by in-person interviews. We calculated odds ratios (OR) as measures of relative risks using logistic regression models. A reduced multiple myeloma risk was found among women who had used antilipid statin therapy [OR, 0.4; 95% confidence interval (95% CI), 0.2-0.8] or estrogen replacement therapy (OR, 0.6; 95% CI, 0.4-0.99) or who had a medical history of allergy (OR, 0.4; 95% CI, 0.3-0.7), scarlet fever (OR, 0.5; 95% CI, 0.2-0.9), or bursitis (OR, 0.4; 95% CI, 0.2-0.7). An increased risk of multiple myeloma was found among women who used prednisone (OR, 5.1; 95% CI, 1.8-14.4), insulin (OR, 3.1; 95% CI, 1.1-9.0), or gout medication (OR, 6.7; 95% CI, 1.2-38.0). If our results are confirmed, mechanistic studies examining how prior use of insulin, prednisone, and, perhaps, gout medication might promote increased occurrence of multiple myeloma and how antilipid statins, estrogen replacement therapy, and certain medical conditions might protect against multiple myeloma may provide insights to the as yet unknown etiology of multiple myeloma.

Top Information Need Priorities of Older Adults Newly Diagnosed With Active Myeloma.

PubMed

Tariman, Joseph D; Doorenbos, Ardith; Schepp, Karen G; Singhal, Seema; Berry, Donna L

2015-01-01

Prioritizing patients' information needs maximizes efficiency. This study examined the information sources and priorities in a sample of older adults newly diagnosed with symptomatic myeloma requiring immediate therapy. An association analysis of whether information needs were influenced by sociodemographic variables such as age, gender, education, marital status, and income was also conducted. The Information Needs Questionnaire (INQ) and an investigator-developed interview schedule were administered to 20 older adults diagnosed with symptomatic myeloma during a 30- to 45-minute semistructured interview. We found that older adults newly diagnosed with symptomatic myeloma have different priorities of information needs when compared with younger patients diagnosed with various types of cancer. The top three priorities related to treatment, prognosis, and self-care. Sociodemographic variables did not influence the priorities of information needs among older adults with symptomatic myeloma. The Internet, physicians, family, and friends were among the top sources of information. Advanced practitioners in oncology should support and identify interventions that can enhance patients' learning process from these sources. Well poised to assist patients in searching credible and reliable Internet sources, advanced practitioners in oncology can provide patient education about different treatments and the impact of such treatments on prognosis (e.g., overall survival and likelihood of cure).

Effectiveness of percutaneous vertebroplasty in patients with multiple myeloma having vertebral pain

PubMed Central

Nas, Ömer Fatih; İnecikli, Mehmet Fatih; Hacıkurt, Kadir; Büyükkaya, Ramazan; Özkaya, Güven; Özkalemkaş, Fahir; Ali, Rıdvan; Erdoğan, Cüneyt; Hakyemez, Bahattin

2016-01-01

PURPOSE We aimed to assess the effectiveness, benefits, and reliability of percutaneous vertebroplasty (PV) in patients with vertebral involvement of multiple myeloma. METHODS PV procedures performed on 166 vertebrae of 41 patients with multiple myeloma were retrospectively evaluated. Most of our patients were using level 3 (moderate to severe pain) analgesics. Magnetic resonance imaging was performed before the procedure to assess vertebral involvement of multiple myeloma. The following variables were evaluated: affected vertebral levels, loss of vertebral body height, polymethylmethacrylate (PMMA) cement amount applied to the vertebral body during PV, PMMA cement leakages, and pain before and after PV as assessed by a visual analogue scale (VAS). RESULTS Median VAS scores of patients decreased from 9 one day before PV, to 6 one day after the procedure, to 3 one week after the procedure, and eventually to 1 three months after the procedure (P < 0.001). During the PV procedure, cement leakage was observed at 68 vertebral levels (41%). The median value of PMMA applied to the vertebral body was 6 mL. CONCLUSION Being a minimally invasive and easily performed procedure with low complication rates, PV should be preferred for serious back pain of multiple myeloma patients. PMID:26912107

MicroRNAs in urine are not biomarkers of multiple myeloma.

PubMed

Sedlaříková, Lenka; Bešše, Lenka; Novosadová, Soňa; Kubaczková, Veronika; Radová, Lenka; Staník, Michal; Krejčí, Marta; Hájek, Roman; Ševčíková, Sabina

2015-09-23

In this study, we aimed to identify microRNA from urine of multiple myeloma patients that could serve as a biomarker for the disease. Analysis of urine samples was performed using Serum/Plasma Focus PCR MicroRNA Panel (Exiqon) and verified using individual TaqMan miRNA assays for qPCR. We found 20 deregulated microRNA (p < 0.05); for further validation, we chose 8 of them. Nevertheless, only differences in expression levels of miR-22-3p remained close to statistical significance. Our preliminary results did not confirm urine microRNA as a potential biomarker for multiple myeloma.

[Molecular mechanisms and relationship of M2-polarized macrophages with early response in multiple myeloma].

PubMed

Chen, X Y; Sun, R X; Zhang, W Y; Liu, T; Zheng, Y H; Wu, Y

2017-06-14

Objective: To investigate the relationship between M2-polarized macrophages and early response in multiple myeloma and its molecular mechanism. Methods: Two hundred and forty bone marrow biopsy tissue were collected and M2-polarized macrophages were stained by anti-CD163 monoclonal antibody. In vitro M2-polarized macrophages were derived from human peripheral blood mononuclear cell or THP-1 cells and identified by flow cytometry. Two myeloma cell lines RPMI 8226 and U266 were co-cultured with M2 macrophages using a transwell system. We measured myeloma cells proliferation through CCK-8 method and the pro-inflammatory cytokines expression (TNF-α and IL-6) by ELISA. Real time PCR was applied to measure chemokines (CCL2 and CCL3) , chemokine receptors (CCR2, CCR5) , VEGF and their receptors. In addition, flow cytometry was used to analyze the apoptosis of myeloma cells induced by dexamethasone. Results: ①Patients with high percentage of M2 macrophage involvement in bone marrow showed poorer response (23.9% versus 73.0%, χ (2)=60.31, P <0.001). ② In vitro the proliferation of RPMI 8226 cells ( P =0.005 at 24 h, P =0.020 at 36 h) or U266 myeloma cells ( P = 0.030 at 24h, P =0.020 at 36h) co-cultured with M2-polarized macrophages was higher than control group. ③In vitro the apoptotic rate of RPMI 8226 cells (29.0% versus 71.0%, t =4.97, P =0.008) or U266 myeloma cells (24.9% versus 67.7%, t =6.99, P =0.002) co-cultured with M2-polarized macrophages was lower than control group. ④ In vitro M2-polarized macrophages promoted myeloma cells secreting higher level of IL-6, TNF-α and higher expression of CCL2, CCL3, CCR2, CCR5, VEGFA, VEGFR-1,-2 compared with the non-macrophage co-culture system. Conclusion: M2-polarized macrophages promote myeloma cells proliferation and inhibit apoptosis through a very complex mechanism involving pro-inflammatory cytokines IL-6 and TNF-α, chemokines and related receptors such as CCL2, CCL3, CCR2, CCR3, and VEGF as well as related

Atypical progression of multiple myeloma with extensive extramedullary disease.

PubMed Central

Jowitt, S N; Jacobs, A; Batman, P A; Sapherson, D A

1994-01-01

Multiple myeloma is a neoplastic disorder caused by the proliferation of a transformed B lymphoid progenitor cell that gives rise to a clone of immunoglobulin-secreting cells. Other plasma cell tumours include solitary plasmacytoma of bone (SPB) and extramedullary plasmacytomas (EMP). Despite an apparent common origin there exist pathological and clinical differences between these neoplasms and the association between them is not completely understood. A case of IgG multiple myeloma that presented with typical clinical and laboratory features, including a bone marrow infiltrated by well differentiated plasma cells, is reported. The tumour had an unusual evolution, with the development of extensive extramedullary disease while maintaining mature histological features. Images PMID:8163701

[Influence of rosiglitazone and all-trans-retinoic acid on angiogenesis and growth of myeloma xenograft in nude mice].

PubMed

Huang, Hai-wen; Chen, Ping; Li, Bing-zong; Fu, Jin-xiang; Li, Jun; Zhang, Xiao-hui; Liu, Rui; Fan, Yin-yin; Zhang, Hong; Chow, Howard C H; Leung, Anska Y H; Liang, Raymond

2012-09-01

To observe the effect of rosiglitazone (RGZ) and all-trans-retinoic acid (ATRA) on the growth of myeloma xenograft in nude mice and to explore the influence of RGZ and ATRA on VEGF expression and angiogenesis in the tumor. VEGF gene expression in myeloma cell line U266 cells was analyzed by semi-quantitative RT-PCR after incubation with RGZ, ATRA, or RGZ + ATRA for 24 h. Myeloma xenograft was established by subcutaneous injection of 10(7) U266 cells in the scapula area of 4-week old nude mice. 7 days later, the nude mice were administered with RGZ, ATRA or RGZ + ATRA, respectively, by intraperitoneal injection once every day for 21 days. The control mice were given equal volume of normal saline instead of the drug. On the 21(st) day of treatment, the mice were sacrificed and the tumors were taken off, and the tumor volume and weight were measured. The tumors were examined by histopathology with HE staining, and microvessel density (MVD), CD34 and VEGF expression in the tumors were analyzed by immunohistochemical staining. VEGF mRNA was highly expressed in U266 cells and was decreased in a dose-dependent manner after incubation with RGZ. The VEGF mRNA level was further more decreased after RGZ + ATRA treatment. Xenografts of U266 cells were developed in all nude mice. The volume and weight of xenografts in the RGZ group were (785 ± 262) mm(3) and (1748 ± 365) mg, respectively, significantly lower than those of the control group (both P < 0.01). More significant inhibition was in the RGZ + ATRA group, (154 ± 89) mm(3) and (626 ± 102) mg, respectively, both were P < 0.05 vs. the RGZ group. RGZ inhibited the angiogenesis in U266 xenografts and immunohistochemical staining showed that the tumor MVD and VEGF expression were significantly decreased by RGZ treatment, and further more inhibited in the RGZ + ATRA group. VEGF protein was expressed in all xenografts in the nude mice. Its immunohistochemical staining intensity was 2.20 ± 0.40 in the control group

Microbial Fuel Cells under Extreme Salinity

NASA Astrophysics Data System (ADS)

Monzon del Olmo, Oihane

I developed a Microbial Fuel Cell (MFC) that unprecedentedly works (i.e., produces electricity) under extreme salinity (≈ 100 g/L NaCl). Many industries, such as oil and gas extraction, generate hypersaline wastewaters with high organic strength, accounting for about 5% of worldwide generated effluents, which represent a major challenge for pollution control and resource recovery. This study assesses the potential for microbial fuel cells (MFCs) to treat such wastewaters and generate electricity under extreme saline conditions. Specifically, the focus is on the feasibility to treat hypersaline wastewater generated by the emerging unconventional oil and gas industry (hydraulic fracturing) and so, with mean salinity of 100 g/L NaCl (3-fold higher than sea water). The success of this novel technology strongly depends on finding a competent and resilient microbial community that can degrade the waste under extreme saline conditions and be able to use the anode as their terminal electron acceptor (exoelectrogenic capability). I demonstrated that MFCs can produce electricity at extremely high salinity (up to 250 g/l NaCl) with a power production of 71mW/m2. Pyrosequencing analysis of the anode population showed the predominance of Halanaerobium spp. (85%), which has been found in shale formations and oil reservoirs. Promoting Quorum sensing (QS, cell to cell communication between bacteria to control gene expression) was used as strategy to increase the attachment of bacteria to the anode and thus improve the MFC performance. Results show that the power output can be bolstered by adding 100nM of quinolone signal with an increase in power density of 30%, for the first time showing QS in Halanaerobium extremophiles. To make this technology closer to market applications, experiments with real wastewaters were also carried out. A sample of produced wastewater from Barnet Shale, Texas (86 g/L NaCl) produced electricity when fed in an MFC, leading to my discovery of another

Combination chemotherapy increases cytotoxicity of multiple myeloma cells by modification of nuclear factor (NF)-κB activity

PubMed Central

Salem, Kelley; Brown, Charles O.; Schibler, Jeanine; Goel, Apollina

2012-01-01

The NF-κB signaling pathway is critical in myeloma cell proliferation, inhibition of apoptosis, and emergence of therapy resistance. The chemotherapeutic drugs, dexamethasone (Dex) and bortezomib (BTZ), are widely used in clinical protocols for multiple myeloma (MM) and inhibit the NF-κB signaling pathway by distinct mechanisms. This study evaluates the efficacy of combination therapy with Dex and BTZ and investigates the mechanistic underpinning of endogenous and therapy-induced NF-κB activation in MM. Human myeloma cells and bone marrow stromal cells (BMSCs) were used in monocultures and co-cultures to determine the cytotoxic effects of Dex and/or BTZ. Our results show that combined treatment of Dex with BTZ enhanced direct apoptosis of drug-sensitive and drug-resistant myeloma cells. In the presence of BMSCs, Dex plus BTZ combination inhibited ionizing radiation (IR)-induced interleukin (IL)-6 secretion from BMSCs and induced myeloma cytotoxicity. Mechanistically, Dex treatment increased IκBα protein and mRNA expression and compensated for BTZ-induced IκBα degradation. Dex plus BTZ combination inhibited basal and therapy-induced NF-κB activity with cytotoxicity in myeloma cells resistant to BTZ. Furthermore, combination therapy down-regulated the NF-κB targeted gene expression of IL-6 and manganese superoxide dismutase (MnSOD), which can induce chemo- and radio-resistance in MM. This study provides mechanistic rationale for combining the NF-κB-targeting drugs Dex and BTZ in myeloma therapy and supports potential combinations of these drugs with radiotherapy and additional chemotherapeutic drugs, for clinical benefit in MM. PMID:23063726

Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing.

PubMed

Ryland, Georgina L; Jones, Kate; Chin, Melody; Markham, John; Aydogan, Elle; Kankanige, Yamuna; Caruso, Marisa; Guinto, Jerick; Dickinson, Michael; Prince, H Miles; Yong, Kwee; Blombery, Piers

2018-05-14

Multiple myeloma is a genomically complex haematological malignancy with many genomic alterations recognised as important in diagnosis, prognosis and therapeutic decision making. Here, we provide a summary of genomic findings identified through routine diagnostic next-generation sequencing at our centre. A cohort of 86 patients with multiple myeloma underwent diagnostic sequencing using a custom hybridisation-based panel targeting 104 genes. Sequence variants, genome-wide copy number changes and structural rearrangements were detected using an inhouse-developed bioinformatics pipeline. At least one mutation was found in 69 (80%) patients. Frequently mutated genes included TP53 (36%), KRAS (22.1%), NRAS (15.1%), FAM46C/DIS3 (8.1%) and TET2/FGFR3 (5.8%), including multiple mutations not previously described in myeloma. Importantly we observed TP53 mutations in the absence of a 17 p deletion in 8% of the cohort, highlighting the need for sequencing-based assessment in addition to cytogenetics to identify these high-risk patients. Multiple novel copy number changes and immunoglobulin heavy chain translocations are also discussed. Our results demonstrate that many clinically relevant genomic findings remain in multiple myeloma which have not yet been identified through large-scale sequencing efforts, and provide important mechanistic insights into plasma cell pathobiology. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Ethanol modifies the effect of handling stress on gene expression: problems in the analysis of two-way gene expression studies in mouse brain.

PubMed

Rulten, Stuart L; Ripley, Tamzin L; Manerakis, Ektor; Stephens, David N; Mayne, Lynne V

2006-08-02

Studies analysing the effects of acute treatments on animal behaviour and brain biochemistry frequently use pairwise comparisons between sham-treated and -untreated animals. In this study, we analyse expression of tPA, Grik2, Smarca2 and the transcription factor, Sp1, in mouse cerebellum following acute ethanol treatment. Expression is compared to saline-injected and -untreated control animals. We demonstrate that acute i.p. injection of saline may alter gene expression in a gene-specific manner and that ethanol may modify the effects of sham treatment on gene expression, as well as inducing specific effects independent of any handling related stress. In addition to demonstrating the complexity of gene expression in response to physical and environmental stress, this work raises questions on the interpretation and validity of studies relying on pairwise comparisons.

Multiple myeloma: Diagnosis and management issues in patients with pre-existing chronic kidney disease.

PubMed

Vadlamudi, Srilatha; Annapareddy, Siva Nagendra Reddy

2016-01-01

Multiple myeloma is one of the most common malignancies encountered in clinical practice. Renal involvement in myeloma is a well-recognized entity. Although rare, another special situation that a nephrologist can encounter is myeloma occurring in a patient with preexisting chronic kidney disease (CKD) due to other etiologies. Anemia, bone pains and hypercalcemia, which commonly indicate the diagnosis of myeloma in the general population, are not useful in the presence of CKD. The sensitivity and specificity of serum free light chain assay is decreased in the presence of renal failure. Chemotherapy-related adverse effects are high compared with that in patients without CKD; this is attributed to the decreased clearance of drugs and the additive effect of chemotherapy-related adverse effects to the complications of CKD. Autologous and allogenic bone marrow transplantation can be attempted in this group of patients with non-myeloablative-conditioning regimens. Combined bone marrow and renal transplantation remains a viable option in this group of patients to increase life expectancy and quality of life.

Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry

PubMed Central

Pessoa de Magalhães, Roberto J.; Vidriales, María-Belén; Paiva, Bruno; Fernandez-Gimenez, Carlos; García-Sanz, Ramón; Mateos, Maria-Victoria; Gutierrez, Norma C.; Lecrevisse, Quentin; Blanco, Juan F; Hernández, Jose; de las Heras, Natalia; Martinez-Lopez, Joaquin; Roig, Monica; Costa, Elaine Sobral; Ocio, Enrique M.; Perez-Andres, Martin; Maiolino, Angelo; Nucci, Marcio; De La Rubia, Javier; Lahuerta, Juan-Jose; San-Miguel, Jesús F.; Orfao, Alberto

2013-01-01

Multiple myeloma remains largely incurable. However, a few patients experience more than 10 years of relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with a complete response, since some patients revert to having a profile of monoclonal gammopathy of undetermined significance. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of multiple myeloma patients with long-term disease control (n=28), patients with newly diagnosed monoclonal gammopathy of undetermined significance (n=23), patients with symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Similarly to the patients with monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8+ T cells and natural killer cells. However, the numbers of bone marrow T-regulatory cells were lower in patients with long-term disease control than in those with symptomatic multiple myeloma. It is noteworthy that B cells were depleted in patients with monoclonal gammopathy of undetermined significance and in those with symptomatic multiple myeloma, but recovered in both the bone marrow and peripheral blood of patients with long-term disease control, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B cells. The number of bone marrow dendritic cells and tissue macrophages differed significantly between patients with long-term disease control and those with symptomatic multiple myeloma, with a trend to cell count recovering in the former group of patients towards levels similar to those found in healthy adults. In summary, our results indicate that multiple myeloma patients with long-term disease control have a constellation of unique immune changes

Exogenous hydrogen sulfide exerts proliferation, anti-apoptosis, migration effects and accelerates cell cycle progression in multiple myeloma cells via activating the Akt pathway.

PubMed

Zheng, Dong; Chen, Ziang; Chen, Jingfu; Zhuang, Xiaomin; Feng, Jianqiang; Li, Juan

2016-10-01

Hydrogen sulfide (H2S), regarded as the third gaseous transmitter, mediates and induces various biological effects. The present study investigated the effects of H2S on multiple myeloma cell progression via amplifying the activation of Akt pathway in multiple myeloma cells. The level of H2S produced in multiple myeloma (MM) patients and healthy subjects was measured using enzyme-linked immunosorbent assay (ELISA). MM cells were treated with 500 µmol/l NaHS (a donor of H2S) for 24 h. The expression levels of phosphorylated-Akt (p-Akt), Bcl-2 and caspase-3 were measured by western blot assay. Cell viability was detected by Cell Counting Kit 8 (CCK-8). The cell cycle was analyzed by flow cytometry. Our results show that the concentration of H2S was higher in MM patients and that it increased in parallel with disease progression. Treating MM cells with 500 µmol/l NaHS for 24 h markedly increased the expression level of Bcl-2 and the activation of p-Akt, however, the expression level of caspase-3 was decreased, cell viability was increased, and cell cycle progression was accelerated in MM cells. NaHS also induced migration in MM cells in transwell migration assay. Furthermore, co-treatment of MM cells with 500 µmol/l NaHS and 50 µmol/l LY294002 for 24 h significantly overset these effects. In conclusion, our findings demonstrate that the Akt pathway contributes to NaHS-induced cell proliferation, migration and acceleration of cell cycle progression in MM cells.

Trends in survival of multiple myeloma: a thirty-year population-based study in a single institution.

PubMed

Ríos-Tamayo, Rafael; Sánchez, María José; Puerta, José Manuel; Sáinz, Juan; Chang, Daysi-Yoe-Ling; Rodríguez, Teresa; López, Pilar; de Pablos, José María; Navarro, Pilar; de Veas, José Luís García; Romero, Antonio; Garrido, Pilar; Moratalla, Lucía; Alarcón-Payer, Carolina; López-Fernández, Elisa; González, Pedro Antonio; Jiménez-Moleón, José Juan; Calleja-Hernández, Miguel Ángel; Jurado, Manuel

2015-10-01

Despite the progress made in recent years, multiple myeloma is still considered an incurable disease. Most survival data come from clinical trials. Little is known about the outcome in unselected real-life patients. Overall survival was analyzed in a cohort of newly diagnosed symptomatic multiple myeloma patients, over the last three decades, in a single institution population-based study. 582 consecutive myeloma patients were included in the study. Survival increased over time in patients younger than 65 years but did not reach statistical significance in patients with 65 years or older. The prognostic factors associated with overall survival were the International Staging System, the serum lactate dehydrogenase level, the renal impairment, the realization of autologous stem cell transplantation, and the presence of concomitant amyloidosis. Overall survival shows a steady improvement over time. The survival of myeloma is improving progressively in real-life patients, particularly after the widespread use of the novel agents. A comprehensive assessment of comorbidity can help to explain the huge heterogeneity of myeloma outcome. The optimization of current therapeutic resources as well as the incorporation of new drugs will allow further improvement of survival in the coming years. Copyright © 2015 Elsevier Ltd. All rights reserved.

Adipose, Bone and Myeloma: Contributions from the Microenvironment

PubMed Central

McDonald, Michelle; Fairfield, Heather; Falank, Carolyne; Reagan, Michaela R.

2017-01-01

Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide [1]. Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90% of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies. PMID:27343063

Update on risk stratification and treatment of newly diagnosed multiple myeloma.

PubMed

Kapoor, Prashant; Rajkumar, S Vincent

2011-10-01

Multiple myeloma is the second most common hematologic malignancy. Chromosomal aberrations are important prognostic determinants that influence the clinical decision-making in newly-diagnosed multiple myeloma (NDMM). Patients are considered high-risk if any of the following features are detected: hypodiploidy, deletion 13 by cytogenetics, t(4;14), t(14;16), t(14;20) and/or 17 p deletion. In the absence of these features patients are considered standard risk. Outside of trials, risk-adapted therapy in the transplant-eligible high-risk patients advocates use of bortezomib-based induction therapy followed by autologous stem cell transplantation (ASCT) and bortezomib-based maintenance therapy. High-risk, transplant-ineligible patients should also utilize bortezomib as initial therapy since it is known to overcome the poor prognosis associated with some high-risk features. The goal of therapy in high-risk patients is to attain and maintain a state of complete remission as much as possible. In contrast, the standard-risk, transplant-eligible patients may be treated with either lenalidomide-dexamethasone or bortezomib-based therapy followed by ASCT. In such patients, ASCT can also be deferred until first relapse if the patients are tolerating initial therapy well. Lenalidomide maintenance therapy in the post-transplant setting in standard-risk patients is controversial and not recommended routinely. For transplant-ineligible standard-risk patients, multiple options exist, although in the absence direct comparisons, we prefer lenalidomide plus low-dose dexamethasone over melphalan-based combinations. This review outlines evidence-based management approaches in NDMM, with a focus on risk-adapted therapy.

Multiple myeloma associated with an Evan’s syndrome

PubMed Central

Bechir, Achour; Haifa, Regaieg; Nesrine, Ben Sayed; Emna, Bouslema; Senda, Mejdoub; Asma, Achour; Amina, Bouatay Bouzouita; Mrabet, Senda; Yosra, Ben Youssef; Mondher, Kortas; Abderrahim, Khelif

2016-01-01

Auto-immun events are rare in multiple myeloma (MM). Here, we report one MM case complicated by Evans syndrome (Autoimmun hemolytic anemia (AIHA) associated with thrombocytopenia). A 52-year-old man was admitted in nephrology department with severe anemia, renal insufficiency and hypergamma globulinemia. Laboratory exams showed acute hemolysis due to an IgG warm autoantibody. Serum electrophoresis revealed the presence of a monoclonal IgG protein and urinary M protein was 2g/day. A whole body CT-Scan showed osteolytic lesions of vertebral body of C5, D4, L3, L4 and the left iliac wing. The diagnosis of multiple myeloma and Evan's syndrome was made, we underwent chemotherapy by BTD (bortezomib-thalidomide-dexamethasone) and continuous corticosteroid therapy but unfortunately the patient died secondary of a Lactic acidosis. The relationship between MM and hemolysis remain unclear. PMID:28292089

Comparative effectiveness and safety of thalidomide and lenalidomide in patients with multiple myeloma in the United States of America: A population-based cohort study.

PubMed

Luo, Jing; Gagne, Joshua J; Landon, Joan; Avorn, Jerry; Kesselheim, Aaron S

2017-01-01

The comparative effectiveness of thalidomide and lenalidomide in the treatment of multiple myeloma has not been established. We conducted an observational cohort study of multiple myeloma patients receiving either thalidomide or lenalidomide in routine care in the United States of America to assess their comparative survival and rates of peripheral neuropathy. Myeloma patients were identified and followed using administrative claims data from a large national health insurance provider (UnitedHealth). Patients were eligible if they initiated treatment with either lenalidomide or thalidomide between 2004 and 2013. Propensity score stratified Cox proportional hazards regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for death and new-onset peripheral neuropathy (defined by International Classification of Disease, Ninth Revision codes or a new prescription intended to treat neuropathic pain). Our cohort included 1264 myeloma patients who initiated either thalidomide or lenalidomide. Among 406 new users of thalidomide, 142 (35%) developed peripheral neuropathy during a mean 499 person-days of follow-up. Among 858 new users of lenalidomide, 244 (29%) developed neuropathy during 587 person-days. Compared with thalidomide initiators, lenalidomide initiators had a reduced risk of peripheral neuropathy (HR 0.71, 95% CI: 0.56-0.92). We found no difference in rates of death (HR 1.00, 95% CI: 0.71-1.41). Our results agree with the findings of recently published trials suggesting that thalidomide and lenalidomide are equivalent with respect to survival outcomes but different with respect to neurotoxicity in clinical practice settings. Copyright © 2016 Elsevier Ltd. All rights reserved.

New developments in the treatment of multiple myeloma - clinical utility of daratumumab.

PubMed

McEllistrim, Cian; Krawczyk, Janusz; O'Dwyer, Michael E

2017-01-01

Multiple myeloma is a clonal disorder of plasma cells that is currently considered incurable. CD38 is a 46 kDa type II transmembrane glycoprotein that is highly expressed on myeloma cells. Daratumumab is a first in-class human IgG1 monoclonal antibody that targets CD38, and has antimyeloma effects through several mechanisms. Single-agent trials show surprising activity in heavily pretreated myeloma patients. Trials in the relapsed setting, where daratumumab is added to lenalidomide and dexamethasone or bortezomib and dexamethasone, have demonstrated significantly improved progression-free survival with acceptable toxicity. In this review, we discuss the mechanism of action, pharmacology and pharmacokinetics of daratumumab and review the available clinical data in detail. We examine how daratumumab interferes with transfusion testing due to the expression of CD38 on the red blood cells, leading to potential difficulties releasing blood products. Daratumumab also affects disease assessments in multiple myeloma, including serum protein electrophoresis, immunofixation and flow cytometry. Strategies to mitigate these effects are discussed. The optimal use of daratumumab has yet to be decided, and several trials are ongoing in the relapsed and upfront setting. We discuss the potential upfront role of this exciting therapy, which has significant potential for increased minimal residual disease negativity and improved progression-free survival even in high-risk groups.

Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma

PubMed Central

Mohanty, Sindhu T.; Seckinger, Anja; Terry, Rachael L.; Pettitt, Jessica A.; Simic, Marija K.; Le, Lawrence M. T.; Kramer, Ina; Falank, Carolyne; Fairfield, Heather; Ghobrial, Irene M.; Baldock, Paul A.; Little, David G.; Kneissel, Michaela; Vanderkerken, Karin; Bassett, J. H. Duncan; Williams, Graham R.; Oyajobi, Babatunde O.; Hose, Dirk

2017-01-01

Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM. PMID:28515094

Treatment Options for Plasma Cell Neoplasms (Including Multiple Myeloma)

MedlinePlus

... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

Treatment Option Overview (Plasma Cell Neoplasms Including Multiple Myeloma)

MedlinePlus

... Health Professional Plasma Cell Neoplasms Treatment Research Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional Version Key Points ...

Multiple myeloma presenting as CEA-producing rectal cancer.

PubMed

Talamo, Giampaolo; Barochia, Amitkumar; Zangari, Maurizio; Loughran, Thomas P

2010-03-31

We report the case of a 57-year-old patient with multiple myeloma, characterized by extramedullary involvement of the rectum at presentation. Malignant plasma cells were found to produce carcinoembryonic antigen (CEA), a tumor antigen more commonly associated with rectal adenocarcinomas.

Adoptive cell therapy in multiple Myeloma.

PubMed

Vallet, Sonia; Pecherstorfer, Martin; Podar, Klaus

2017-12-01

Recent breakthrough advances in Multiple Myeloma (MM) immunotherapy have been achieved with the approval of the first two monoclonal antibodies, elotuzumab and daratumumab. Adoptive cell therapy (ACT) represents yet another, maybe the most powerful modality of immunotherapy, in which allogeneic or autologous effector cells are expanded and activated ex vivo followed by their re-infusion back into patients. Infused effector cells belong to two categories: naturally occurring, non-engineered cells (donor lymphocyte infusion, myeloma infiltrating lymphocytes, deltagamma T cells) or genetically- engineered antigen-specific cells (chimeric antigen receptor T or NK cells, TCR-engineered cells). Areas covered: This review article summarizes our up-to-date knowledge on ACT in MM, its promises, and upcoming strategies to both overcome its toxicity and to integrate it into future treatment paradigms. Expert opinion: Early results of clinical studies using CAR T cells or TCR- engineered T cells in relapsed and refractory MM are particularly exciting, indicating the potential of long-term disease control or even cure. Despite several caveats including toxicity, costs and restricted availability in particular, these forms of immunotherapy are likely to once more revolutionize MM therapy.

Patterns of relapse and outcome of elderly multiple myeloma patients treated as front-line therapy with novel agents combinations☆

PubMed Central

Lopez, Aurelio; Mateos, Maria-Victoria; Oriol, Albert; Valero, Marta; Martínez, Joaquín; Lorenzo, Jose Ignacio; Perez, Montserrat; Martinez, Rafael; de Paz, Raquel; Granell, Miguel; De Arriba, Felipe; Blanchard, M. Jesús; Peñalver, Francisco Javier; Bello, Jose Luis; Martin, Maria Luisa; Bargay, Joan; Blade, Joan; Lahuerta, Juan Jose; San Miguel, Jesús F.; de la Rubia, Javier

2015-01-01

We report the characteristics of relapse, treatment response, and outcomes of 145 elderly patients with multiple myeloma in first relapse after front-line treatment with VMP or VTP. Reappearance of CRAB symptoms (113 patients) and more aggressive forms of disease (32 patients) were the most common patterns of relapse. After second-line therapy, 75 (51.7%) patients achieved at partial response and 16 (11%) complete response (CR). Overall survival was longer among patients receiving VMP as front-line induction (21.4 vs. 14.4 months, P=0.037), in patients achieving CR (28.3 vs. 14.8 months; P=0.04), and in patients without aggressive relapse (28.6 vs. 7.6 months; P=0.0007). PMID:26500850

Effects of statins on the recovery of olfactory function in a 3-methylindole-induced anosmia mouse model.

PubMed

Kim, Hyo Yeol; Kim, Joon Ho; Dhong, Hun-Jong; Kim, Ki Ryung; Chung, Seung-Kyu; Chung, Soo-Chan; Kang, Jeong Min; Jung, Yong Gi; Jang, Seong Yun; Hong, Sang Duk

2012-01-01

Despite the importance of olfactory function, no effective medications have been identified to treat olfactory disorders. This study was performed to evaluate the functional recovery of olfaction damaged by 3-methylindole (3MI) in a mouse model with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins). In a randomized placebo-controlled trial, 24 healthy female BALB/c mice (aged 9-10 weeks and weighing 18-20 g each) were randomly allocated to statin-treated or control groups. Olfactory loss was induced by i.p. injections of 3MI. Atorvastatin (10 mg/kg) or normal saline was then administered per os with a gastric tube for 3 weeks. The effects of treatment were evaluated by food-finding tests and Western blot analysis. Both groups showed complete losses of olfactory function 1 week after 3MI injection. Three weeks after 3MI injection, 9 of the 12 mice in the statin-treated group (75%) passed a food-finding test, in which they were able to find the food within 3 minutes, at least two times out of three trials. However, only two mice in the control group (16.6%) passed the food-finding test, and this difference was statistically significant (p = 0.004; chi-square test). The expression level of the olfactory marker protein was also elevated in the statin-treated group (p = 0.030; Wilcoxon rank sum test). Statins are associated with recovery of olfaction after 3MI injection in a mouse model.

Monoclonal antibody-purged bone marrow transplantation therapy for multiple myeloma.

PubMed

Anderson, K C; Andersen, J; Soiffer, R; Freedman, A S; Rabinowe, S N; Robertson, M J; Spector, N; Blake, K; Murray, C; Freeman, A

1993-10-15

Forty patients with plasma cell dyscrasias underwent high-dose chemoradiotherapy and either anti-B-cell monoclonal antibody (MoAb)-treated autologous, anti-T-cell MoAb-treated HLA-matched sibling allogeneic or syngeneic bone marrow transplantation (BMT). The majority of patients had advanced Durie-Salmon stage myeloma at diagnosis, all were pretreated with chemotherapy, and 17 had received prior radiotherapy. At the time of BMT, all patients demonstrated good performance status with Karnofsky score of 80% or greater and had less than 10% marrow tumor cells; 34 patients had residual monoclonal marrow plasma cells and 38 patients had paraprotein. Following high-dose chemoradiotherapy, there were 18 complete responses (CR), 18 partial responses, one non-responder, and three toxic deaths. Granulocytes greater than 500/microL and untransfused platelets greater than 20,000/microL were noted at a median of 23 (range, 12 to 46) and 25 (range, 10 to 175) days posttransplant (PT), respectively, in 24 of the 26 patients who underwent autografting. In the 14 patients who received allogeneic or syngeneic grafts, granulocytes greater than 500/microL and untransfused platelets greater than 20,000/microL were noted at a median of 19 (range, 12 to 24) and 16 (range, 5 to 32) days PT, respectively. With 24 months median follow-up for survival after autologous BMT, 16 of 26 patients are alive free from progression at 2+ to 55+ months PT; of these, 5 patients remain in CR at 6+ to 55+ months PT. With 24 months median follow-up for survival after allogeneic and syngeneic BMT, 8 of 14 patients are alive free from progression at 8+ to 34+ months PT; of these, 5 patients remain in CR at 8+ to 34+ months PT. This therapy has achieved high response rates and prolonged progression-free survival in some patients and proven to have acceptable toxicity. However, relapses post-BMT, coupled with slow engraftment post-BMT in heavily pretreated patients, suggest that such treatment strategies

Spinal focal lesion detection in multiple myeloma using multimodal image features

NASA Astrophysics Data System (ADS)

Fränzle, Andrea; Hillengass, Jens; Bendl, Rolf

2015-03-01

Multiple myeloma is a tumor disease in the bone marrow that affects the skeleton systemically, i.e. multiple lesions can occur in different sites in the skeleton. To quantify overall tumor mass for determining degree of disease and for analysis of therapy response, volumetry of all lesions is needed. Since the large amount of lesions in one patient impedes manual segmentation of all lesions, quantification of overall tumor volume is not possible until now. Therefore development of automatic lesion detection and segmentation methods is necessary. Since focal tumors in multiple myeloma show different characteristics in different modalities (changes in bone structure in CT images, hypointensity in T1 weighted MR images and hyperintensity in T2 weighted MR images), multimodal image analysis is necessary for the detection of focal tumors. In this paper a pattern recognition approach is presented that identifies focal lesions in lumbar vertebrae based on features from T1 and T2 weighted MR images. Image voxels within bone are classified using random forests based on plain intensities and intensity value derived features (maximum, minimum, mean, median) in a 5 x 5 neighborhood around a voxel from both T1 and T2 weighted MR images. A test data sample of lesions in 8 lumbar vertebrae from 4 multiple myeloma patients can be classified at an accuracy of 95% (using a leave-one-patient-out test). The approach provides a reasonable delineation of the example lesions. This is an important step towards automatic tumor volume quantification in multiple myeloma.

Early myeloma-related death in elderly patients: development of a clinical prognostic score and evaluation of response sustainability role.

PubMed

Rodríguez-Otero, Paula; Mateos, María Victoria; Martínez-López, Joaquín; Martín-Calvo, Nerea; Hernández, Miguel-Teodoro; Ocio, Enrique M; Rosiñol, Laura; Martínez, Rafael; Teruel, Ana-Isabel; Gutiérrez, Norma C; Bargay, Joan; Bengoechea, Enrique; González, Yolanda; de Oteyza, Jaime Pérez; Gironella, Mercedes; Encinas, Cristina; Martín, Jesús; Cabrera, Carmen; Palomera, Luis; de Arriba, Felipe; Cedena, María Teresa; Paiva, Bruno; Puig, Noemí; Oriol, Albert; Bladé, Joan; Lahuerta, Juan José; San Miguel, Jesús F

2018-02-23

Although survival of elderly myeloma patients has significantly improved there is still a subset of patients who, despite being fit and achieving optimal responses, will die within 2 years of diagnosis due to myeloma progression. The objective of this study was to define a scoring prognostic index to identify this group of patients. We have evaluated the outcome of 490 newly diagnosed elderly myeloma patients included in two Spanish trials (GEM2005-GEM2010). Sixty-eight patients (13.8%) died within 2 years of diagnosis (early deaths) due to myeloma progression. Our study shows that the use of simple scoring model based on 4 widely available markers (elevated LDH, ISS 3, high risk CA or >75 years) can contribute to identify up-front these patients. Moreover, unsustained response (<6 months duration) emerged as one important predictor of early myeloma-related mortality associated with a significant increase in the risk of death related to myeloma progression. The identification of these patients at high risk of early death is relevant for innovative trials aiming to maintain the depth of first response, since many of them will not receive subsequent lines of therapy.

RNAseq analysis reveals pathways and candidate genes associated with salinity tolerance in a spaceflight-induced wheat mutant.

PubMed

Xiong, Hongchun; Guo, Huijun; Xie, Yongdun; Zhao, Linshu; Gu, Jiayu; Zhao, Shirong; Li, Junhui; Liu, Luxiang

2017-06-02

Salinity stress has become an increasing threat to food security worldwide and elucidation of the mechanism for salinity tolerance is of great significance. Induced mutation, especially spaceflight mutagenesis, is one important method for crop breeding. In this study, we show that a spaceflight-induced wheat mutant, named salinity tolerance 1 (st1), is a salinity-tolerant line. We report the characteristics of transcriptomic sequence variation induced by spaceflight, and show that mutations in genes associated with sodium ion transport may directly contribute to salinity tolerance in st1. Furthermore, GO and KEGG enrichment analysis of differentially expressed genes (DEGs) between salinity-treated st1 and wild type suggested that the homeostasis of oxidation-reduction process is important for salt tolerance in st1. Through KEGG pathway analysis, "Butanoate metabolism" was identified as a new pathway for salinity responses. Additionally, key genes for salinity tolerance, such as genes encoding arginine decarboxylase, polyamine oxidase, hormones-related, were not only salt-induced in st1 but also showed higher expression in salt-treated st1 compared with salt-treated WT, indicating that these genes may play important roles in salinity tolerance in st1. This study presents valuable genetic resources for studies on transcriptome variation caused by induced mutation and the identification of salt tolerance genes in crops.

Multiple myeloma presenting as CEA-producing rectal cancer

PubMed Central

Talamo, Giampaolo; Barochia, Amitkumar; Zangari, Maurizio; Loughran, Thomas P

2010-01-01

We report the case of a 57-year-old patient with multiple myeloma, characterized by extramedullary involvement of the rectum at presentation. Malignant plasma cells were found to produce carcinoembryonic antigen (CEA), a tumor antigen more commonly associated with rectal adenocarcinomas. PMID:21139949

Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial

PubMed Central

García-Sanz, Ramón; Oriol, Albert; Moreno, María J.; de la Rubia, Javier; Payer, Angel R.; Hernández, Miguel T.; Palomera, Luis; Teruel, Ana I.; Blanchard, María J.; Gironella, Mercedes; Ribas, Paz; Bargay, Joan; Abellá, Eugenia; Granell, Miquel; Ocio, Enrique M.; Ribera, Josep M.; San Miguel, Jesús F.; Mateos, María V.

2015-01-01

This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse. One hundred patients were randomized to receive either zoledronic acid (4 mg iv/4 weeks, 12 doses) (n=51) or not (n=49). Experimental and control groups were well balanced for disease and prognostic features. Zoledronic acid did not show an antitumor effect according to changes in M-component. However, there were fewer symptomatic progressions in the experimental group than in the control group (34 versus 41, respectively; P=0.05) resulting in a median time to symptoms of 16 versus 10 months (P=0.161). The median time to next therapy was also slightly longer for the treated group than the untreated, control group (13.4 versus 10.1 months), although the difference was not statistically significant (P=0.360). The pattern of relapses was different for treated versus control patients: progressive bone disease (8 versus 20), anemia (24 versus 18), renal dysfunction (1 versus 2), and plasmacytomas (1 versus 1, respectively). This concurred with fewer skeletal-related events in the treated group than in the control group (2 versus 14), with a projected 4-year event proportion of 6% versus 40% (P<0.001). In summary, zoledronic acid monotherapy does not show an antitumor effect on biochemical relapses in multiple myeloma, but does reduce the risk of progression with symptomatic bone disease and skeletal complications. This trial was registered in the ClinicalTrials.gov database with code NCT01087008 PMID:26069291

The effects of salinity on nitrification using halophilic nitrifiers in a Sequencing Batch Reactor treating hypersaline wastewater.

PubMed

Cui, You-Wei; Zhang, Hong-Yu; Ding, Jie-Ran; Peng, Yong-Zhen

2016-04-25

With annual increases in the generation and use of saline wastewater, the need to avoid environmental problems such as eutrophication is critical. A previous study identified ways to start up a halophilic sludge domesticated from estuarine sediments to remove nitrogen from wastewater with a salinity of 30 g/L. This investigation expands that work to explore the impact of salinity on nitrogen removal. This study demonstrated that the mixed halophilic consortia removed nitrogen from wastewater with a salinity of 30-85 g/L. A kinetic analysis showed that halophilic nitrifiers selected based on hypersalinity were characterized by low Ks, μmax and specific ammonium oxidization rates. This explains the decrease in ammonium removal efficiency in the high salinity operational phases. Salinity inhibited ammonia oxidizing bacteria (AOB) activity, as well as the number of dominant AOB, but did not significantly affect the AOB dominant species. Three most dominant AOB lineages in the halophilic sludge were Nitrosomonas marina, Nitrosomonas europaea, and Nitrosococcus mobilis. Nitrosomonas europaea and Nitrosococcus mobilis were mainly affected by salinity, while nitrite accumulation and ammonia loading played the key role in determining the abundance of Nitrosococcus mobilis and Nitrosococcus europaea. The study contributes insights about shifts in halophilic nitrifying bacterial populations.

The effects of salinity on nitrification using halophilic nitrifiers in a Sequencing Batch Reactor treating hypersaline wastewater

PubMed Central

Cui, You-Wei; Zhang, Hong-Yu; Ding, Jie-Ran; Peng, Yong-Zhen

2016-01-01

With annual increases in the generation and use of saline wastewater, the need to avoid environmental problems such as eutrophication is critical. A previous study identified ways to start up a halophilic sludge domesticated from estuarine sediments to remove nitrogen from wastewater with a salinity of 30 g/L. This investigation expands that work to explore the impact of salinity on nitrogen removal. This study demonstrated that the mixed halophilic consortia removed nitrogen from wastewater with a salinity of 30–85 g/L. A kinetic analysis showed that halophilic nitrifiers selected based on hypersalinity were characterized by low Ks, μmax and specific ammonium oxidization rates. This explains the decrease in ammonium removal efficiency in the high salinity operational phases. Salinity inhibited ammonia oxidizing bacteria (AOB) activity, as well as the number of dominant AOB, but did not significantly affect the AOB dominant species. Three most dominant AOB lineages in the halophilic sludge were Nitrosomonas marina, Nitrosomonas europaea, and Nitrosococcus mobilis. Nitrosomonas europaea and Nitrosococcus mobilis were mainly affected by salinity, while nitrite accumulation and ammonia loading played the key role in determining the abundance of Nitrosococcus mobilis and Nitrosococcus europaea. The study contributes insights about shifts in halophilic nitrifying bacterial populations. PMID:27109617

Evaluation of the Revised International Staging System in an independent cohort of unselected patients with multiple myeloma

PubMed Central

Kastritis, Efstathios; Terpos, Evangelos; Roussou, Maria; Gavriatopoulou, Maria; Migkou, Magdalini; Eleutherakis-Papaiakovou, Evangelos; Fotiou, Despoina; Ziogas, Dimitrios; Panagiotidis, Ioannis; Kafantari, Eftychia; Giannouli, Stavroula; Zomas, Athanasios; Konstantopoulos, Konstantinos; Dimopoulos, Meletios A.

2017-01-01

The Revised International Staging System (R-ISS) was recently introduced in order to improve risk stratification over that provided by the widely used standard International Staging System. In addition to the parameters of the standard system, the R-ISS incorporates the presence of chromosomal abnormalities detected by interphase fluorescence in situ hybridization [t(4;14), t(14;16) and del17p] and elevated serum lactate dehydrogenase. The R-ISS was formulated on the basis of a large dataset of selected patients who had participated in clinical trials and has not been validated in an independent cohort of unselected patients. Thus, we evaluated the R-ISS in 475 consecutive, unselected patients, treated in a single center. Our patients were older and more often had severe renal dysfunction than those in the original publication on the R-ISS. As regards distribution by group, 18% had R-ISS-1, 64.5% R-ISS-2 and 18% R-ISS-3. According to R-ISS group, the 5-year survival rate was 77%, 53% and 19% for R-ISS-1, -2 and -3, respectively (P<0.001). The R-ISS could identify three groups with distinct outcomes among patients treated with or without autologous stem cell transplantation, among those treated with either bortezomib-based or immunomodulatory drug-based primary therapy and in patients ≤65, 66–75 or >75 years. However, in patients with severe renal dysfunction the distinction between groups was less clear. In conclusion, our data in consecutive, unselected patients, with differences in the characteristics and treatment approaches compared to the original International Myeloma Working Group cohort, verified that R-ISS is a robust tool for risk stratification of newly diagnosed patients with symptomatic myeloma. PMID:27789676

Fludarabine Phosphate, Cyclophosphamide, Total-Body Irradiation, and Donor Bone Marrow Transplant Followed by Donor Natural Killer Cell Therapy, Mycophenolate Mofetil, and Tacrolimus in Treating Patients With Hematologic Cancer

ClinicalTrials.gov

2017-11-08

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Aggressive Non-Hodgkin Lymphoma; Diffuse Large B-Cell Lymphoma; Previously Treated Myelodysplastic Syndrome; Recurrent Chronic Lymphocytic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Indolent Adult Non-Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; Waldenstrom Macroglobulinemia

Cyclophosphamide, bortezomib and dexamethasone (CyBorD) induction for newly diagnosed multiple myeloma: High response rates in a phase II clinical trial

PubMed Central

Reeder, Craig B.; Reece, Donna E.; Kukreti, Vishal; Chen, Christine; Trudel, Suzanne; Hentz, Joseph; Noble, Brie; Pirooz, Nicholas A.; Spong, Jacy E.; Piza, Jesus G.; Zepeda, Victor H. Jimenez; Mikhael, Joseph R.; Leis, Jose F.; Bergsagel, P. Leif; Fonseca, Rafael; Stewart, A. Keith

2009-01-01

We have studied a three drug combination with bortezomib, cyclophosphamide and dexamethasone (CyBorD) on a 28 day cycle in the treatment of newly diagnosed multiple myeloma patients to assess response and toxicity. The primary endpoint of response was evaluated after four cycles. Thirty-three newly diagnosed, symptomatic patients with multiple myeloma received bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8, 11, cyclophosphamide 300 mg/m2 orally days 1, 8, 15, 22 and dexamethasone 40 mg orally days 1-4, 9-12, 17-20 on a 28 day cycle for four cycles. Responses were rapid with a mean 80% decline in the sentinel monoclonal protein at the end of two cycles. The overall intent to treat response rate (≥ partial response) was 88% with 61% ≥VGPR and 39% CR/nCR. For the 28 patients that completed all 4 cycles of therapy the CR/nCR rate was 46% and ≥VGPR rate 71%. All patients undergoing stem cell harvest had a successful collection. Twenty three patients underwent SCT and are evaluable through day 100 with CR/nCR documented in 70% and ≥VGPR in 74%. In conclusion, CyBorD produces a rapid and profound response in patients with newly diagnosed multiple myeloma with manageable toxicity. PMID:19225538

Reversal of P-glycoprotein overexpression by Ginkgo biloba extract in the brains of pentylenetetrazole-kindled and phenytoin-treated mice.

PubMed

Zhang, Ce; Fan, Qing; Chen, Shu-Liang; Ma, Hui

2015-08-01

The purpose of this study was to investigate the combined effects of Ginkgo biloba extract and phenytoin (PHT) sodium as a dose regimen simulating the clinical treatment of patients with epilepsy, on P-glycoprotein (P-GP) overexpression in a pentylenetetrazole-kindled mouse model of epilepsy. Epilepsy was induced by intraperitoneal administration of pentylenetetrazole (40 mg/kg) for 7 days followed by intragastric administration of PHT (40 mg/kg) for 14 days. Thirty mice that developed seizures were randomly divided into three groups and administered PHT as well as the following treatments: saline (negative control); verapamil (20 mg/kg, positive control); and G. biloba (30 mg/kg). Seizure severity was recorded 30 minutes after treatment on Day 4 of drug administration, after which the mice were euthanized, and their brains isolated. Western blots and immunohistochemistry were performed to analyze the expression of P-GP and caspase-3, respectively, in the brain tissue. High-performance liquid chromatography was used to measure the concentrations of PHT in the brains of the treated mice. After 4 consecutive days of treatment, the seizure severity in the mice in the G. biloba extract group was more significantly reduced than the seizure severity in the saline control group, and a significant difference was observed between the G. biloba extract and verapamil control groups (p < 0.05). P-GP expression in the brain more significantly decreased in the mice treated with G. biloba extract and verapamil than it did in the saline-treated control group (p < 0.05). Compared with the saline-treated control group, the mice treated with G. biloba extract and verapamil showed significantly increased brain PHT concentrations (p < 0.05). Furthermore, caspase-3 expression in the brain tissue of the G. biloba extract group was significantly lower than that in the vehicle control group (p < 0.05); this finding demonstrated the neuroprotective effects of G. biloba. Therefore, this

Evaluation of two hybrid poplar clones as constructed wetland plant species for treating saline water high in boron and selenium, or waters only high in boron

USDA-ARS?s Scientific Manuscript database

Wetland mesocosms were constructed to assess two salt- and B-tolerant hybrid poplar clones (Populus trichocarpa ×P. deltoides×P. nigra '345-1' and '347-14') for treating saline water high in boron (B) and selenium (Se). In addition, a hydroponic experiment was performed to test the B tolerance and B...

HIF-2α-ILK Is Involved in Mesenchymal Stromal Cell Angiogenesis in Multiple Myeloma Under Hypoxic Conditions

PubMed Central

Zhang, Xiaoying; Xu, Yinhui; Liu, Hongbo; Zhao, Pan; Chen, Yafang; Yue, Zhijie; Zhang, Zhiqing; Wang, Xiaofang

2018-01-01

Mesenchymal stromal cells are proven to be likely induce the angiogenic response in multiple myeloma and thus represent an enticing target for antiangiogenesis therapies for multiple myeloma. Substantial evidence indicates that angiogenesis in multiple myeloma is complex and involves direct production of angiogenic cytokines by abnormal plasma cells and these B-cell neoplasia generated pathophysiology change within the microenvironment. In this study, we demonstrated that mesenchymal stromal cells cultured with U266/Lp-1 under hypoxic conditions resulted in an increased α-smooth muscle actin expression and high productive levels of both hypoxia-inducible factor-2α and integrin-linked kinase proteins. Moreover, inhibition of hypoxia-inducible factor-2α by Small interfering RNA (siRNA) in mesenchymal stromal cells decreased the protein levels of both α-smooth muscle actin and integrin-linked kinase after mesenchymal stromal cells cultured with U266 under hypoxic conditions. We further demonstrated that transfection of integrin-linked kinase-siRNA reduced the protein level of α-smooth muscle actin and attenuated angiogenesis in vitro by decreasing the attachment of Q-dot labeled cells and secretion of angiogenic factors. In conclusion, our research showed that mesenchymal stromal cells cultured with myeloma cells under hypoxia participated in the angiogenesis of multiple myeloma, which is regulated by the hypoxia-inducible factor-2α-integrin-linked kinase pathway. Thus, targeting integrin-linked kinase may represent an effective strategy to block hypoxia-inducible factor-2α-induced angiogenesis in the treatment of multiple myeloma. PMID:29656700

Adipose, Bone, and Myeloma: Contributions from the Microenvironment.

PubMed

McDonald, Michelle M; Fairfield, Heather; Falank, Carolyne; Reagan, Michaela R

2017-05-01

Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide (Podar et al. in Expert Opin Emerg Drugs 14:99-127, 2009). Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90 % of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes, and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies.

Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model.

PubMed

Kim, Chulwon; Lee, Seok-Geun; Yang, Woong Mo; Arfuso, Frank; Um, Jae-Young; Kumar, Alan Prem; Bian, Jinsong; Sethi, Gautam; Ahn, Kwang Seok

2018-05-29

Aberrant reactions of signal transducer and transcriptional activator (STAT) are frequently detected in multiple myeloma (MM) cancers and can upregulate the expression of multiple genes related to cell proliferation, survival, metastasis, and angiogenesis. Therefore, agents capable of inhibiting STAT activation can form the basis of novel therapies for MM patients. In the present study, we investigated whether the potential anti-cancer effects of Formononetin (FT), a naturally occurring isoflavone derived from Astragalus membranaceus, Trifolium pratense, Glycyrrhiza glabra, and Pueraria lobata, against MM cell lines and human multiple myeloma xenograft tumors in athymic nu/nu mice model are mediated through the negative regulation of STAT3 and STAT5 pathways. Data from the in vitro studies indicated that FT could significantly inhibit cell viability, and induce apoptosis. Interestingly, FT also suppressed constitutive STAT3 (tyrosine residue 705 and serine residue 727) and STAT5 (tyrosine residue 694/699) activation, which correlated with the suppression of the upstream kinases (JAK1, JAK2, and c-Src) in MM cells, and this effect was found to be mediated via an increased production of reactive oxygen species (ROS) due to GSH/GSSG imbalance. Also, FT abrogated STAT3 and STAT5 DNA binding capacity and nuclear translocation. FT induced cell cycle arrest, downregulated the expression of STAT3-regulated anti-apoptotic, angiogenetic, and proliferative gene products; and this correlated with induction of caspase-3 activation and cleavage of PARP. Intraperitoneal administration of FT significantly suppressed the tumor growth in the multiple myeloma xenograft mouse model without exhibiting any significant adverse effects. Overall, our findings indicate that FT exhibits significant anti-cancer effects in MM that may be primarily mediated through the ROS-regulated inhibition of the STAT3 and STAT5 signaling cascade. Copyright © 2018 Elsevier B.V. All rights reserved.

The Effect of Radiation on the Normal and Oestrone-treated Mouse Vagina Grown in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lasnitzki, Ilse

1961-06-01

The effect of radiation on the differentiation of normal and oestrone- treated organ cultures of the mouse vagina was studied during growth in natural and in chemically defined medium. After explanation into either type of medium without addition of the hormone the vaginal epithelium spontaneously forms new squamous keratinising epithelium which displaces the original secretory epithelium. Addition of oestrone to the medium stimulates the growth of the new cells and hastens and increases keratin synthesis. Exposure to 200 r of x rays given one day after explanation inhibits the squamous development, suppresses keratin formation and preserves the original epithelium inmore » both normal and oestrone-treated explants grown in natural medium. Radiation of cultures kept in defined medium fails to influence the normal squamous differentiation and keratinisation. The mechanism of radiation action is discussed in the light of the differnet results obtained under the two conditions. (auth)« less

Incidence of neutropenia and use of granulocyte colony-stimulating factors in multiple myeloma: is current clinical practice adequate?

PubMed

Leleu, Xavier; Gay, Francesca; Flament, Anne; Allcott, Kim; Delforge, Michel

2018-03-01

Although immunomodulatory drugs, alkylating agents, corticosteroids, protease inhibitors, and therapeutic monoclonal antibodies improve multiple myeloma outcomes, treatment burden is still an issue. Neutropenia is a known complication of cytotoxic cancer therapy and is often associated with infections; it is an important consideration in myeloma given the fact that patients often have a weakened immune system. The risk of febrile neutropenia increases with severe and persisting neutropenia. Recombinant granulocyte colony-stimulating factors (G-CSFs) are commonly used to reduce the incidence, duration, and severity of febrile neutropenia. Here, we review the risk and management of neutropenia associated with new and commonly used anti-myeloma agents. Few papers report the use of G-CSF in patients with multiple myeloma receiving anti-cancer treatments, and fewer describe whether G-CSF was beneficial. None of the identified studies reported G-CSF primary prophylaxis. Further studies are warranted to evaluate the need for G-CSF prophylaxis in multiple myeloma. Prophylaxis may be particularly useful in patients at high risk of prolonged severe neutropenia.

Iterative Decomposition of Water and Fat with Echo Asymmetry and Least-Squares Estimation (IDEAL) Magnetic Resonance Imaging as a Biomarker for Symptomatic Multiple Myeloma

PubMed Central

Takasu, Miyuki; Kaichi, Yoko; Tani, Chihiro; Date, Shuji; Akiyama, Yuji; Kuroda, Yoshiaki; Sakai, Akira; Awai, Kazuo

2015-01-01

Introduction To evaluate the effectiveness of iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) magnetic resonance imaging (MRI) to discriminate between symptomatic and asymptomatic myeloma in lumbar bone marrow without visible focal lesions. Materials and Methods The lumbar spine was examined with 3-T MRI in 11 patients with asymptomatic myeloma and 24 patients with symptomatic myeloma. The fat-signal fraction was calculated from the ratio of the signal intensity in the fat image divided by the signal intensity of the corresponding ROI in the in-phase IDEAL image. The t test was used to compare the asymptomatic and symptomatic groups. ROC curves were constructed to determine the ability of variables to discriminate between symptomatic and asymptomatic myeloma. Results Univariate analysis showed that β2-microglobulin and bone marrow plasma cell percent (BMPC%) were significantly higher and fat-signal fraction was significantly lower with symptomatic myeloma than with asymptomatic myeloma. Areas under the curve were 0.847 for β2;-microglobulin, 0.834 for fat-signal fraction, and 0.759 for BMPC%. Conclusion The fat-signal fraction as a biomarker for multiple myeloma enables discrimination of symptomatic myeloma from asymptomatic myeloma. The fat-signal fraction offers superior sensitivity and specificity to BMPC% of biopsy specimens. PMID:25706753

General Information about Plasma Cell Neoplasms (Including Multiple Myeloma)

MedlinePlus

... Including Multiple Myeloma) Treatment (PDQ®)–Patient Version General Information About Plasma Cell Neoplasms Go to Health Professional ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

PubMed Central

Corre, Jill; Mahtouk, Karène; Attal, Michel; Gadelorge, Mélanie; Huynh, Anne; Fleury-Cappellesso, Sandrine; Danho, Clotaire; Laharrague, Patrick; Klein, Bernard; Rème, Thierry; Bourin, Philippe

2007-01-01

Recent literature suggested that cell of the microenvironment of solid tumors could be abnormal as well. To address this hypothesis in multiple myeloma (MM), we studied bone marrow mesenchymal stem cells (BMMSCs), the only long-lived cells of the bone marrow microenvironment, by gene expression with Affymetrix arrays and phenotypic and functional study in 3 groups of individuals: patients with MM and those with monoclonal gamopathy of undefined significance (MGUS), and healthy aged-matched subjects. Gene expression profile independently classified the BMMSCs of these individuals in a normal and in a MM group. MGUS BMMSCs were interspersed between those 2 groups. Among the 145 distinct genes differentially expressed in MM and normal BMMSCs 46% were involved in tumor-microenvironment cross-talk. Known soluble factors involved in MM pathophysiologic features, (interleukin (IL)-6, IL-1β, DKK1 and amphiregulin, were revealed and new ones found. In particular, GDF-15 was found to induce dose-dependant growth of MOLP-6, a stromal cell-dependent myeloma cell line. Functionally, MM BMMSCs induced an over-growth of MOLP-6, and their capacity to differentiate into an osteoblastic lineage was impaired. Thus, BMMSCs from MM patients could create a very efficient niche to support the survival and proliferation of the myeloma stem cells. PMID:17344918

LDH is an adverse prognostic factor independent of ISS in transplant-eligible myeloma patients receiving bortezomib-based induction regimens.

PubMed

Chim, Chor Sang; Sim, Joycelyn; Tam, Sidney; Tse, Eric; Lie, Albert Kwok Wai; Kwong, Yok Lam

2015-04-01

Serum lactate dehydrogenase (LDH) has been an adverse prognostic factor for myeloma but does not feature in the International Staging System (ISS). We examined whether elevated serum LDH at diagnosis remains an adverse risk factor independent of ISS for survivals transplant-eligible myeloma patients receiving early/frontline bortezomib-based induction, followed by autologous stem cell transplantation (ASCT). Seventy-seven transplant-eligible Chinese patients received three induction regimens [staged approach (N = 25), PAD (N = 19), VTD (N = 33)], followed by ASCT and thalidomide maintenance. Five-year overall (OS) and event-free (EFS) survivals were 66.4% and 36.2%. There was no difference in demographics, complete remission/near complete remission (CR/nCR rates postinduction or ASCT, and survivals among patients induced by the three induction regimens. Elevated LDH was associated with male gender (P = 0.006), ISS III (P = 0.042) and serum β2-microglobulin (P = 0.040). Univariate analysis showed that elevated LDH, ISS III, high β2-microglobulin, and failure to attain CR/nCR post-ACST were risk factors adversely impacting both OS and EFS. Multivariate analysis showed that elevated LDH was the only factor impacting both OS (P = 0.007) and EFS (P = 0.008). In this uniformly treated cohort of transplant-eligible myeloma patients, elevated serum LDH is an adverse risk factor independent of ISS for both OS and EFS. Bortezomib-based induction/ASCT regimen had not abolished the adverse impact of elevated LDH. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

IgD multiple myeloma a descriptive report of 17 cases: survival and response to therapy

PubMed Central

2012-01-01

Background Immunoglobulin D multiple myeloma (MM) is rare and has a poorer prognosis than other MM isotypes. Design and methods Seventeen patients (pts) diagnosed from 1993 to 2009 with IgD MM were selected from six institutions of Multiple Myeloma Latium-Region GIMEMA Working Group. Results Median age was 55 years, 14 patients had bone lesions, eight had renal impairment with estimated glomerular filtration rate (eGFR) < 50 ml/min, one serum calcium ≥ 12 mg/dl, 11 had lambda light chains, five stage III of ISS, six with chromosomal abnormalities. Six pts received conventional chemotherapy (CT): five melphalan + steroids based regimens. Eleven underwent high-doses of chemotherapy with autologous stem cell transplantation (HDT/ASCT), five single and six tandem ASCT: six received bortezomib and/or thalidomide as induction therapy and five VAD. Thalidomide maintenance was used in two pts: one in HDT/ASCT and one in CT group; bortezomib was used in one patient after HDT/ASCT. At a median follow up of 38 (range 19-60) and 50 months (range 17-148) for pts treated with CT and HDT/ASCT, respectively, the overall response rate (ORR) was 83% and 90%. In the group of patients treated with CT, median overall survival (OS) was 34 months (95% CI 15- 54 months), median progression free survival (PFS) was 18 months (95% CI 3-33 months) and median duration of response (DOR) was 7 months (95% CI 5-9 months). Median OS, PFS and DOR were not reached at the time of this analysis in the HDT/ASCT group of patients. Death was observed in 27.3% of pts treated with HDT/ASCT and in 66.7% undergone CT. Conclusions Despite the retrospective analysis and the small number of pts our study showed that the use of HDT/ASCT seems to improve also the prognosis of IgD MM patients. Treatment options including new drugs, before and after stem cell transplantation, may further improve the outcomes of these patients. PMID:22381082

MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin.

PubMed

Nardiello, Tricia; Jungbluth, Achim A; Mei, Anna; Diliberto, Maurizio; Huang, Xiangao; Dabrowski, Ania; Andrade, Valéria C C; Wasserstrum, Rebecca; Ely, Scott; Niesvizky, Ruben; Pearse, Roger; Coleman, Morton; Jayabalan, David S; Bhardwaj, Nina; Old, Lloyd J; Chen-Kiang, Selina; Cho, Hearn Jay

2011-07-01

The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67(+) malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells. The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups: newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by short hairpin RNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis. MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared with newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A showed that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of proapoptotic Bax expression and by reduction of survivin expression through both p53-dependent and -independent mechanisms. These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms.

MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin

PubMed Central

Nardiello, Tricia; Jungbluth, Achim A.; Mei, Anna; DiLiberto, Maurizio; Huang, Xiangao; Dabrowski, Ania; Andrade, Valéria C. C.; Wasserstrum, Rebecca; Ely, Scott; Niesvizky, Ruben; Pearse, Roger; Coleman, Morton; Jayabalan, David S.; Bhardwaj, Nina; Old, Lloyd J.; Chen-Kiang, Selina; Cho, Hearn Jay

2011-01-01

Purpose The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67+ malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells. Experimental Design The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups; newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by shRNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis. Results MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared to newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A demonstrated that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of pro-apoptotic Bax expression and by reduction of survivin expression through both p53-dependent and independent mechanisms. Conclusions These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms. PMID:21565982

Multiple Myeloma and Glyphosate Use: A Re-Analysis of US Agricultural Health Study (AHS) Data

PubMed Central

Sorahan, Tom

2015-01-01

A previous publication of 57,311 pesticide applicators enrolled in the US Agricultural Health Study (AHS) produced disparate findings in relation to multiple myeloma risks in the period 1993–2001 and ever-use of glyphosate (32 cases of multiple myeloma in the full dataset of 54,315 applicators without adjustment for other variables: rate ratio (RR) 1.1, 95% confidence interval (CI) 0.5 to 2.4; 22 cases of multiple myeloma in restricted dataset of 40,719 applicators with adjustment for other variables: RR 2.6, 95% CI 0.7 to 9.4). It seemed important to determine which result should be preferred. RRs for exposed and non-exposed subjects were calculated using Poisson regression; subjects with missing data were not excluded from the main analyses. Using the full dataset adjusted for age and gender the analysis produced a RR of 1.12 (95% CI 0.50 to 2.49) for ever-use of glyphosate. Additional adjustment for lifestyle factors and use of ten other pesticides had little effect (RR 1.24, 95% CI 0.52 to 2.94). There were no statistically significant trends for multiple myeloma risks in relation to reported cumulative days (or intensity weighted days) of glyphosate use. The doubling of risk reported previously arose from the use of an unrepresentative restricted dataset and analyses of the full dataset provides no convincing evidence in the AHS for a link between multiple myeloma risk and glyphosate use. PMID:25635915

Multiple myeloma and glyphosate use: a re-analysis of US Agricultural Health Study (AHS) data.

PubMed

Sorahan, Tom

2015-01-28

A previous publication of 57,311 pesticide applicators enrolled in the US Agricultural Health Study (AHS) produced disparate findings in relation to multiple myeloma risks in the period 1993-2001 and ever-use of glyphosate (32 cases of multiple myeloma in the full dataset of 54,315 applicators without adjustment for other variables: rate ratio (RR) 1.1, 95% confidence interval (CI) 0.5 to 2.4; 22 cases of multiple myeloma in restricted dataset of 40,719 applicators with adjustment for other variables: RR 2.6, 95% CI 0.7 to 9.4). It seemed important to determine which result should be preferred. RRs for exposed and non-exposed subjects were calculated using Poisson regression; subjects with missing data were not excluded from the main analyses. Using the full dataset adjusted for age and gender the analysis produced a RR of 1.12 (95% CI 0.50 to 2.49) for ever-use of glyphosate. Additional adjustment for lifestyle factors and use of ten other pesticides had little effect (RR 1.24, 95% CI 0.52 to 2.94). There were no statistically significant trends for multiple myeloma risks in relation to reported cumulative days (or intensity weighted days) of glyphosate use. The doubling of risk reported previously arose from the use of an unrepresentative restricted dataset and analyses of the full dataset provides no convincing evidence in the AHS for a link between multiple myeloma risk and glyphosate use.

Dexamethasone, all trans retinoic acid and interferon alpha 2a in patients with refractory multiple myeloma.

PubMed

Avilés, A; Rosas, A; Huerta-Guzmán, J; Talavera, A; Cleto, S

1999-02-01

Few effective regimen are available for patients with refractory multiple myeloma (RMM). Generally, responses are scarce and disease free survival is very short. We developed a new therapeutic option in these patients using dexamethasone (40 mg/m2, i.v., daily, days 1 to 4), all-trans retinoic acid (45 mg/m2, po, daily, days 5 to 14) and interferon alpha 2a (9.0 MU, daily, subcutaneously, days 5 to 14). The treatment was administered every 21 days for 6 cycles. In a pilot study, 12 patients, heavily treated with chemotherapy and radiotherapy and in some cases with interferon, were allocated to receive the afore mentioned treatment. Response was observed in 10 patients (83%). With a median follow-up of 36.1 months (range 27 to 41), seven patients remain alive and disease-free without any treatment. Two patients were failures and have died due to tumor progression. Toxicity was mild and all patients received treatment according to the planned doses of drugs. The use of biological modifiers in combination with dexamethasone offer a safe and effective therapeutic option in patients with refractory multiple myeloma. More studies are warranted to define the role of this type of treatment.

Subsurface injection of treated sewage into a saline-water aquifer at St. Petersburg, Florida - Water-quality changes and potential for recovery of injected sewage

USGS Publications Warehouse

Hickey, J.J.; Ehrlich, G.G.

1984-01-01

The city of St. Petersburg is testing subsurface injection of treated sewage into the Floridan aquifer as a means of eliminating discharge of sewage to surface waters and as a means of storing treated sewage for future nonpotable reuse. The injection zone at the test site at the start of injection contained saline water with chloride concentrations ranging from 14,000 to 20,000 milligrams per liter (mg/l). Treated sewage with a mean chloride concentration of 170 mg/ml was injected through a single well for 12 months at a mean rate of 4.7 x 105 cubic feet per day. The volume of water injected during the year was 1.7x108 cubic feet. Dissolved oxygen was contained in the sewage prior to injection. Water removed from the injection zone during injection was essentially free of oxygen. Probable growth of denitrifying bacteria and, thus, microbial denitrification, was suggested by bacterial counts in water from two observation wells that were close to the injection well. The volume fraction of treated sewage in water from wells located 35 feet and 733 feet from the injection well and open to the upper part of the injection zone stabilized at about 0.9 and 0.75, respectively. Chloride concentrations stabilized at about 1,900 mg/l in water from the well that was 35 feet from the injection well and stabilized at about 4,000 mg/l in water from the well that was 733 feet from the injection well. These and other data suggest that very little near injection-quality treated sewage would be recoverable from storage in the injection zone.The city of St. Petersburg is testing subsurface injection of treated sewage into the Floridan aquifer as a means of eliminating discharge of sewage to surface waters and as a means of storing treated sewage for future nonpotable reuse. The injection zone at the test site at the start of injection contained saline water with chloride concentrations ranging from 14,000 to 20,000 milligrams per liter (mg/l). Data suggest that very little near

Alteration of metabolite profiling by cold atmospheric plasma treatment in human myeloma cells.

PubMed

Xu, Dehui; Xu, Yujing; Ning, Ning; Cui, Qingjie; Liu, Zhijie; Wang, Xiaohua; Liu, Dingxin; Chen, Hailan; Kong, Michael G

2018-01-01

Despite new progress of chemotherapy in multiple myeloma (MM) clinical treatment, MM is still a refractory disease and new technology is needed to improve the outcomes and prolong the survival. Cold atmospheric plasma is a rapidly developed technology in recent years, which has been widely applied in biomedicine. Although plasma could efficiently inactivate various tumor cells, the effects of plasma on tumor cell metabolism have not been studied yet. In this study, we investigated the metabolite profiling of He plasma treatment on myeloma tumor cells by gas-chromatography time-of-flight (GC-TOF) mass-spectrometry. Meanwhile, by bioinformatic analysis such as GO and KEGG analysis we try to figure out the metabolism pathway that was significantly affected by gas plasma treatment. By GC-TOF mass-spectrometry, 573 signals were detected and evaluated using PCA and OPLS-DA. By KEGG analysis we listed all the differential metabolites and further classified into different metabolic pathways. The results showed that beta-alanine metabolism pathway was the most significant change after He gas plasma treatment in myeloma cells. Besides, propanoate metabolism and linoleic acid metabolism should also be concerned during gas plasma treatment of cancer cells. Cold atmospheric plasma treatment could significantly alter the metabolite profiling of myeloma tumor cells, among which, the beta-alanine metabolism pathway is the most susceptible to He gas plasma treatment.

New developments in the treatment of multiple myeloma – clinical utility of daratumumab

PubMed Central

McEllistrim, Cian; Krawczyk, Janusz; O’Dwyer, Michael E

2017-01-01

Multiple myeloma is a clonal disorder of plasma cells that is currently considered incurable. CD38 is a 46 kDa type II transmembrane glycoprotein that is highly expressed on myeloma cells. Daratumumab is a first in-class human IgG1 monoclonal antibody that targets CD38, and has antimyeloma effects through several mechanisms. Single-agent trials show surprising activity in heavily pretreated myeloma patients. Trials in the relapsed setting, where daratumumab is added to lenalidomide and dexamethasone or bortezomib and dexamethasone, have demonstrated significantly improved progression-free survival with acceptable toxicity. In this review, we discuss the mechanism of action, pharmacology and pharmacokinetics of daratumumab and review the available clinical data in detail. We examine how daratumumab interferes with transfusion testing due to the expression of CD38 on the red blood cells, leading to potential difficulties releasing blood products. Daratumumab also affects disease assessments in multiple myeloma, including serum protein electrophoresis, immunofixation and flow cytometry. Strategies to mitigate these effects are discussed. The optimal use of daratumumab has yet to be decided, and several trials are ongoing in the relapsed and upfront setting. We discuss the potential upfront role of this exciting therapy, which has significant potential for increased minimal residual disease negativity and improved progression-free survival even in high-risk groups. PMID:28442888

Prognostic factors in multiple myeloma: selection using Cox's proportional hazard model.

PubMed

Pasqualetti, P; Collacciani, A; Maccarone, C; Casale, R

1996-01-01

The pretreatment characteristics of 210 patients with multiple myeloma, observed between 1980 and 1994, were evaluated as potential prognostic factors for survival. Multivariate analysis according to Cox's proportional hazard model identified in the 160 dead patients with myeloma, among 26 different single prognostic variables, the following factors in order of importance: beta 2-microglobulin; bone marrow plasma cell percentage, hemoglobinemia, degree of lytic bone lesions, serum creatinine, and serum albumin. By analysis of these variables a prognostic index (PI), that considers the regression coefficients derived by Cox's model of all significant factors, was obtained. Using this it was possible to separate the whole patient group into three stages: stage I (PI < 1.485, 67 patients), stage II (PI: 1.485-2.090, 76 patients), and stage III (PI > 2.090, 67 patients), with a median survivals of 68, 36 and 13 months (P < 0.0001), respectively. Also the responses to therapy (P < 0.0001) and the survival curves (P < 0.00001) presented significant differences among the three subgroups. Knowledge of these factors could be of value in predicting prognosis and in planning therapy in patients with multiple myeloma.

Raman spectroscopy differentiates between sensitive and resistant multiple myeloma cell lines

NASA Astrophysics Data System (ADS)

Franco, Domenico; Trusso, Sebastiano; Fazio, Enza; Allegra, Alessandro; Musolino, Caterina; Speciale, Antonio; Cimino, Francesco; Saija, Antonella; Neri, Fortunato; Nicolò, Marco S.; Guglielmino, Salvatore P. P.

2017-12-01

Current methods for identifying neoplastic cells and discerning them from their normal counterparts are often nonspecific and biologically perturbing. Here, we show that single-cell micro-Raman spectroscopy can be used to discriminate between resistant and sensitive multiple myeloma cell lines based on their highly reproducible biomolecular spectral signatures. In order to demonstrate robustness of the proposed approach, we used two different cell lines of multiple myeloma, namely MM.1S and U266B1, and their counterparts MM.1R and U266/BTZ-R subtypes, resistant to dexamethasone and bortezomib, respectively. Then, micro-Raman spectroscopy provides an easily accurate and noninvasive method for cancer detection for both research and clinical environments. Characteristic peaks, mostly due to different DNA/RNA ratio, nucleic acids, lipids and protein concentrations, allow for discerning the sensitive and resistant subtypes. We also explored principal component analysis (PCA) for resistant cell identification and classification. Sensitive and resistant cells form distinct clusters that can be defined using just two principal components. The identification of drug-resistant cells by confocal micro-Raman spectroscopy is thus proposed as a clinical tool to assess the development of resistance to glucocorticoids and proteasome inhibitors in myeloma cells.

Initial genome sequencing and analysis of multiple myeloma

PubMed Central

Chapman, Michael A.; Lawrence, Michael S.; Keats, Jonathan J.; Cibulskis, Kristian; Sougnez, Carrie; Schinzel, Anna C.; Harview, Christina L.; Brunet, Jean-Philippe; Ahmann, Gregory J.; Adli, Mazhar; Anderson, Kenneth C.; Ardlie, Kristin G.; Auclair, Daniel; Baker, Angela; Bergsagel, P. Leif; Bernstein, Bradley E.; Drier, Yotam; Fonseca, Rafael; Gabriel, Stacey B.; Hofmeister, Craig C.; Jagannath, Sundar; Jakubowiak, Andrzej J.; Krishnan, Amrita; Levy, Joan; Liefeld, Ted; Lonial, Sagar; Mahan, Scott; Mfuko, Bunmi; Monti, Stefano; Perkins, Louise M.; Onofrio, Robb; Pugh, Trevor J.; Vincent Rajkumar, S.; Ramos, Alex H.; Siegel, David S.; Sivachenko, Andrey; Trudel, Suzanne; Vij, Ravi; Voet, Douglas; Winckler, Wendy; Zimmerman, Todd; Carpten, John; Trent, Jeff; Hahn, William C.; Garraway, Levi A.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Golub, Todd R.

2013-01-01

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumor genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the dataset. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signaling was suggested by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge. PMID:21430775

Cardioverter-defibrillator implantation in myeloma-associated cardiac amyloidosis

PubMed Central

Campanile, Alfonso; Sozzi, Fabiola B; Canetta, Ciro; Danzi, Gian Battista

2013-01-01

A 62-year-old woman with multiple myeloma and light-chain amyloidosis with significant heart involvement developed an in-hospital cardiac arrest. After cardiopulmonary resuscitation, a stable sinus rhythm without any cerebral damage was restored, and the patient was admitted to the coronary care unit. A cardioverter-defibrillator was implanted, and it successfully intervened in two sustained ventricular tachycardia episodes and one ventricular fibrillation episode, which were recorded during hospitalization. After achieving discrete cardiac compensation, the patient was transferred to the emergency medicine department where she underwent chemotherapy for multiple myeloma. The patient died 40 days after admission from refractory heart failure. In the literature, there are studies that describe the use of cardioverter-defibrillator implantation in cardiac amyloidosis; however, at present, there is no evidence of a beneficial effect on survival with the use of this intervention. A high index of suspicion for amyloid heart disease and early diagnosis are critical to improving outcomes. PMID:24294034

Cardioverter-defibrillator implantation in myeloma-associated cardiac amyloidosis.

PubMed

Campanile, Alfonso; Sozzi, Fabiola B; Canetta, Ciro; Danzi, Gian Battista

2013-01-01

A 62-year-old woman with multiple myeloma and light-chain amyloidosis with significant heart involvement developed an in-hospital cardiac arrest. After cardiopulmonary resuscitation, a stable sinus rhythm without any cerebral damage was restored, and the patient was admitted to the coronary care unit. A cardioverter-defibrillator was implanted, and it successfully intervened in two sustained ventricular tachycardia episodes and one ventricular fibrillation episode, which were recorded during hospitalization. After achieving discrete cardiac compensation, the patient was transferred to the emergency medicine department where she underwent chemotherapy for multiple myeloma. The patient died 40 days after admission from refractory heart failure. In the literature, there are studies that describe the use of cardioverter-defibrillator implantation in cardiac amyloidosis; however, at present, there is no evidence of a beneficial effect on survival with the use of this intervention. A high index of suspicion for amyloid heart disease and early diagnosis are critical to improving outcomes.

Menogaril in the treatment of relapsed multiple myeloma. A phase II trial of the Cancer Center of Wake Forest University.

PubMed

Cruz, J M; Case, L D; Dalton, H B; Ramseur, W L; Richards, F; Jackson, D V; Muss, H B; Zekan, P J; Brodkin, R A; Brown, R C

1992-04-01

Fifteen patients with relapsed multiple myeloma (MM) were treated with menogaril 160 mg/m2 intravenously (IV) every 28 days. No responses were seen: 8 patients had stable disease, 4 progressed after one course of therapy, and 3 patients were removed from study after 1 course for other reasons. Four of the 8 patients with stable disease had an improved performance status, and 3 had a decrease in analgesic use. The major toxicity was myelosuppression. The median progression-free interval was 3.0 months with a range of 0.7 to 22 months and median survival was 11.3 months with a range of 0.7 to 39+ months. Menogaril displays little activity in patients with previously treated MM.

Calvarial Plasmacytoma Mimicking Meningioma as the Initial Presentation of Multiple Myeloma

PubMed Central

Pisapia, David; Ramakrishna, Rohan

2017-01-01

Plasmacytoma of the calvarium is a well-described feature of multiple myeloma and in some cases has been reported as a solitary lesion. However, when associated with multiple myeloma these are typically identified after the initial diagnosis is made. This case is unusual in that the diagnosis of plasmacytoma was first suspected in a patient thought to have a meningioma on the day of surgery, when a magnetic resonance imaging (MRI) demonstrated spontaneous involution of the mass. Recognition of evolving changes in a calvarial or dural-based lesion should prompt the practitioner to consider alternative diagnoses other than meningioma prior to proceeding with surgical resection. PMID:28465873

Clinical features, outcome, and prognostic factors for survival and evolution to multiple myeloma of solitary plasmacytomas: a report of the Greek myeloma study group in 97 patients.

PubMed

Katodritou, Eirini; Terpos, Evangelos; Symeonidis, Argiris S; Pouli, Anastasia; Kelaidi, Charikleia; Kyrtsonis, Marie-Christine; Kotsopoulou, Maria; Delimpasi, Sosana; Christoforidou, Anna; Giannakoulas, Nikolaos; Viniou, Nora-Athina; Stefanoudaki, Ekaterini; Hadjiaggelidou, Christina; Christoulas, Dimitrios; Verrou, Evgenia; Gastari, Vassiliki; Papadaki, Sofia; Polychronidou, Genovefa; Papadopoulou, Athina; Giannopoulou, Evlambia; Kastritis, Efstathios; Kouraklis, Alexandra; Konstantinidou, Pavlina; Anagnostopoulos, Achilles; Zervas, Konstantinos; Dimopoulos, Meletios A

2014-08-01

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by the presence of bone or extramedullary plasma cell tumors. The treatment of choice is local radiotherapy (R/T) ± surgical excision. The role of adjuvant chemotherapy (C/T) or novel agents (NA) is uncertain. Data related to prognostic factors are inconclusive. Herein, we describe the clinical features, survival and prognosis of 97 consecutive patients, 65 with bone SP (SBP), and 32 with extramedullary SP (SEP), diagnosed and treated in 12 Greek Myeloma Centers. Objective response rate (≥PR) and complete response (CR) was 91.8% and 61.9%, respectively, and did not differ between the 2 groups. Overall, 38 patients relapsed or progressed to multiple myeloma (MM). After a median follow-up of 60 months, 5 and 10-year overall survival (OS) probability was 92% and 89% in SEP and 86% and 69% in SBP, respectively (P = 0.2). The 5- and 10-year MM-free survival (MMFS) probability was 90% and 70% for patients with SEP vs. 59% and 50% for patients with SBP, respectively (P = 0.054). Overall, the 5- and 10-year OS probability, plasmacytoma relapse-free survival (PRFS), progression-free survival and MMFS was 84% and 78%, 72% and 58%, 58% and 43%, and 70% and 59%, respectively. In the multivariate analysis, prolonged PRFS and young age were positive predictors of OS. Achievement of CR was the only positive predictor of PRFS. Immunoparesis was the only negative predictor of progression to MM. The addition of C/T or NA-based treatment increased toxicity without offering any survival advantage over R/T. © 2014 Wiley Periodicals, Inc.

Interleukin-13 protects mouse intestine from ischemia and reperfusion injury through regulation of innate and adaptive immunity.

PubMed

Farmer, Douglas G; Ke, Bibo; Shen, Xiu-Da; Kaldas, Fady M; Gao, Feng; Watson, Melissa J; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W

2011-04-15

Ischemia-reperfusion (I/R) injury is a major factor leading to intestinal dysfunction or graft loss after intestinal surgery or transplantation. This study investigated the cytoprotective effects and putative mechanisms of interleukin (IL)-13 after intestinal I/R injury in the mouse. Mouse warm intestinal I/R injury induced by clamping the superior mesenteric artery for 100 min with tissue analysis at 4 and 24 hr after reperfusion. Treated animals received intravenous recombinant murine IL-13 (rIL-13) and anti-IL-13 antibody, whereas controls received saline. rIL-13 administration markedly prolonged animal survival (100% vs. 50% in saline controls) and resulted in near normal histopathological architecture. rIL-13 treatment also significantly decreased myeloperoxidase activity. Mice conditioned with rIL-13 had a markedly depressed Toll-like receptor-4 expression and increased the expression of Stat6, antioxidant hemeoxygenase-1, and antiapoptotic A20, Bcl-2/Bcl-xl, compared with that of controls. Unlike in controls, the expression of mRNA coding for IL-2/interferon-γ, and interferon-γ-inducible protein (IP)-10/monocyte chemotactic protein-1 remained depressed, whereas that of IL-13/IL-4 reciprocally increased in the mice treated with rIL-13. Administration of anti-IL13 antibody alone or in combination with rIL-13 resulted in outcomes similar to that seen in controls. This study demonstrates for the first time that IL-13 plays a protective role in intestinal warm I/R injury and a critical role in the regulation of Stat6 and Toll-like receptor-4 signaling. The administration of IL-13 exerts cytoprotective effects in this model by regulating innate and adaptive immunity while the removal of IL-13 using antibody therapy abrogates this effect.

Antithyroid drugs induced agranulocytosis and multiple myeloma: case report and general considerations.

PubMed

Dănciulescu Miulescu, R; Carşote, M; Trifănescu, R; Ferechide, D; Poiană, C

2013-09-15

Antithyroid drugs as thionamides are largely used in the treatment of the thyrotoxicosis. Side effects were reported in less than 10% of the cases, especially hematological, hepatic or skin allergies. One of the most severe manifestations is agranulocytosis, probably based on an immune mechanism that is exacerbated by the presence of the thyroid autoimmune disease itself. If the presence of the severe leucopenia is actually an epiphenomenon of a preexisting hematological disturbance as multiple myeloma is debated. The myeloma may also be correlated with an autoimmune predisposition. We present the case of a 56 years old female patient diagnosed with Graves' disease, who developed agranulocytosis after 8 months of therapy with thiamazole. Two months after antithyroid drug's withdrawal, the granulocytes number increased and she received therapy with radioiodine. Two years later she came back for diffuse bone pain that turned out to be caused by a multiple myeloma, confirmed by bone marrow biopsy. It might be a connection between the severe form of leucopenia that the patient developed and the medullar malignancy.

Antithyroid drugs induced agranulocytosis and multiple myeloma: case report and general considerations

PubMed Central

Dănciulescu Miulescu, R; Carșote, M; Trifănescu, R; Ferechide, D; Poiană, C

2013-01-01

Antithyroid drugs as thionamides are largely used in the treatment of the thyrotoxicosis. Side effects were reported in less than 10% of the cases, especially hematological, hepatic or skin allergies. One of the most severe manifestations is agranulocytosis, probably based on an immune mechanism that is exacerbated by the presence of the thyroid autoimmune disease itself. If the presence of the severe leucopenia is actually an epiphenomenon of a preexisting hematological disturbance as multiple myeloma is debated. The myeloma may also be correlated with an autoimmune predisposition. We present the case of a 56 years old female patient diagnosed with Graves’ disease, who developed agranulocytosis after 8 months of therapy with thiamazole. Two months after antithyroid drug’s withdrawal, the granulocytes number increased and she received therapy with radioiodine. Two years later she came back for diffuse bone pain that turned out to be caused by a multiple myeloma, confirmed by bone marrow biopsy. It might be a connection between the severe form of leucopenia that the patient developed and the medullar malignancy. PMID:24155785

Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma

PubMed Central

Liu, Huan; Liu, Zhiqiang; Du, Juan; He, Jin; Lin, Pei; Amini, Behrang; Starbuck, Michael W.; Novane, Nora; Shah, Jatin J.; Davis, Richard E.; Hou, Jian; Gagel, Robert F.; Yang, Jing

2016-01-01

Myelomatous bone disease is characterized by the development of lytic bone lesions and a concomitant reduction in bone formation, leading to chronic bone pain and fractures. To understand the underlying mechanism, we investigated the contribution of myeloma-expressed thymidine phosphorylase (TP) to bone lesions. In osteoblast progenitors, TP upregulated the methylation of RUNX2 and osterix, leading to decreased bone formation. In osteoclast progenitors, TP upregulated the methylation of IRF8, thereby enhanced expression of NFATc1, leading to increased bone resorption. TP reversibly catalyzes thymidine into thymine and 2DDR. Myeloma-secreted 2DDR bound to integrin αVβ3/α5β1 in the progenitors, activated PI3K/Akt signaling, and increased DNMT3A expression, resulting in hypermethylation of RUNX2, osterix, and IRF8. This study elucidates an important mechanism for myeloma-induced bone lesions, suggesting that targeting TP may be a viable approach to healing resorbed bone in patients. As TP overexpression is common in bone-metastatic tumors, our findings could have additional mechanistic implications. PMID:27559096

From the bench to the bedside: emerging new treatments in multiple myeloma

PubMed Central

Mitsiades, Constantine S.; Hayden, Patrick J.; Anderson, Kenneth C.; Richardson, Paul G.

2012-01-01

Within the last decade, several novel classes of anti-myeloma therapeutics have become available. The clinical successes achieved by thalidomide, lenalidomide, and the proteasome inhibitor bortezomib, and in particular the ability of these agents to lead to major clinical responses in patients resistant to conventional or high-dose chemotherapy, have highlighted the importance of expanding even further the spectrum of classes of agents utilized for the treatment of myeloma. Herein, we review the current state of the field of development of novel anti-myeloma agents, with emphasis on classes of therapeutics which have already translated into clinical trials or those in advanced stages of preclinical development. These include second-generation proteasome inhibitors (NPI-0052 and PR-171), heat shock protein 90 (hsp90) inhibitors, 2-methoxyestradiol, histone deacetylase (HDAC) inhibitors (e.g. SAHA, tubacin and LBH589), fibroblast growth factor receptor 3 (FGF-R3) inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, mTOR inhibitors, monoclonal antibodies, and agents targeting the tumor microenvironment, including defibrotide. PMID:18070720

Hypophosphatemic osteomalacia: an unusual clinical presentation of multiple myeloma.

PubMed

Reyskens, M; Sleurs, K; Verresen, L; Janssen, M; van den Bergh, J; van den Berg, J; Geusens, P

2015-07-01

An unusual case of a 75-year-old man is presented who had multiple stress fractures due to adult onset hypophosphatemic osteomalacia, which was the result of Fanconi syndrome, with light chain cast proximal tubulopathy due to multiple myeloma. A 75-year-old man presented with diffuse pain and muscle weakness. He had multiple stress fractures, low serum phosphate, decreased renal tubular reabsorption of phosphate, and normal PTH and FGF23, indicating adult onset hypophosphatemic osteomalacia. Phosphate supplements with calcitriol resulted in clinical recovery and healing of stress fractures. Because of proteinuria, a renal biopsy was performed that revealed Fanconi syndrome with light chain cast proximal tubulopathy and light kappa chains were found in serum and urine. A bone biopsy confirmed the diagnosis of multiple myeloma, and treatment with chemotherapy resulted in cytological and clinical recovery.

Salinity control in a clay soil beneath an orchard irrigated with treated waste water in the presence of a high water table: A numerical study

NASA Astrophysics Data System (ADS)

Russo, David; Laufer, Asher; Bardhan, Gopali; Levy, Guy J.

2015-12-01

A citrus orchard planted on a structured, clay soil associated with a high water table, irrigated by drip irrigation system using treated waste water (TWW) and local well water (LWW) was considered here. The scope of the present study was to analyze transport of mixed-ion, interacting salts in a combined vadose zone-groundwater flow system focusing on the following issues: (i) long-term effects of irrigation with TWW on the response of the flow system, identifying the main factors (e.g., soil salinity, soil sodicity) that control these effects, and (ii) salinity control aiming at improving both crop productivity and groundwater quality. To pursue this two-fold goal, 3-D numerical simulations of field-scale flow and transport were performed for an extended period of time, considering realistic features of the soil, water table, crop, weather and irrigation, and the coupling between the flow and the transport through the dependence of the soil hydraulic functions, K(ψ) and θ(ψ), on soil solution concentration C, and sodium adsorption ratio, SAR. Results of the analyses suggest that in the case studied, the long-term effect of irrigation with TWW on the response of the flow system is attributed to the enhanced salinity of the TWW, and not to the increase in soil sodicity. The latter findings are attributed to: (i) the negative effect of soil salinity on water uptake, and the tradeoff between water uptake and drainage flux, and, concurrently, solute discharge below the root zone; and, (ii) the tradeoff between the effects of C and SAR on K(ψ) and θ(ψ). Furthermore, it was demonstrated that a data-driven protocol for soil salinity control, based on alternating irrigation water quality between TWW and desalinized water, guided by the soil solution salinity at the centroid of the soil volume active in water uptake, may lead to a substantial increase in crop yield, and to a substantial decrease in the salinity load in the groundwater.

Survival of multiple myeloma patients aged 65-70 years in the era of novel agents and autologous stem cell transplantation. A multicenter retrospective collaborative study of the Japanese Society of Myeloma and the European Myeloma Network.

PubMed

Ozaki, Shuji; Harada, Takeshi; Saitoh, Takayuki; Shimazaki, Chihiro; Itagaki, Mitsuhiro; Asaoku, Hideki; Kuroda, Yoshiaki; Chou, Takaaki; Yoshiki, Yumiko; Suzuki, Kenshi; Murakami, Hirokazu; Hayashi, Kunihiko; Mina, Roberto; Palumbo, Antonio; Shimizu, Kazuyuki

2014-01-01

Novel agents such as thalidomide, lenalidomide and bortezomib have dramatically changed the treatment paradigm of multiple myeloma (MM). However, it is not clear whether these agents improve the prognosis of elderly patients who have undergone autologous stem cell transplantation (auto-SCT). We retrospectively analyzed the outcome of 318 newly diagnosed patients aged 65–70 years who were treated between January 1, 2004, and December 31, 2009. As initial therapy, 192 patients were treated with conventional chemotherapy,88 with novel agent-containing regimens, 21 with conventional chemotherapy plus auto-SCT and the remaining 17 with novel agents plus auto-SCT. The median progression-free survival was 19.1, 24.5, 26.8 and 35.2 months, respectively, and the 5-year overall survival (OS) was 40, 62, 63 and 87%, respectively. Initial therapy with novel agents (p < 0.001) or auto-SCT (p < 0.02) significantly improved OS compared with the group without these treatment modalities. Salvage therapy with novel agents also significantly improved survival after relapse compared with conventional chemotherapy alone (p < 0.04). In a multivariate analysis, the use of novel agents was an independent prognostic factor significantly associated with extended OS(p < 0.003). These results indicate that novel agents and auto-SCT had a major impact on OS in eligible patients in this subgroup of MM. © 2014 S. Karger AG, Basel

Molecular profiling of multiple myeloma: from gene expression analysis to next-generation sequencing.

PubMed

Agnelli, Luca; Tassone, Pierfrancesco; Neri, Antonino

2013-06-01

Multiple myeloma is a fatal malignant proliferation of clonal bone marrow Ig-secreting plasma cells, characterized by wide clinical, biological, and molecular heterogeneity. Herein, global gene and microRNA expression, genome-wide DNA profilings, and next-generation sequencing technology used to investigate the genomic alterations underlying the bio-clinical heterogeneity in multiple myeloma are discussed. High-throughput technologies have undoubtedly allowed a better comprehension of the molecular basis of the disease, a fine stratification, and early identification of high-risk patients, and have provided insights toward targeted therapy studies. However, such technologies are at risk of being affected by laboratory- or cohort-specific biases, and are moreover influenced by high number of expected false positives. This aspect has a major weight in myeloma, which is characterized by large molecular heterogeneity. Therefore, meta-analysis as well as multiple approaches are desirable if not mandatory to validate the results obtained, in line with commonly accepted recommendation for tumor diagnostic/prognostic biomarker studies.

'Halophyte filters': the potential of constructed wetlands for application in saline aquaculture.

PubMed

De Lange, H J; Paulissen, M P C P; Slim, P A

2013-01-01

World consumption of seafood continues to rise, but the seas and oceans are already over-exploited. Land-based (saline) aquaculture may offer a sustainable way to meet the growing demand for fish and shellfish. A major problem of aquaculture is nutrient waste, as most of the nutrients added through feed are released into the environment in dissolved form. Wetlands are nature's water purifiers. Constructed wetlands are commonly used to treat contaminated freshwater effluent. Experience with saline systems is more limited. This paper explores the potential of constructed saline wetlands for treating the nutrient-rich discharge from land-based saline aquaculture systems. The primary function of constructed wetlands is water purification, but other ancillary benefits can also be incorporated into treatment wetland designs. Marsh vegetation enhances landscape beauty and plant diversity, and wetlands may offer habitat for fauna and recreational areas. Various approaches can be taken in utilizing plants (halophytes, macro-algae, micro-algae) in the treatment of saline aquaculture effluent. Their strengths and weaknesses are reviewed here, and a conceptual framework is presented that takes into account economic and ecological benefits as well as spatial constraints. Use of the framework is demonstrated for assessing various saline aquaculture systems in the southwestern delta region of the Netherlands.

CDK2 phosphorylation of Smad2 disrupts TGF-beta transcriptional regulation in resistant primary bone marrow myeloma cells.

PubMed

Baughn, Linda B; Di Liberto, Maurizio; Niesvizky, Ruben; Cho, Hearn J; Jayabalan, David; Lane, Joseph; Liu, Fang; Chen-Kiang, Selina

2009-02-15

Resistance to growth suppression by TGF-beta1 is common in cancer; however, mutations in this pathway are rare in hematopoietic malignancies. In multiple myeloma, a fatal cancer of plasma cells, malignant cells accumulate in the TGF-beta-rich bone marrow due to loss of both cell cycle and apoptotic controls. Herein we show that TGF-beta activates Smad2 but fails to induce cell cycle arrest or apoptosis in primary bone marrow myeloma and human myeloma cell lines due to its inability to activate G(1) cyclin-dependent kinase (CDK) inhibitors (p15(INK4b), p21(CIP1/WAF1), p27(KIP1), p57(KIP2)) or to repress c-myc and Bcl-2 transcription. Correlating with aberrant activation of CDKs, CDK-dependent phosphorylation of Smad2 on Thr(8) (pT8), a modification linked to impaired Smad activity, is elevated in primary bone marrow myeloma cells, even in asymptomatic monoclonal gammopathy of undetermined significance. Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. Our findings provide the first direct evidence that pT8 Smad2 couples dysregulation of CDK2 to TGF-beta resistance in primary cancer cells, and they suggest that disruption of Smad2 function by CDK2 phosphorylation acts as a mechanism for TGF-beta resistance in multiple myeloma.

Vitamin D Receptor Expression in Plasmablastic Lymphoma and Myeloma Cells Confers Susceptibility to Vitamin D

PubMed Central

Lyne, Linden; Spearman, Hayley; Buffa, Francesca M.; Soilleux, Elizabeth J.; Banham, Alison H.

2017-01-01

Plasmablastic B-cell malignancies include plasmablastic lymphoma and subsets of multiple myeloma and diffuse large B-cell lymphomaDLBCL. These diseases can be difficult to diagnose and treat, and they lack well-characterized cell line models. Here, immunophenotyping and FOXP1 expression profiling identified plasmablastic characteristics in DLBCL cell lines HLY-1 and SU-DHL-9, associated with CTNNAL1, HPGD, RORA, IGF1, and/or vitamin D receptor (VDR) transcription. We demonstrated VDR protein expression in primary plasmablastic tumor cells and confirmed in cell lines expression of both VDR and the metabolic enzyme CYP27B1, which catalyzes active vitamin D3 production. Although Vdr and Cyp27b1 transcription in normal B cells were activated by interleukin 4 (IL-4) and CD40 signaling, respectively, unstimulated malignant plasmablastic cells lacking IL-4 expressed both VDR and CYP27B1. Positive autoregulation evidenced intact VDR function in all plasmablastic lines, and inhibition of growth by active vitamin D3 was both dependent on MYC protein inhibition and could be enhanced by cotreatment with a synthetic ROR ligand SR-1078. Furthermore, a VDR polymorphism, FOK1, was associated with greater vitamin D3–dependent growth inhibition. In summary, HLY-1 provides an important model of strongly plasmablastic lymphoma, and disruption of VDR pathway activity may be of therapeutic benefit in both plasmablastic lymphoma and myeloma. PMID:28001444

THE IMMUNOGLOBULINS OF MICE

PubMed Central

Fahey, John L.; Wunderlich, John; Mishell, Robert

1964-01-01

Two subclasses of mouse 7S γ2-globulins are identified, and are designated γ2a- and γ2b-globulins. They are distinguished from 7S γ1-globulins, γ1A (β2A)-globulins, and γ1M-globulins of mouse serum. Antibody activity was detected among the γ2a-globulins and γ2b-globulins of hyperimmune mouse serum. γ2a- and γ2b-myeloma proteins were identified. The genetically determined isoantigen, Iga-1, was present on γ2a-myeloma proteins, but not on γ2b-myeloma proteins. These findings indicate a complexity among the 7S γ2-globulins which must be taken into account in structural, functional, and genetic studies of immunoglobulins. PMID:14206439

Pituitary adenylate cyclase-activating polypeptide is a potent inhibitor of the growth of light chain-secreting human multiple myeloma cells.

PubMed

Li, Min; Cortez, Shirley; Nakamachi, Tomoya; Batuman, Vecihi; Arimura, Akira

2006-09-01

Multiple myeloma represents a malignant proliferation of plasma cells in the bone marrow, which often overproduces immunoglobulin light chains. We have shown previously that pituitary adenylate cyclase-activating polypeptide (PACAP) markedly suppresses the release of proinflammatory cytokines from light chain-stimulated human renal proximal tubule epithelial cells and prevents the resulting tubule cell injury. In this study, we have shown that PACAP suppresses the proliferation of human kappa and lambda light chain-secreting multiple myeloma-derived cells. The addition of PACAP suppressed light chain-producing myeloma cell-stimulated interleukin 6 (IL-6) secretion by the bone marrow stromal cells (BMSCs). A specific antagonist to either the human PACAP-specific receptor or the vasoactive intestinal peptide receptor attenuated the suppressive effect of PACAP on IL-6 production in the adhesion of human multiple myeloma cells to BMSCs. The secretion of IL-6 by BMSCs was completely inhibited by 10(-9) mol/L PACAP, which also attenuated the phosphorylation of both p42/44 and p38 mitogen-activated protein kinases (MAPK) as well as nuclear factor-kappaB (NF-kappaB) activation in response to the adhesion of multiple myeloma cells to BMSCs, whereas the inhibition of p42/44 MAPK signaling attenuated PACAP action. The signaling cascades involved in the inhibitory effect of PACAP on IL-6-mediated paracrine stimulation of light chain-secreting myeloma cell growth was mediated through the suppression of p38 MAPK as well as modulation of activation of transcription factor NF-kappaB. These findings suggest that PACAP may be a new antitumor agent that directly suppresses light chain-secreting myeloma cell growth and indirectly affects tumor cell growth by modifying the bone marrow milieu of the multiple myeloma.

Challenging the current approaches to multiple myeloma- and other cancer-related bone diseases: from bisphosphonates to targeted therapy.

PubMed

Kleber, Martina; Udi, Josefina; Metzke, Barbara; Terpos, Evangelos; Roodmann, G David; Morgan, Gareth; Dispenzieri, Angela; Einsele, Hermann; Wäsch, Ralph; Engelhardt, Monika

2012-06-01

An international myeloma meeting entitled "Challenging the current approaches to multiple myeloma- and other cancer-related bone diseases: from bisphosphonates to targeted therapy" was held in Freiburg, Germany in July 2011 to discuss novel insights into and approaches to myeloma bone disease and other bone-seeking tumors. This review briefly summarizes the most prominent data of the meeting and current literature on our understanding of bone disease, the role of imaging techniques, operative interventions and systemic bone-seeking treatment, all of which should further improve our future therapeutic choices.

The simultaneous occurrence of multiple myeloma and JAK2 positive myeloproliferative neoplasms - Report on two cases

PubMed Central

Badelita, S; Dobrea, C; Colita, A; Dogaru, M; Dragomir, M; Jardan, C; Coriu, D

2015-01-01

Multiple myeloma and JAK2 positive chronic myeloproliferative neoplasms are hematologic malignancies with a completely different cellular origin. Two cases of simultaneous occurrence of multiple myeloma, one with primary myelofibrosis and another one with essential thrombocythemia are reported in this article. In such cases, an accurate diagnosis requires a molecular testing, including gene sequencing and differential diagnosis of pancytosis associated with splenic amyloidosis. In general, in such cases, of two coexisting malignant hematologic diseases, the treatment of the most aggressive one is recommended. For our two cases, it was decided to start a Velcade based therapy. The main concern was the medullar toxicity, especially when a multiple myeloma was associated with a primary myelofibrosis. Abbreviations:JAK2 = Janus kinase 2 gene, PMF = primary myelofibrosis, MPNs = myeloproliferative neoplasms, ET = essential thrombocythemia, PV = polycythemia vera, MM = multiple myeloma, WBC = white blood cells, Hb = haemoglobin, Ht = haematocrit, Plt = platelets, BMB = bone marrow biopsy, CBC = blood cell count, CT = computerized tomography, LAP = leukocyte alkaline phosphatase, MGUS = monoclonal gammopathy of undetermined significance. PMID:25914740

Melphalan-induced apoptosis in multiple myeloma cells is associated with a cleavage of Mcl-1 and Bim and a decrease in the Mcl-1/Bim complex.

PubMed

Gomez-Bougie, Patricia; Oliver, Lisa; Le Gouill, Steven; Bataille, Régis; Amiot, Martine

2005-12-01

Multiple myeloma (MM) is a rapidly fatal plasma-cell malignancy that evolves mainly in the bone marrow. Melphalan is widely used to treat patients with MM but as yet its mechanisms of action are poorly documented. In the current study, we demonstrate that melphalan induces a drastic downregulation of Mcl-1L, Bcl-x(L) and BimEL in human melphalan-sensitive myeloma cells while the most potent proapoptotic isoforms, BimL and S, are affected to a lesser extent. Moreover, Mcl-1L and BimEL disappearance is associated with the generation of proapoptotic cleaved forms generated by a caspase cleavage. In myeloma cells, we have previously shown that Mcl-1 neutralizes the proapoptotic function of Bim and therefore, prevents the activation of death effectors. In this study, we demonstrate that melphalan disrupts the Mcl-1/Bim complex whereas the Bcl-2/Bim complex is not modified. The disappearance of full length Mcl-1 allows the release of Bim isoforms, particularly L and S, which can exert their proapoptotic function and leads to Bax activation and cytochrome c release. Thus, we can hypothesize that the cleaved 26 kDa proapoptotic Mcl-1 and the 19 and 12 kDa of Bim, generated during melphalan treatment could contribute to the amplification loop of apoptosis.

A Next-Generation Sequencing Strategy for Evaluating the Most Common Genetic Abnormalities in Multiple Myeloma.

PubMed

Jiménez, Cristina; Jara-Acevedo, María; Corchete, Luis A; Castillo, David; Ordóñez, Gonzalo R; Sarasquete, María E; Puig, Noemí; Martínez-López, Joaquín; Prieto-Conde, María I; García-Álvarez, María; Chillón, María C; Balanzategui, Ana; Alcoceba, Miguel; Oriol, Albert; Rosiñol, Laura; Palomera, Luis; Teruel, Ana I; Lahuerta, Juan J; Bladé, Joan; Mateos, María V; Orfão, Alberto; San Miguel, Jesús F; González, Marcos; Gutiérrez, Norma C; García-Sanz, Ramón

2017-01-01

Identification and characterization of genetic alterations are essential for diagnosis of multiple myeloma and may guide therapeutic decisions. Currently, genomic analysis of myeloma to cover the diverse range of alterations with prognostic impact requires fluorescence in situ hybridization (FISH), single nucleotide polymorphism arrays, and sequencing techniques, which are costly and labor intensive and require large numbers of plasma cells. To overcome these limitations, we designed a targeted-capture next-generation sequencing approach for one-step identification of IGH translocations, V(D)J clonal rearrangements, the IgH isotype, and somatic mutations to rapidly identify risk groups and specific targetable molecular lesions. Forty-eight newly diagnosed myeloma patients were tested with the panel, which included IGH and six genes that are recurrently mutated in myeloma: NRAS, KRAS, HRAS, TP53, MYC, and BRAF. We identified 14 of 17 IGH translocations previously detected by FISH and three confirmed translocations not detected by FISH, with the additional advantage of breakpoint identification, which can be used as a target for evaluating minimal residual disease. IgH subclass and V(D)J rearrangements were identified in 77% and 65% of patients, respectively. Mutation analysis revealed the presence of missense protein-coding alterations in at least one of the evaluating genes in 16 of 48 patients (33%). This method may represent a time- and cost-effective diagnostic method for the molecular characterization of multiple myeloma. Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report

PubMed Central

Bringhen, Sara; Mateos, Maria-Victoria; Larocca, Alessandra; Facon, Thierry; Kumar, Shaji K.; Offidani, Massimo; McCarthy, Philip; Evangelista, Andrea; Lonial, Sagar; Zweegman, Sonja; Musto, Pellegrino; Terpos, Evangelos; Belch, Andrew; Hajek, Roman; Ludwig, Heinz; Stewart, A. Keith; Moreau, Philippe; Anderson, Kenneth; Einsele, Hermann; Durie, Brian G. M.; Dimopoulos, Meletios A.; Landgren, Ola; San Miguel, Jesus F.; Richardson, Paul; Sonneveld, Pieter; Rajkumar, S. Vincent

2015-01-01

We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective trials. At diagnosis, a geriatric assessment had been performed. An additive scoring system (range 0-5), based on age, comorbidities, and cognitive and physical conditions, was developed to identify 3 groups: fit (score = 0, 39%), intermediate fitness (score = 1, 31%), and frail (score ≥2, 30%). The 3-year overall survival was 84% in fit, 76% in intermediate-fitness (hazard ratio [HR], 1.61; P = .042), and 57% in frail (HR, 3.57; P < .001) patients. The cumulative incidence of grade ≥3 nonhematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR, 1.23; P = .217), and 34.0% in frail (HR, 1.74; P < .001) patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fitness (HR, 1.41; P = .052), and 31.2% in frail (HR, 2.21; P < .001) patients. Our frailty score predicts mortality and the risk of toxicity in elderly myeloma patients. The International Myeloma Working group proposes this score for the measurement of frailty in designing future clinical trials. These trials are registered at www.clinicaltrials.gov as #NCT01093136 (EMN01), #NCT01190787 (26866138MMY2069), and #NCT01346787 (IST-CAR-506). PMID:25628469

Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis.

PubMed

Boido, Marina; Piras, Antonio; Valsecchi, Valeria; Spigolon, Giada; Mareschi, Katia; Ferrero, Ivana; Vizzini, Andrea; Temi, Santa; Mazzini, Letizia; Fagioli, Franca; Vercelli, Alessandro

2014-08-01

Mesenchymal stromal cells (MSCs), after intraparenchymal, intrathecal and endovenous administration, have been previously tested for cell therapy in amyotrophic lateral sclerosis in the SOD1 (superoxide dismutase 1) mouse. However, every administration route has specific pros and cons. We administrated human MSCs (hMSCs) in the cisterna lumbaris, which is easily accessible and could be used in outpatient surgery, in the SOD1 G93A mouse, at the earliest onset of symptoms. Control animals received saline injections. Motor behavior was checked starting from 2 months of age until the mice were killed. Animals were killed 2 weeks after transplantation; lumbar motoneurons were stereologically counted, astrocytes and microglia were analyzed and quantified after immunohistochemistry and cytokine expression was assayed by means of real-time polymerase chain reaction. We provide evidence that this route of administration can exert strongly positive effects. Motoneuron death and motor decay were delayed, astrogliosis was reduced and microglial activation was modulated. In addition, hMSC transplantation prevented the downregulation of the anti-inflammatory interleukin-10, as well as that of vascular endothelial growth factor observed in saline-treated transgenic mice compared with wild type, and resulted in a dramatic increase in the expression of the anti-inflammatory interleukin-13. Our results suggest that hMSCs, when intracisternally administered, can exert their paracrine potential, influencing the inflammatory response of the host. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Analysis on the Alpinia katsumadai components of Zingiberaceae plants and their functions on myeloma resistance.

PubMed

Wang, Jue; Qiu, Rubiao; Yuan, Lianjing; Meng, Fei; Tang, Qian

2015-05-01

Generally speaking, zingiberaceae plants with sweet fragrance are commonly seen as perennial herbs that contains numerous well-known crude drugs and fragrant plants like Amomum villosum, Amomumtsao-ko, Ginger, Alpinia katsumadai and Radix curcumae, which are widely used in daily life. This paper analyzed chemical components of Alpinia katsumadai of zingiberaceae and applied several laminar analysis to further develop its active ingredients, aiming to make sure its function on tumor assistance. Actually, cardamomin contained in Alpinia katsumadai has been recorded to act notably in myeloma resistance, which was verified by cholecystokinin-octopeptide (CCK-8) in this paper. Cardamom in is proved to have multiple anti-myeloma effects, including myeloma cell activity and proliferation control, cell cycle retardant and apoptosis induction, which indicates its value in the field of medical pharmacy.

A novel option for reducing free light chains in myeloma kidney: supra-hemodiafiltration with endogenous reinfusion (HFR).

PubMed

Pasquali, Sonia; Iannuzzella, Francesco; Corradini, Mattia; Mattei, Silvia; Bovino, Achiropita; Stefani, Alfredo; Palladino, Giuseppe; Caiazzo, Marialuisa

2015-04-01

In myeloma cast nephropathy, fast reduction of serum free light chain (FLC) levels correlates with renal recovery. Recently, extracorporeal treatments using filters with a high-molecular weight cut-off have been successfully used for FLC removal. However, using these new filters, high cost and elevated albumin leakage are common drawbacks. We studied a new and cheaper therapeutic approach with adsorbent resins to evaluate its efficacy. We treated four patients, affected by dialysis-dependent acute kidney injury (AKI) due to biopsy proven de novo FLC myeloma cast nephropathy. Each patient underwent bortezomib chemotherapy and extracorporeal treatment with the supra-hemodiafiltration with endogenous reinfusion (HFR) technique (Supra-HFR, Bellco Mirandola, Modena, Italy). Supra-HFR is a kind of hemodiafiltration that utilizes separated convection, diffusion and adsorption. The sorbent cartridge has a high affinity for FLC (both κ and λ) but is able to re-infuse albumin, avoiding the need for albumin perfusions. Supra HFR treatments (4 h each) were carried out for eight consecutive days and then every other day. All patients showed a significant reduction of serum FLC, whereas serum albumin concentration remained unchanged. Renal function recovered in three out of four patients. FLC removal with adsorbent resins represents an effective therapeutic strategy that does not require replacement with albumin .

Hydrogen-rich saline promotes survival of retinal ganglion cells in a rat model of optic nerve crush.

PubMed

Sun, Jing-chuan; Xu, Tao; Zuo, Qiao; Wang, Ruo-bing; Qi, Ai-qing; Cao, Wen-luo; Sun, Ai-jun; Sun, Xue-jun; Xu, Jiajun

2014-01-01

To investigate the effect of molecular hydrogen (H2) in a rat model subjected to optic nerve crush (ONC). We tested the hypothesis that after optic nerve crush (ONC), retinal ganglion cell (RGC) could be protected by H₂. Rats in different groups received saline or hydrogen-rich saline every day for 14 days after ONC. Retinas from animals in each group underwent measurements of hematoxylin and eosin (H&E) staining, cholera toxin beta (CTB) tracing, gamma synuclein staining, and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining 2 weeks post operation. Flash visual evoked potentials (FVEP) and pupillary light reflex (PLR) were then tested to evaluate the function of optic nerve. The malondialdehyde (MDA) level in retina was evaluated. H&E, gamma synuclein staining and CTB tracing showed that the survival rate of RGCs in hydrogen saline-treated group was significantly higher than that in saline-treated group. Apoptosis of RGCs assessed by TUNEL staining were less observed in hydrogen saline-treated group. The MDA level in retina of H₂ group was much lower than that in placebo group. Furthermore, animals treated with hydrogen saline showed better function of optic nerve in assessments of FVEP and PLR. These results demonstrated that H₂ protects RGCs and helps preserve the visual function after ONC and had a neuroprotective effect in a rat model subjected to ONC.

Predicting the impact of combined therapies on myeloma cell growth using a hybrid multi-scale agent-based model.

PubMed

Ji, Zhiwei; Su, Jing; Wu, Dan; Peng, Huiming; Zhao, Weiling; Nlong Zhao, Brian; Zhou, Xiaobo

2017-01-31

Multiple myeloma is a malignant still incurable plasma cell disorder. This is due to refractory disease relapse, immune impairment, and development of multi-drug resistance. The growth of malignant plasma cells is dependent on the bone marrow (BM) microenvironment and evasion of the host's anti-tumor immune response. Hence, we hypothesized that targeting tumor-stromal cell interaction and endogenous immune system in BM will potentially improve the response of multiple myeloma (MM). Therefore, we proposed a computational simulation of the myeloma development in the complicated microenvironment which includes immune cell components and bone marrow stromal cells and predicted the effects of combined treatment with multi-drugs on myeloma cell growth. We constructed a hybrid multi-scale agent-based model (HABM) that combines an ODE system and Agent-based model (ABM). The ODEs was used for modeling the dynamic changes of intracellular signal transductions and ABM for modeling the cell-cell interactions between stromal cells, tumor, and immune components in the BM. This model simulated myeloma growth in the bone marrow microenvironment and revealed the important role of immune system in this process. The predicted outcomes were consistent with the experimental observations from previous studies. Moreover, we applied this model to predict the treatment effects of three key therapeutic drugs used for MM, and found that the combination of these three drugs potentially suppress the growth of myeloma cells and reactivate the immune response. In summary, the proposed model may serve as a novel computational platform for simulating the formation of MM and evaluating the treatment response of MM to multiple drugs.

Enhanced anticancer efficacy of snake venom combined with silica nanoparticles in a murine model of human multiple myeloma: molecular targets for cell cycle arrest and apoptosis induction.

PubMed

Al-Sadoon, Mohamed K; Rabah, Danny M; Badr, Gamal

2013-01-01

Multiple myeloma (MM) is a clonal disease of plasma cells that reside in the bone marrow (BM). MM is an incurable disease; thus, screening for novel anti-myeloma drugs remains critically important. We recently described a silica nanoparticle-based snake venom delivery model that targets cancer cells, but not normal cells. Using this model, we demonstrated a strong enhancement of the antitumor activity of snake venom extracted from Walterinnesia aegyptia (WEV) in two breast carcinoma cell lines when the venom was combined with silica nanoparticles (WEV+NP). In the present study, we aimed to delineate the in vivo therapeutic efficacy of WEV+NP in an MM-bearing experimental nude mouse model. We found that treatment with WEV+NP or WEV alone significantly inhibited tumor growth compared to treatment with NP or vehicle. WEV+NP- and WEV-treated cancer cells exhibited marked elevations in oxidative stress and robust reductions in the levels of interleukin-6 (IL-6) and B cell-activating factor (BAFF). WEV+NP also decreased the surface expression of the chemokine receptors CXCR3, CXCR4 and CXCR6 to a greater extent than WEV alone, and WEV+NP subsequently reduced migration in response to the cognate ligands CXCL10, CXCL12 and CXCL16. Furthermore, we found that WEV+NP strongly inhibited insulin-like growth factor 1 (EGF-1)- and IL-6-mediated MM cell proliferation, altered the cell cycle and enhanced the induction of apoptosis of MM cells. In addition, the results of treatment with WEV+NP or WEV alone revealed that the combination of WEV with NP robustly decreased the expression of cyclin D1, Bcl-2 and the phosphorylation of AKT; increased the expression of cyclin B1; altered the mitochondrial membrane potential; increased the activity of caspase-3, -8 and -9; and sensitized MM cells to growth arrest and apoptosis. Our data reveal the therapeutic potential of the nanoparticle-sustained delivery of snake venom to fight cancer cells. Copyright © 2013 Elsevier Inc. All rights

Multiple Myeloma: Clinical Updates From the American Society of Hematology Annual Meeting, 2017.

PubMed

Terpos, Evangelos

2018-05-01

The novel clinical data for myeloma that were presented in the 2017 Annual Meeting of the American Society of Hematology are summarized here. Studies with curative approach (CESAR) or prolonging progression-free survival (CENTAURUS) for patients with high-risk smoldering multiple myeloma (SMM) are described. Updated data from large phase III studies for patients with newly diagnosed MM (NDMM) who are eligible for autologous stem cell transplantation (ASCT) (EMN02, MRC XI) are described, along with the results of studies using novel anti-myeloma drug combinations for induction, consolidation, and maintenance as first-line therapy. The role of minimal residual disease for patients with MM is also discussed. We also present the results of novel phase III studies in patients with NDMM who are not eligible for ASCT (ALCYONE) and new data for their treatment. Recent updates of important studies in the field of relapsed/refractory MM (ASPIRE, POLLUX) along with novel immunotherapy approaches (anti-BCMA monoclonal antibodies, CART cells) are also reported. Finally, levofloxacin prophylaxis reduces febrile episodes and death events in NDMM, whereas 2 doses of high-dose influenza vaccine seem to maintain higher rates of seroprotection compared with those who received standard vaccination. All these data provide the basis for possible changes in the way we manage myeloma in the near future trying to "cure" the disease in many patients. Copyright © 2018 Elsevier Inc. All rights reserved.

The shaping and functional consequences of the dosage effect landscape in multiple myeloma.

PubMed

Samur, Mehmet K; Shah, Parantu K; Wang, Xujun; Minvielle, Stéphane; Magrangeas, Florence; Avet-Loiseau, Hervé; Munshi, Nikhil C; Li, Cheng

2013-10-02

Multiple myeloma (MM) is a malignant proliferation of plasma B cells. Based on recurrent aneuploidy such as copy number alterations (CNAs), myeloma is divided into two subtypes with different CNA patterns and patient survival outcomes. How aneuploidy events arise, and whether they contribute to cancer cell evolution are actively studied. The large amount of transcriptomic changes resultant of CNAs (dosage effect) pose big challenges for identifying functional consequences of CNAs in myeloma in terms of specific driver genes and pathways. In this study, we hypothesize that gene-wise dosage effect varies as a result from complex regulatory networks that translate the impact of CNAs to gene expression, and studying this variation can provide insights into functional effects of CNAs. We propose gene-wise dosage effect score and genome-wide karyotype plot as tools to measure and visualize concordant copy number and expression changes across cancer samples. We find that dosage effect in myeloma is widespread yet variable, and it is correlated with gene expression level and CNA frequencies in different chromosomes. Our analysis suggests that despite the enrichment of differentially expressed genes between hyperdiploid MM and non-hyperdiploid MM in the trisomy chromosomes, the chromosomal proportion of dosage sensitive genes is higher in the non-trisomy chromosomes. Dosage-sensitive genes are enriched by genes with protein translation and localization functions, and dosage resistant genes are enriched by apoptosis genes. These results point to future studies on differential dosage sensitivity and resistance of pro- and anti-proliferation pathways and their variation across patients as therapeutic targets and prognosis markers. Our findings support the hypothesis that recurrent CNAs in myeloma are selected by their functional consequences. The novel dosage effect score defined in this work will facilitate integration of copy number and expression data for identifying driver

Real-World Use of 3rd Line Therapy for Multiple Myeloma in Austria: An Austrian Myeloma Registry (AMR) Analysis of the Therapeutic Landscape and Clinical Outcomes prior to the Use of Next Generation Myeloma Therapeutics.

PubMed

Willenbacher, Ella; Weger, Roman; Rochau, Ursula; Siebert, Uwe; Willenbacher, Wolfgang

2016-01-01

Clinical trials demonstrate improving survival in patients with multiple myeloma (MM) after treatment. However, it is unclear whether increased survival translates to a similar benefit in a real world setting. We analyzed the overall survival of 347 multiple myeloma patients in Austria by means of a national registry (AMR), focused on results from 3rd and later lines of therapy. This benchmark was chosen to define a baseline prior to the broad application of upcoming 2nd generation drugs (carfilzomib, pomalidomide). Projected 10 years survival for patients with MM in Austria is estimated to be 56% in patients diagnosed in between the years 2011-2014, 21% in patients with a diagnosis made between 2000-2005, and 39% in those with a diagnosis made between 2006-2010). For the same intervals a significant increase in the use of both bortezomib, lenalidomide and thalidomide-so called IMiDs (from 2005 onwards) and their simultaneous use in combination therapies (from 2010 onwards) could be shown. The use of autologous transplantation (ASCT) remained more or less constant at ~ 35% of patients in the 1st line setting over the whole period, comparing well to international practice patterns, while the use of 2nd line ASCT increased from 5.5% to 18.7% of patients. Patients in 3rd or later line treatment (n = 105), showed that even in relapsed and refractory disease median survival was 27 months with a considerable proportion of long-term survivors (~20%). With the expected emergence of additional active anti-myeloma compounds, we aim to assess survival in patients with relapsed and refractory MM.

Abnormal neural activation patterns underlying working memory impairment in chronic phencyclidine-treated mice.

PubMed

Arime, Yosefu; Akiyama, Kazufumi

2017-01-01

Working memory impairment is a hallmark feature of schizophrenia and is thought be caused by dysfunctions in the prefrontal cortex (PFC) and associated brain regions. However, the neural circuit anomalies underlying this impairment are poorly understood. The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP) mouse model of schizophrenia, and to identify the neural substrates of working memory. To address this issue, we conducted the following experiments for mice after withdrawal from chronic administration (14 days) of either saline or PCP (10 mg/kg): (1) a discrete paired-trial variable-delay task in T-maze to assess working memory, and (2) brain-wide c-Fos mapping to identify activated brain regions relevant to this task performance either 90 min or 0 min after the completion of the task, with each time point examined under working memory effort and basal conditions. Correct responses in the test phase of the task were significantly reduced across delays (5, 15, and 30 s) in chronic PCP-treated mice compared with chronic saline-treated controls, suggesting delay-independent impairments in working memory in the PCP group. In layer 2-3 of the prelimbic cortex, the number of working memory effort-elicited c-Fos+ cells was significantly higher in the chronic PCP group than in the chronic saline group. The main effect of working memory effort relative to basal conditions was to induce significantly increased c-Fos+ cells in the other layers of prelimbic cortex and the anterior cingulate and infralimbic cortex regardless of the different chronic regimens. Conversely, this working memory effort had a negative effect (fewer c-Fos+ cells) in the ventral hippocampus. These results shed light on some putative neural networks relevant to working memory impairments in mice chronically treated with PCP, and emphasize the importance of the layer 2-3 of the prelimbic cortex of the PFC.

Abnormal neural activation patterns underlying working memory impairment in chronic phencyclidine-treated mice

PubMed Central

Akiyama, Kazufumi

2017-01-01

Working memory impairment is a hallmark feature of schizophrenia and is thought be caused by dysfunctions in the prefrontal cortex (PFC) and associated brain regions. However, the neural circuit anomalies underlying this impairment are poorly understood. The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP) mouse model of schizophrenia, and to identify the neural substrates of working memory. To address this issue, we conducted the following experiments for mice after withdrawal from chronic administration (14 days) of either saline or PCP (10 mg/kg): (1) a discrete paired-trial variable-delay task in T-maze to assess working memory, and (2) brain-wide c-Fos mapping to identify activated brain regions relevant to this task performance either 90 min or 0 min after the completion of the task, with each time point examined under working memory effort and basal conditions. Correct responses in the test phase of the task were significantly reduced across delays (5, 15, and 30 s) in chronic PCP-treated mice compared with chronic saline-treated controls, suggesting delay-independent impairments in working memory in the PCP group. In layer 2–3 of the prelimbic cortex, the number of working memory effort-elicited c-Fos+ cells was significantly higher in the chronic PCP group than in the chronic saline group. The main effect of working memory effort relative to basal conditions was to induce significantly increased c-Fos+ cells in the other layers of prelimbic cortex and the anterior cingulate and infralimbic cortex regardless of the different chronic regimens. Conversely, this working memory effort had a negative effect (fewer c-Fos+ cells) in the ventral hippocampus. These results shed light on some putative neural networks relevant to working memory impairments in mice chronically treated with PCP, and emphasize the importance of the layer 2–3 of the prelimbic cortex of the PFC. PMID:29253020

Old but Still Relevant: High Resolution Electrophoresis and Immunofixation in Multiple Myeloma.

PubMed

Misra, Aroonima; Mishra, Jyoti; Chandramohan, Jagan; Sharma, Atul; Raina, Vinod; Kumar, Rajive; Soni, Sushant; Chopra, Anita

2016-03-01

High resolution electrophoresis (HRE) and immunofixation (IFX) of serum and urine are integral to the diagnostic work-up of multiple myeloma. Unusual electrophoresis patterns are common and may be misinterpreted. Though primarily the responsibility of the hematopathologist, clinicians who are responsible for managing myelomas may benefit from knowledge of these. In this review article we intend to discuss the patterns and importance of electrophoresis in present day scenario. Patterns of HRE and IFX seen in our laboratory over the past 15 years were studied. Monoclonal proteins are seen on HRE as sharply defined bands, sometimes two, lying from γ- to α-globulin regions on a background of normal, increased or decreased polyclonal γ-globulins, showing HRE to be a rapid and dependable method of detecting M-protein in serum or urine. Immunofixation complements HRE and due to its greater sensitivity, is able to pick up small or light chain bands, not apparent on electrophoresis, including biclonal disease even when electrophoresis shows only one M-band. Special features liable to misinterpretation are discussed. Familiarity with the interpretation of the varied patterns seen in health and disease is essential for providing dependable laboratory support in the management of multiple myeloma.

Investigation of the antioxidant status in multiple myeloma patients: effects of therapy.

PubMed

Mehdi, Wesen A; Zainulabdeen, Jwan A; Mehde, Atheer A

2013-01-01

Multiple myeloma is a malignant silent incurable plasma cell disorder. The present study aimed to assessed the activation of the oxidative stress pathway in affected patients. Advanced oxidation protein products (AOPPs), malondialdehyde (MDA), adenosine deaminase (ADA), total antioxidant capacity (TAC) levels, glutathione, ascorbic acid (vitamin C), α-tocopherol (vitamin E) in addition to related enzymes glutathione peroxidase (GSH-Px), glutathione reductase (GSH-R) and superoxide dismutase (SOD) were analyzed in sixty patients with multiple myeloma before and after one month treatment with induction therapy. The results of the study showed a significant elevation in AOPPs, MDA, ADA levels in patients with multiple myeloma before and after treatment in comparison to healthy control samples In contrast TAC glutathione, vitamin C and E, and the antioxidant enzymes levels were decreased significantly. On comparing samples of MM patients after treatment, there was significant increase of TAC glutathione, vitamin C and E, and the antioxidant enzymes in parallel with decreasing AOPPs, MDA and ADA levels in comparison with samples of patients before treatment. The results indicate oxidative stress and DNA damage activity increase in MM and are alleviated in response to therapy.

Cytogenetic effects of sildenafil citrate (Viagra) on SWR/J mouse bone marrow cells.

PubMed

Abou-Tarboush, Faisal Mohamed; Abdel-Samad, Mohamed Fathy

2010-10-01

The present study was conducted to investigate the cytogenetic effects of sildenafil citrate in SWR/J mouse bone marrow cells. Thirty-six males and 36 females were used and divided into four groups. Each group contained 18 animals (9 males and 9 females), weighing 30-35 g. These animals were orally administered with a single dose of 13, 26 or 40 mg/kg sildenafil citrate solution. A control group received normal saline in an identical condition. The animals were sacrificed at 12, 24 or 48 h, after the treatment. Chromosome aberrations were investigated in 50 metaphases per animal. No significant differences in the percentages of mitotic indices or in the frequencies of chromosome aberrations were observed between treated male and female mice at any doses or at any time intervals used, therefore, data from the two sexes were pooled when analyzed statistically. No significant (p < 0.05) differences in the percentages of mitotic indices or in the frequencies of chromosome aberrations were observed between sildenafil citrate-treated groups and the control group at any doses or at any time intervals used. However, the percentages of centromeric adhesions increased significantly (p < 0.01) in treated groups as compared with the control group at all doses and at all time intervals used. In conclusion, the results of the present study suggest that sildenafil citrate does not have cytogenetic effects on mouse bone marrow cells, but the centromeric adhesions induced by this drug need further studies to confirm them and to investigate the possible mechanism(s) responsible for such effect.

Cytogenetic effects of sildenafil citrate (Viagra) on SWR/J mouse bone marrow cells

PubMed Central

Abou-Tarboush, Faisal Mohamed; Abdel-Samad, Mohamed Fathy

2010-01-01

The present study was conducted to investigate the cytogenetic effects of sildenafil citrate in SWR/J mouse bone marrow cells. Thirty-six males and 36 females were used and divided into four groups. Each group contained 18 animals (9 males and 9 females), weighing 30–35 g. These animals were orally administered with a single dose of 13, 26 or 40 mg/kg sildenafil citrate solution. A control group received normal saline in an identical condition. The animals were sacrificed at 12, 24 or 48 h, after the treatment. Chromosome aberrations were investigated in 50 metaphases per animal. No significant differences in the percentages of mitotic indices or in the frequencies of chromosome aberrations were observed between treated male and female mice at any doses or at any time intervals used, therefore, data from the two sexes were pooled when analyzed statistically. No significant (p < 0.05) differences in the percentages of mitotic indices or in the frequencies of chromosome aberrations were observed between sildenafil citrate-treated groups and the control group at any doses or at any time intervals used. However, the percentages of centromeric adhesions increased significantly (p < 0.01) in treated groups as compared with the control group at all doses and at all time intervals used. In conclusion, the results of the present study suggest that sildenafil citrate does not have cytogenetic effects on mouse bone marrow cells, but the centromeric adhesions induced by this drug need further studies to confirm them and to investigate the possible mechanism(s) responsible for such effect. PMID:23961094

Hemophagocytic syndrome in a cat with multiple myeloma.

PubMed

Dunbar, Mark D; Lyles, Sarah

2013-03-01

An 11-year-old, castrated male, Domestic Medium Hair cat was presented to the University of Florida Small Animal Hospital with a 2-week history of upper respiratory infection and increased serum globulins, as reported by the referring veterinarian. Physical examination was unremarkable other than melanosis of the left iris, with no evidence of ocular, nasal, or respiratory disease. Laboratory abnormalities included moderate nonregenerative anemia, mild leukopenia, mild hyperfibrinogenemia, severe hyperglobulinemia, mild hypoalbuminemia, and hypocholesterolemia. Abdominal radiographs and ultrasonographic examination revealed mild splenomegaly with no other abnormalities. Thoracic radiographs revealed no abnormalities. Cytologic evaluation of fine-needle aspirates from the spleen, liver, and bone marrow revealed numerous plasma cells and many vacuolated macrophages exhibiting marked phagocytosis of mature erythrocytes and platelets, occasionally metarubricytes and leukocytes, and rarely plasma cells. The cytologic interpretation was multiple myeloma and associated hemophagocytic syndrome (HPS). Serum protein electrophoresis revealed a monoclonal gammopathy, providing further evidence for a multiple myeloma. To the authors' knowledge, this is the first report of HPS secondary to neoplasia in a cat. © 2012 American Society for Veterinary Clinical Pathology.

[The combination of chronic myeloid leukemia and multiple myeloma in one patient].

PubMed

Romanenko, N A; Bessmel'tsev, S S; Udal'eva, V Iu; Zenina, M N; Martynkevich, I S; Rugal', V I; Abdulkadyrov, K M

2013-01-01

The article describes the clinical observation of a patient with simultaneous course of lymphoid and myeloid neoplasms. The patient developed two diseases--chronic myeloid leukemia (CML) and multiple myeloma (MM), which were confirmed by corroborated hemogram, myelogram, immunophenotyping of bone marrow cells, biopsy, immunohistochemical, cytogenetic, biochemical and radiological studies. Target therapy of CML with tyrosine kinase inhibitors (imatinib at the standard dose of 400 mg per day) has provided a complete cytogenetic remission at 6 months and major molecular response at 18 months of treatment. Administration of 2 courses of programmed treatment "BD" > (bortezomib + dexamethasone) resulted in a very good partial response, which was maintained through a year and a half. However, against the background of programmed treatment there were developed complications as polyneuropathy of grade 2, which was treated with thioctacide, milgamy, and anemia of grade 2, successfully treated with epoetin beta. Subsequently, the patient was administered continuously with imatinib 400 mg that kept the major molecular response. Relapsed MM was revealed in 20 months and confirmed by a full clinical and hematological examination. The absence of organ dysfunction allowed choosing a supervisory tactics for the patient.

Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway.

PubMed

Tremblay-LeMay, Rosemarie; Rastgoo, Nasrin; Chang, Hong

2018-03-27

Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.

IgG4 plasma cell myeloma: new insights into the pathogenesis of IgG4-related disease.

PubMed

Geyer, Julia T; Niesvizky, Ruben; Jayabalan, David S; Mathew, Susan; Subramaniyam, Shivakumar; Geyer, Alexander I; Orazi, Attilio; Ely, Scott A

2014-03-01

IgG4-related disease is a newly described systemic fibroinflammatory process, characterized by increase in IgG4-positive plasma cells. Its pathogenesis, including the role of IgG4, remains poorly understood. Plasma cell myeloma is typically associated with a large monoclonal serum spike, which is frequently of IgG isotype. We sought to identify and characterize a subset of IgG4-secreting myeloma, as it may provide a biological model of disease with high serum levels of IgG4. Six out of 158 bone marrow biopsies (4%) from patients with IgG myeloma expressed IgG4. Four patients were men and two were women, with a mean age of 64 (range 53-87) years. Imaging showed fullness of pancreatic head (1), small non-metabolic lymphadenopathy (1), and bone lytic lesions (6). Two patients developed necrotizing fasciitis. All had elevated serum M-protein (mean 2.4, range 0.5-4.2 g/dl), and none had definite signs or symptoms of IgG4-related disease. Four myelomas had plasmablastic morphology. Four had kappa and two had lambda light chain expression. Three cases expressed CD56. Two patients had a complex karyotype. In conclusion, the frequency of IgG4 myeloma correlates with the normal distribution of IgG4 isoform. The patients with IgG4 myeloma appear to have a high rate of plasmablastic morphology and could be predisposed to necrotizing fasciitis. Despite high serum levels of IgG4, none had evidence of IgG4-related disease. These findings suggest that the increased number of IgG4-positive plasma cells is not the primary etiologic agent in IgG4-related disease. Elevated serum levels of IgG4 is not sufficient to produce the typical disease presentation and should not be considered diagnostic of IgG4-related disease.

Plasma Cell Neoplasms (Including Multiple Myeloma)—Health Professional Version

Cancer.gov

There are several types of plasma cell neoplasms, including monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, and multiple myeloma. Find evidence-based information on plasma cell neoplasms treatment, research, and statistics.

Plasma Cell Neoplasms (Including Multiple Myeloma)—Patient Version

Cancer.gov

Plasma cell neoplasms occur when abnormal plasma cells form cancerous tumors. When there is only one tumor, the disease is called a plasmacytoma. When there are multiple tumors, it is called multiple myeloma. Start here to find information on plasma cell neoplasms treatment, research, and statistics.

Investigations in Marine Chemistry: Salinity I.

ERIC Educational Resources Information Center

Schlenker, Richard M.

Presented is a unit designed for curriculum infusion and which relies on the hands-on discovery method as an instructive device. The student is introduced to the theory of a functioning salt water conductivity meter. The student explores the resistance of salt water as salinity increases and he treats the data which he has gathered,…

Massive macroglossia, amyloidosis and myeloma.

PubMed Central

Jacobs, P.; Sellars, S.; King, H. S.

1988-01-01

A 74 year old man with light-chain myeloma developed amyloidosis with macroglossia after 10 years of therapy with alkylating agents. Over a 2-year period his tongue enlarged to persistently protrude from his mouth, inhibit his speech, interfere with normal swallowing and eventually threaten his airway. As a life-saving procedure the tumorous anterior two-thirds of the tongue was resected, with excellent primary healing. Within two weeks the patient's speech became comprehensible and his ability to eat returned to normal. Although rare in amyloidosis, massive macroglossia may occur and surgical correction is easily achieved. Images Figure 1 PMID:3150784

Stokes shift spectroscopy for the early diagnosis of epithelial precancers in DMBA treated mouse skin carcinogenesis

NASA Astrophysics Data System (ADS)

Jeyasingh, Ebenezar; Singaravelu, Ganesan; Prakasarao, Aruna

2018-02-01

In this study, we aim to characterize the tissue transformation in dimethylbenz(a)anthracene (DMBA) treated mouse skin tumor model using stokes shift spectroscopy (SSS) technique for early detection of the neoplastic changes. Stokes shift (SS) spectra measured by scanning both excitation and emission wavelength simultaneously with a fixed wavelength of interval (Δλ=20 nm) in vivo from 33 DMBA treated animals and 6 control animals. The SS spectra of normal (n=6), hyperplasia (n=10), dysplasia (n=10), and WDSCC (n=13) of mice skin shows the distinct peaks around 300, 350, and 386 nm may be attributed to tryptophan, collagen, and NADH respectively. From the observed spectral differences and the ratio variables that resulted in better classification between groups, it is concluded that tryptophan, collagen, and NADH are the key fluorophores that undergo changes during tissue transformation process and hence they can be targeted as tumor markers for early neoplastic changes.

The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma.

PubMed

Munugalavadla, V; Mariathasan, S; Slaga, D; Du, C; Berry, L; Del Rosario, G; Yan, Y; Boe, M; Sun, L; Friedman, L S; Chesi, M; Leif Bergsagel, P; Ebens, A

2014-01-16

The phosphatidylinositol 3'-kinase (PI3K) pathway is dysregulated in multiple myeloma (MM); we therefore tested a highly selective class I PI3K inhibitor, GDC-0941, for anti-myeloma activity. Functional and mechanistic studies were first performed in MM cell lines, then extended to primary MM patient samples cultured in vitro. GDC-0941 was then assessed as a single agent and in various combinations in myeloma tumor xenograft models. We show p110 α and β are the predominant PI3K catalytic subunits in MM and that a highly selective class I PI3K inhibitor, GDC-0941, has robust activity as a single agent to induce cell cycle arrest and apoptosis of both MM cell lines and patient myeloma cells. Mechanistic studies revealed an induction of cell cycle arrest at G0/G1, with decreased phospho-FoxO1/3a levels, decreased cyclin D1 and c-myc expression, and an increase in the cell cycle inhibitor, p27kip. Induction of apoptosis correlated with increased expression of the pro-apoptotic BH3-only protein BIM, cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP). In vitro, GDC-0941 synergized with dexamethasone (Dex) and lenalidomide (combination index values of 0.3-0.4 and 0.4-0.8, respectively); in vivo GDC-0941 has anti-myeloma activity and significantly increases the activity of the standard of care agents in several murine xenograft tumor models (additional tumor growth inhibition of 37-53% (Dex) and 22-72% (lenalidomide)). These data provide a clear therapeutic hypothesis for the inhibition of PI3K and provide a rationale for clinical development of GDC-0941 in myeloma.

Multiple myeloma and family history of lymphohaematopoietic cancers: Results from the International Multiple Myeloma Consortium.

PubMed

Schinasi, Leah H; Brown, Elizabeth E; Camp, Nicola J; Wang, Sophia S; Hofmann, Jonathan N; Chiu, Brian C; Miligi, Lucia; Beane Freeman, Laura E; de Sanjose, Silvia; Bernstein, Leslie; Monnereau, Alain; Clavel, Jacqueline; Tricot, Guido J; Atanackovic, Djordje; Cocco, Pierluigi; Orsi, Laurent; Dosman, James A; McLaughlin, John R; Purdue, Mark P; Cozen, Wendy; Spinelli, John J; de Roos, Anneclaire J

2016-10-01

Family clusters of multiple myeloma (MM) suggest disease heritability. Nevertheless, patterns of inheritance and the importance of genetic versus environmental risk factors in MM aetiology remain unclear. We pooled data from eleven case-control studies from the International Multiple Myeloma Consortium to characterize the association of MM risk with having a first-degree relative with a history of a lympho-haematapoietic cancer. Unconditional logistic regression models, adjusted for study, sex, age and education level, were used to estimate associations between MM risk and having a first-degree relative with a history of non-Hodgkin lymphoma, Hodgkin lymphoma, leukaemia or MM. Sex, African American race/ethnicity and age were explored as effect modifiers. A total of 2843 cases and 11 470 controls were included. MM risk was elevated in association with having a first-degree relative with any lympho-haematapoietic cancer (Odds Ratio (OR) = 1·29, 95% Confidence Interval (CI): 1·08-1·55). The association was particularly strong for having a first-degree relative with MM (OR = 1·90, 95% CI: 1·26-2·87), especially among men (OR = 4·13, 95% CI: 2·17-7·85) and African Americans (OR = 5·52, 95% CI: 1·87-16·27).These results support the hypothesis that genetic inheritance plays a role in MM aetiology. Future studies are warranted to characterize interactions of genetic markers with environmental exposures. © 2016 John Wiley & Sons Ltd.

Enhancement of Anaerobic Digestion to Treat Saline Sludge from Recirculating Aquaculture Systems

PubMed Central

Luo, Guo-zhi; Ma, Niannian; Li, Ping; Tan, Hong-xin; Liu, Wenchang

2015-01-01

The effectiveness of carbohydrate addition and the use of ultrasonication as a pretreatment for the mesophilic anaerobic digestion of saline aquacultural sludge was assessed. Analyses were conducted using an anaerobic sequencing batch reactor (ASBR), which included stopped gas production attributed to the saline inhibition. After increasing the C : N ratio, gas production was observed, and the total chemical oxygen demand (TCOD) removal efficiency increased from 75% to 80%. The TCOD removal efficiency of the sonication period was approximately 85%, compared to 75% for the untreated waste. Ultrasonication of aquaculture sludge was also found to enhance the gas production rate and the TCOD removal efficiency. The average volatile fatty acid (VFA) to alkalinity ratios ranged from 0.1 to 0.05, confirming the stability of the digesters. Furthermore, soluble chemical oxygen demand (SCOD), VFA, and PO4 3− concentrations increased in the effluents. There was a 114% greater gas generation during the ultrasonication period, with an average production of 0.08 g COD/L·day−1. PMID:26301258

Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model.

PubMed

Menu, Eline; Jernberg-Wiklund, Helena; Stromberg, Thomas; De Raeve, Hendrik; Girnita, Leonard; Larsson, Olle; Axelson, Magnus; Asosingh, Kewal; Nilsson, Kenneth; Van Camp, Ben; Vanderkerken, Karin

2006-01-15

Insulin-like growth factor 1 (IGF-1) plays a pleiotropic role in multiple myeloma (MM), that is, in survival, proliferation, chemotaxis, and angiogenesis. Strategies targeting the IGF-1 receptor (IGF-1R) may therefore be important to develop efficient anti-MM agents. In this work we investigated the effect of an IGF-1R tyrosine kinase (IGF-1RTK) inhibitor (picropodophyllin or PPP) in the 5T33MM mouse model. In vitro data showed that PPP reduced IGF-1R autophosphorylation and downstream ERK activation, leading to inhibition of IGF-1-stimulated proliferation and vascular endothelial growth factor (VEGF) secretion of MM cells. In an in vivo study, PPP reduced the bone marrow tumor burden and serum paraprotein in 5T33MM mice by 77% and 90%, respectively, compared to vehicle-treated animals. Angiogenesis was assessed by quantifying the microvessel density on CD31-stained paraffin sections and this was reduced by 60% in the PPP-treated group. In a separate survival experiment, Kaplan-Meier analysis demonstrated a significant increase in survival in PPP-treated 5T33MM animals compared to the vehicle controls (28 versus 18 days). These data suggest that the IGF-1RTK inhibitor PPP possesses a marked antitumor activity and strongly points to the possibility of using IGF-1R inhibitors in the treatment of MM.

Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter case series.

PubMed

Wolf, Jeffrey; Richardson, Paul G; Schuster, Michael; LeBlanc, Annette; Walters, Ian B; Battleman, David S

2008-10-01

Bortezomib therapy has become an important part of the standard of care for patients with relapsed multiple myeloma, and preliminary clinical evidence suggests that bortezomib retreatment in patients previously treated with the drug may prolong disease control. This retrospective study was designed to clarify the utility of bortezomib as a repeat therapy. We reviewed records from 3 major cancer centers that had participated in the phase II (SUMMIT or CREST) or phase III (APEX) registration studies to identify patients who were subsequently retreated off protocol with bortezomib-based therapy. We found 22 patients who received bortezomib retreatment following a 60 or more day gap between bortezomib treatments. Twelve patients had intervening therapy between initial bortezomib treatment and bortezomib retreatment. During retreatment, 14 of 22 patients received bortezomib in combination with another antineoplastic agent. The overall response rate for bortezomib retreatment was 50% (9% complete responses). The median length of retreatment was 5.1 months in responding patients and 2.4 months in nonresponding patients. Therapy was terminated due to unmanageable toxicity in 2 patients during retreatment, compared with 6 patients during initial treatment. During retreatment, no patients required dose reduction due to peripheral neuropathy, compared to 4 patients during their initial treatment. Thus, bortezomib retreatment appears to be safe and effective. Favorable observed response rates with bortezomib retreatment suggest that it may be a viable option for relapsed or refractory multiple myeloma, even in patients previously exposed to bortezomib.

Vitamin D Receptor Expression in Plasmablastic Lymphoma and Myeloma Cells Confers Susceptibility to Vitamin D.

PubMed

Gascoyne, Duncan M; Lyne, Linden; Spearman, Hayley; Buffa, Francesca M; Soilleux, Elizabeth J; Banham, Alison H

2017-03-01

Plasmablastic B-cell malignancies include plasmablastic lymphoma and subsets of multiple myeloma and diffuse large B-cell lymphomaDLBCL. These diseases can be difficult to diagnose and treat, and they lack well-characterized cell line models. Here, immunophenotyping and FOXP1 expression profiling identified plasmablastic characteristics in DLBCL cell lines HLY-1 and SU-DHL-9, associated with CTNNAL1, HPGD, RORA, IGF1, and/or vitamin D receptor (VDR) transcription. We demonstrated VDR protein expression in primary plasmablastic tumor cells and confirmed in cell lines expression of both VDR and the metabolic enzyme CYP27B1, which catalyzes active vitamin D3 production. Although Vdr and Cyp27b1 transcription in normal B cells were activated by interleukin 4 (IL-4) and CD40 signaling, respectively, unstimulated malignant plasmablastic cells lacking IL-4 expressed both VDR and CYP27B1. Positive autoregulation evidenced intact VDR function in all plasmablastic lines, and inhibition of growth by active vitamin D3 was both dependent on MYC protein inhibition and could be enhanced by cotreatment with a synthetic ROR ligand SR-1078. Furthermore, a VDR polymorphism, FOK1, was associated with greater vitamin D3-dependent growth inhibition. In summary, HLY-1 provides an important model of strongly plasmablastic lymphoma, and disruption of VDR pathway activity may be of therapeutic benefit in both plasmablastic lymphoma and myeloma. Copyright © 2017 by the Endocrine Society.

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways.

PubMed

Kobayashi, T; Kuroda, J; Ashihara, E; Oomizu, S; Terui, Y; Taniyama, A; Adachi, S; Takagi, T; Yamamoto, M; Sasaki, N; Horiike, S; Hatake, K; Yamauchi, A; Hirashima, M; Taniwaki, M

2010-04-01

Galectins constitute a family of lectins that specifically exhibit the affinity for beta-galactosides and modulate various biological events. Galectin-9 is a tandem-repeat type galectin with two carbohydrate recognition domains and has recently been shown to have an anti-proliferative effect on cancer cells. We investigated the effect of recombinant protease-resistant galectin-9 (hGal9) on multiple myeloma (MM). In vitro, hGal9 inhibited the cell proliferation of five myeloma cell lines examined, including a bortezomib-resistant subcell line, with IC(50) between 75.1 and 280.0 nM, and this effect was mediated by the induction of apoptosis with the activation of caspase-8, -9, and -3. hGal9-activated Jun NH(2)-terminal kinase (JNK) and p38 MAPK signaling pathways followed by H2AX phosphorylation. Importantly, the inhibition of either JNK or p38 MAPK partly inhibited the anti-proliferative effect of hGal9, indicating the crucial role of these pathways in the anti-MM effect of hGal9. hGal9 also induced cell death in patient-derived myeloma cells, some with poor-risk factors, such as chromosomal deletion of 13q or translocation t(4;14)(p16;q32). Finally, hGal9 potently inhibited the growth of human myeloma cells xenografted in nude mice. These suggest that hGal9 is a new therapeutic target for MM that may overcome resistance to conventional chemotherapy.

Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Buck, Nicole E., E-mail: nicole.buck@mcri.edu.au; Pennell, Samuel D.; Wood, Leonie R.

Highlights: Black-Right-Pointing-Pointer Fetal cells were transplanted into a methylmalonic acid mouse model. Black-Right-Pointing-Pointer Cell engraftment was detected in liver, spleen and bone marrow. Black-Right-Pointing-Pointer Biochemical disease correction was measured in blood samples. Black-Right-Pointing-Pointer A double dose of 5 million cells (1 week apart) proved more effective. Black-Right-Pointing-Pointer Higher levels of engraftment may be required for greater disease correction. -- Abstract: Methylmalonic aciduria is a rare disorder caused by an inborn error of organic acid metabolism. Current treatment options are limited and generally focus on disease management. We aimed to investigate the use of fetal progenitor cells to treat this disordermore » using a mouse model with an intermediate form of methylmalonic aciduria. Fetal liver cells were isolated from healthy fetuses at embryonic day 15-17 and intravenously transplanted into sub-lethally irradiated mice. Liver donor cell engraftment was determined by PCR. Disease correction was monitored by urine and blood methylmalonic acid concentration and weight change. Initial studies indicated that pre-transplantation sub-lethal irradiation followed by transplantation with 5 million cells were suitable. We found that a double dose of 5 million cells (1 week apart) provided a more effective treatment. Donor cell liver engraftment of up to 5% was measured. Disease correction, as defined by a decrease in blood methylmalonic acid concentration, was effected in methylmalonic acid mice transplanted with a double dose of cells and who showed donor cell liver engraftment. Mean plasma methylmalonic acid concentration decreased from 810 {+-} 156 (sham transplanted) to 338 {+-} 157 {mu}mol/L (double dose of 5 million cells) while mean blood C3 carnitine concentration decreased from 20.5 {+-} 4 (sham transplanted) to 5.3 {+-} 1.9 {mu}mol/L (double dose of 5 million cells). In conclusion, higher levels of

Value of FDG PET in the assessment of patients with multiple myeloma.

PubMed

Bredella, Miriam A; Steinbach, Lynne; Caputo, Gary; Segall, George; Hawkins, Randall

2005-04-01

Our objective was to evaluate if whole-body PET with FDG is able to detect bone marrow involvement in patients with multiple myeloma and to assess its appearance and distribution pattern. Seventeen whole-body FDG PET scans were performed in 13 patients with multiple myeloma. Four patients were referred for evaluation of extent of disease pretherapy and nine patients were referred for assessment of therapy response (chemotherapy, radiation therapy, bone marrow transplant). FDG PET images were evaluated for distribution and uptake pattern. Standardized uptake values were obtained to quantify FDG uptake. Results of other imaging examinations (MRI, CT, radiography), laboratory data, biopsies, and the clinical course were used for verification of detected lesions. FDG PET was able to detect medullary involvement of multiple myeloma. There were two false-negative results. In one patient, the radiographic skeletal survey showed subcentimeter lytic lesions within the ribs that were not detected on FDG PET and in the other patient, a lytic lesion detected on radiographs showed only mildly increased FDG uptake that was not identified prospectively. There was one false-positive FDG PET result in a patient who had undergone radiation therapy 3 weeks before PET. FDG PET was helpful in differentiating between posttherapeutic changes and residual/recurrent tumor and in assessing response to therapy. FDG PET resulted in upstaging of disease in four patients, which influenced subsequent management and prognosis. Sensitivity of FDG PET in detecting myelomatous involvement was 85% and specificity was 92%. FDG PET is able to detect bone marrow involvement in patients with multiple myeloma. FDG PET is useful in assessing extent of disease at time of initial diagnosis, contributing to staging that is more accurate. FDG PET is also useful for evaluating therapy response.

The road to cure in multiple myeloma starts with smoldering disease

PubMed Central

Salem, Karma Z; Ghobrial, Irene M

2015-01-01

Introduction Smoldering multiple myeloma (SMM) is a heterogeneous clinical entity that defines patients in the spectrum of disease progression from monoclonal gammopathy of undetermined significance to multiple myeloma (MM). Current standard of care is observation until end organ damage occurs. In spite of this, the scientific community has begun to question whether the strategy of watchful waiting should be replaced with earlier therapeutic intervention with the ultimate goal of preventing clonal heterogeneity and end organ damage. Areas covered In this review, we challenge the concept of observation as the best option of therapy in SMM. We present current data on diagnosis, prognostic factors of disease progression and studies that have been conducted to date to determine whether earlier therapeutic interventions will lead to an improvement in overall survival of patients with MM. Expert opinion If the recommendations of treatment of SMM were to change, the scientific body of evidence would have to overcome four major hurdles: to demonstrate that early intervention leads to prolonged survival and delay in development of end organ damage, that it does not have long-term toxicities, that it is implemented in patients with a high-likelihood of developing myeloma and that it does not lead to the outgrowth of more resistant clones. Only well-designed clinical trials will determine whether cure can be achieved with earlier interventions. PMID:25995973

[Recommendations for early identification of damage to the skeleton by malignant processes, and for early diagnosis of multiple myeloma].

PubMed

Adam, Z; Bednarík, J; Neubauer, J; Chaloupka, R; Fojtík, Z; Vanícek, J; Pour, L; Cermákova, Z; Scudla, V; Maisnar, V; Straub, J; Schützová, M; Gregora, E; Weinreb, M; Stuchlíková, K; Stanícek, J; Hájek, R; Krejcí, M; Vorlícek, J

2006-11-01

The number of newly diagnosed cases of multiple myeloma in the Czech Republic is about 3-4 per 100 000 persons per year. In the higher age groups, the incidence increases. Multiple myeloma is an illness that reacts well to treatment which can result in periods of remission lasting for years. Some of the patients are even able to return to work. A pre-requisite for successful treatment is early diagnosis and this is usually in the hands of first line physicians. This is the reason why the Czech Myeloma Group, in conjunction with neurologists, orthopedicians and radio diagnosticians has issued the following recommendations for first line physicians containing a more detailed description of the symptoms and the diagnostic pitfalls of the disease. This disease reminds a chameleon for the variety of its symptoms. For the sake of clarification, we shall divide multiple myeloma symptoms into five points, each of which is reason enough to warrant an examination to confirm or rule out a malignant cause of health problems (a negative result does not automatically mean exclusion). If any of the recommended examinations results positive, the diagnostic process must be continued, in which case a general practitioner refers the patient to a specialist health centre. Observing these recommendations should minimize the number of cases of late diagnosis. 1. Bone destruction symptoms. - Unexplained backache for more than one month in any part of spine even without nerve root irritability or without pain in other part of skeleton (ribs, hips, or long bones). - Pain at the beginning of myeloma disease is very similar to benigne common discopathy, however the intensity of backache is decreasing within one months in benigne disease. In the case of malignant process the intensity of bone pain is steadily increasing. - Immediate imaging and laboratory investigation are indicated by resting and night pain in spinal column or in any part of skeleton. - Backache with the sign of spinal cord

Autologous cellular vaccine overcomes cancer immunoediting in a mouse model of myeloma.

PubMed

Mazzocco, Marta; Martini, Matteo; Rosato, Antonio; Stefani, Elisabetta; Matucci, Andrea; Dalla Santa, Silvia; De Sanctis, Francesco; Ugel, Stefano; Sandri, Sara; Ferrarini, Giovanna; Cestari, Tiziana; Ferrari, Sergio; Zanovello, Paola; Bronte, Vincenzo; Sartoris, Silvia

2015-09-01

In the Sp6 mouse plasmacytoma model, a whole-cell vaccination with Sp6 cells expressing de novo B7-1 (Sp6/B7) induced anatomically localized and cytotoxic T cell (CTL)-mediated protection against wild-type (WT) Sp6. Both WT Sp6 and Sp6/B7 showed down-regulated expression of MHC H-2 L(d). Increase of H-2 L(d) expression by cDNA transfection (Sp6/B7/L(d)) raised tumour immune protection and shifted most CTL responses towards H-2 L(d)-restricted antigenic epitopes. The tumour-protective responses were not specific for the H-2 L(d)-restricted immunodominant AH1 epitope of the gp70 common mouse tumour antigen, although WT Sp6 and transfectants were able to present it to specific T cells in vitro. Gp70 transcripts, absent in secondary lymphoid organs of naive mice, were detected in immunized mice as well as in splenocytes from naive mice incubated in vitro with supernatants of CTL-lysed Sp6 cell cultures, containing damage-associated molecular patterns (DAMPs). It has been shown that Toll-like receptor triggering induces gp70 expression. Damage-associated molecular patterns are released by CTL-mediated killing of Sp6/B7-Sp6/B7/L(d) cells migrated to draining lymph nodes during immunization and may activate gp70 expression and presentation in most resident antigen-presenting cells. The same could also apply for Mus musculus endogenous ecotropic murine leukaemia virus 1 particles present in Sp6-cytosol, discharged by dying cells and superinfecting antigen-presenting cells. The outcome of such a massive gp70 cross-presentation would probably be tolerogenic for the high-affinity AH1-gp70-specific CTL clones. In this scenario, autologous whole-tumour-cell vaccines rescue tumour-specific immunoprotection by amplification of subdominant tumour antigen responses when those against the immune dominant antigens are lost. © 2015 The Authors. Immunology Published by John Wiley & Sons Ltd.

Autologous cellular vaccine overcomes cancer immunoediting in a mouse model of myeloma

PubMed Central

Mazzocco, Marta; Martini, Matteo; Rosato, Antonio; Stefani, Elisabetta; Matucci, Andrea; Dalla Santa, Silvia; De Sanctis, Francesco; Ugel, Stefano; Sandri, Sara; Ferrarini, Giovanna; Cestari, Tiziana; Ferrari, Sergio; Zanovello, Paola; Bronte, Vincenzo; Sartoris, Silvia

2015-01-01

In the Sp6 mouse plasmacytoma model, a whole-cell vaccination with Sp6 cells expressing de novo B7-1 (Sp6/B7) induced anatomically localized and cytotoxic T cell (CTL) -mediated protection against wild-type (WT) Sp6. Both WT Sp6 and Sp6/B7 showed down-regulated expression of MHC H-2 Ld. Increase of H-2 Ld expression by cDNA transfection (Sp6/B7/Ld) raised tumour immune protection and shifted most CTL responses towards H-2 Ld-restricted antigenic epitopes. The tumour-protective responses were not specific for the H-2 Ld-restricted immunodominant AH1 epitope of the gp70 common mouse tumour antigen, although WT Sp6 and transfectants were able to present it to specific T cells in vitro. Gp70 transcripts, absent in secondary lymphoid organs of naive mice, were detected in immunized mice as well as in splenocytes from naive mice incubated in vitro with supernatants of CTL-lysed Sp6 cell cultures, containing damage-associated molecular patterns (DAMPs). It has been shown that Toll-like receptor triggering induces gp70 expression. Damage-associated molecular patterns are released by CTL-mediated killing of Sp6/B7-Sp6/B7/Ld cells migrated to draining lymph nodes during immunization and may activate gp70 expression and presentation in most resident antigen-presenting cells. The same could also apply for Mus musculus endogenous ecotropic murine leukaemia virus 1 particles present in Sp6-cytosol, discharged by dying cells and superinfecting antigen-presenting cells. The outcome of such a massive gp70 cross-presentation would probably be tolerogenic for the high-affinity AH1-gp70-specific CTL clones. In this scenario, autologous whole-tumour-cell vaccines rescue tumour-specific immunoprotection by amplification of subdominant tumour antigen responses when those against the immune dominant antigens are lost. PMID:25959091

Cost-effectiveness analysis of low-molecular-weight heparin versus aspirin thromboprophylaxis in patients newly diagnosed with multiple myeloma.

PubMed

Chalayer, Emilie; Bourmaud, Aurélie; Tinquaut, Fabien; Chauvin, Franck; Tardy, Bernard

2016-09-01

The aim of this study was to assess the cost-effectiveness of low molecular weight heparin versus aspirin as primary thromboprophylaxis throughout chemotherapy for newly diagnosed multiple myeloma patients treated with protocols including thalidomide from the perspective of French health care providers. We used a modeling approach combining data from the only randomized trial evaluating the efficacy of the two treatments and secondary sources for costs, and utility values. We performed a decision-tree analysis and our base case was a hypothetical cohort of 10,000 patients. A bootstrap resampling technique was used. The incremental cost-effectiveness ratio was calculated using estimated quality-adjusted life years as the efficacy outcome. Incremental costs and effectiveness were estimated for each strategy and the incremental cost-effectiveness ratio was calculated. One-way sensitivity analyses were performed. The number of quality-adjusted life years was estimated to be 0.300 with aspirin and 0.299 with heparin. The estimated gain with aspirin was therefore approximately one day. Over 6months, the mean total cost was € 1518 (SD=601) per patient in the heparin arm and € 273 (SD=1019) in the aspirin arm. This resulted in an incremental cost of € 1245 per patient treated with heparin. The incremental cost-effectiveness ratio for the aspirin versus heparin strategy was calculated to be - 687,398 € (95% CI, -13,457,369 to -225,385). Aspirin rather than heparin thromboprophylaxis, during the first six months of chemotherapy for myeloma, is associated with significant cost savings per patient and also with an unexpected slight increase in quality of life. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identifying professional education gaps and barriers in multiple myeloma patient care: findings of the Managing Myeloma Continuing Educational Initiative Advisory Committee.

PubMed

Raje, Noopur; Faiman, Beth; Harvey, R Donald; Kurtin, Sandra E; Lonial, Sagar; Kumar, Shaji K; Cohen, Adam D; Conde, Miguel A; Giralt, Sergio A; Recine, Marie Sabo; Tombler, Eugene R; Stadtmauer, Edward; Jagannath, Sundar; Anderson, Kenneth C

2014-10-01

Advances in the past decade and a half have led to unprecedented improved outcomes for patients with multiple myeloma (MM), and this disease appears to be transitioning to one more characteristic of a chronic disease in large part due to rapid translation of clinical insights into practice at the community level. Although evidence-based guidelines and consensus recommendations remain an important resource for managing cancer patients, they do not fill the gap between the principles of disease management today and the translation of tailoring treatment for individual patient needs. Thus, there is a continuing need for concise, focused educational activities and resources that facilitate improved knowledge and understanding of appropriate, individualized therapeutic strategies for assessing and caring for patients with MM. The next several years will truly be a time of shifting paradigms in the treatment of MM in which new agents will be approved, response criteria will be updated, and new approaches to risk assessment and monitoring minimal residual disease will evolve and enter practice. New groundbreaking therapeutic approaches, such as immunotherapy, might result in significant changes in how MM is treated and managed over the entire life cycle of the disease. Even the definition of the disease might be further amended as insights grow regarding who should be treated and who might benefit more from observation. As such, oncology clinicians will have to carefully review and update their management approaches accordingly even as they begin to focus even more on the survivorship needs of their MM patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Saline aquifer mapping project in the southeastern United States

USGS Publications Warehouse

Williams, Lester J.; Spechler, Rick M.

2011-01-01

In 2009, the U.S. Geological Survey initiated a study of saline aquifers in the southeastern United States to evaluate the potential use of brackish or saline water from the deeper portions of the Floridan aquifer system and the underlying Coastal Plain aquifer system (Fig. 1). The objective of this study is to improve the overall understanding of the available saline water resources for potential future development. Specific tasks are to (1) develop a digital georeferenced database of borehole geophysical data to enable analysis and characterization of saline aquifers (see locations in Fig. 1), (2) identify and map the regional extent of saline aquifer systems and describe the thickness and character of hydrologic units that compose these systems, and (3) delineate salinity variations at key well sites and along section lines to provide a regional depiction of the freshwater-saltwater interfaces. Electrical resistivity and induction logs, coupled with a variety of different porosity logs (sonic, density, and neutron), are the primary types of borehole geophysical logs being used to estimate the water quality in brackish and saline formations. The results from the geophysical log calculations are being compared to available water-quality data obtained from water wells and from drill-stem water samples collected in test wells. Overall, the saline aquifer mapping project is helping to improve the understanding of saline water resources in the area. These aquifers may be sources of large quantities of water that could be treated by using reverse osmosis or similar technologies, or they could be used for aquifer storage and recovery systems.

[Correlation of Th17 Cells and IL-17 Level in Multiple Myeloma Patients with Pathogenesis of Multiple Myeloma].

PubMed

DU, Chao-Yang; Yang, Ru-Yu; Li, Chao; Duan, Li-Juan

2017-02-01

To explore the correlation of Th17 cell rate and IL-17 level with pathogenetis of multiple myeloma(MM). Forty-five cases of MM were enrolled in MM group, while 45 healthy volunteers were selected in control group. The rate of Th17 cells, levels of IL-17 and β2-microglobulin(β2-MG) in patients subgrouping according to ISS staging and treatment were detected by using flow cytometer and IL-17 assay kit. The correlation of Th17 cell rate and IL-17 level with MM was analyzed. The rate of Th17 cells and level of IL-17 in MM group were higher than those in control group(P<0.05), the rate of Th17 cells and level of IL-17 in ISS III stage patients were higher than those in ISS I and II stage patients(P<0.05); the rate of Th17 cells and level of IL-17 in ISS I and ISS II stage patients were not significant difference (P>0.05); the rate of Th17 cells and level of IL-17 in firstly treated, retreated/refractory patients were significantly higher than those in patients with effective treatment(P<0.05), while the rate of Th17 cells and level of IL-17 between firstly treated patients and retreated/refractory patients were not significant difference (P>0.05). The Th17 rate and IL-17 level in MM patients positively correlated with β2-MG level (r=0.422, r=0.416, P<0.05). The obvious increase of Th17 rate, IL-17 and β2-MG levels closely relates with pathogenesis of MM. The Th17 rate and IL-17 level may be used as important evidence for evaluation of ISS stage and therapeutic efficacy of MM.

Gamabufotalin triggers c-Myc degradation via induction of WWP2 in multiple myeloma cells.

PubMed

Yu, Zhenlong; Li, Tao; Wang, Chao; Deng, Sa; Zhang, Baojing; Huo, Xiaokui; Zhang, Bo; Wang, Xiaobo; Zhong, Yuping; Ma, Xiaochi

2016-03-29

Deciding appropriate therapy for multiple myeloma (MM) is challenging because of the occurrence of multiple chromosomal changes and the fatal nature of the disease. In the current study, gamabufotalin (GBT) was isolated from toad venom, and its tumor-specific cytotoxicity was investigated in human MM cells. We found GBT inhibited cell growth and induced apoptosis with the IC50 values <50 nM. Mechanistic studies using functional approaches identified GBT as an inhibitor of c-Myc. Further analysis showed that GBT especially evoked the ubiquitination and degradation of c-Myc protein, thereby globally repressing the expression of c-Myc target genes. GBT treatment inhibited ERK and AKT signals, while stimulating the activation of JNK cascade. An E3 ubiquitin-protein ligase, WWP2, was upregulated following JNK activation and played an important role in c-Myc ubiquitination and degradation through direct protein-protein interaction. The antitumor effect of GBT was validated in a xenograft mouse model and the suppression of MM-induced osteolysis was verified in a SCID-hu model in vivo. Taken together, our study identified the potential of GBT as a promising therapeutic agent in the treatment of MM.

Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma

PubMed Central

Zhu, Yuan Xiao; Kortuem, K. Martin; Stewart, A. Keith

2014-01-01

Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance. PMID:22966948

Start-up of two moving bed membrane bioreactors treating saline wastewater contaminated by hydrocarbons.

PubMed

Campo, R; Di Prima, N; Freni, G; Giustra, M G; Di Bella, G

2016-01-01

This work aims to assess the acclimation of microorganisms to a gradual increase of salinity and hydrocarbons, during the start-up of two moving bed membrane bioreactors (MB-MBRs) fed with saline oily wastewater. In both systems an ultrafiltration membrane was used and two types of carriers were employed: polyurethane sponge cubes (MB-MBRI) and polyethylene cylindrical carriers (MB-MBRII). A decreasing dilution factor of slops has been adopted in order to allow biomass acclimation. The simultaneous effect of salinity and hydrocarbons played an inhibitory role in biomass growth and this resulted in a decrease of the biological removal efficiencies. A reduction of bound extracellular polymeric substances and a simultaneous release of soluble microbial products (SMPs) were observed, particularly in the MB-MBRII system, probably due to the occurrence of a greater suspended biomass stress as response to the recalcitrance of substrate. On the one hand, a clear attachment of biomass occurred only in MB-MBRI and this affected the fouling deposition on the membrane surface. The processes of detachment and entrapment of biomass, from and into the carriers, significantly influenced the superficial cake deposition and its reversibility. On the other hand, in MB-MBRII, the higher production of SMPs implied a predominance of the pore blocking.

Delineation of a novel pre-B cell component in plasma cell myeloma: immunochemical, immunophenotypic, genotypic, cytologic, cell culture, and kinetic features.

PubMed

Grogan, T M; Durie, B G; Lomen, C; Spier, C; Wirt, D P; Nagle, R; Wilson, G S; Richter, L; Vela, E; Maxey, V

1987-10-01

A novel pre-B cell component in direct and cultured myeloma bone marrow material has been delineated by using immunochemistry and flow cytometry techniques. Our phenotypic studies suggest a novel hybrid expression of pre-B and plasma cell antigens with coexpression of cytoplasmic mu, common acute lymphoblastic leukemia antigen, terminal deoxynucleotidyl transferase, and plasma cell antigens (PCA-1 and PC-1). This suggests that myeloma pre-B-like cells are aberrant malignant cells and not normal pre-B lymphocytic counterparts. With the advantage of a pure and stable source of these cells from M3 culture to allow molecular characterization, we performed one- and two-dimensional gel electrophoresis and Western blotting. We found that the cytoplasmic mu in myeloma pre-B-like cells has a molecular weight of 74,000 daltons and an isoelectric point of 6.3 and that it is strikingly homogeneous and discrete in size and charge compared with standard secretory mu, which suggests an aberrant, mutant, or monoclonal form of mu. Monoclonality was further evidenced by heavy- and light-chain immunoglobulin gene rearrangements demonstrated with JH and C kappa probes. We also established that this novel myeloma pre-B component is a major proliferative element as determined by double-labeling experiments with phenotype coupled to labeling/proliferative indexes. Our stimulatory studies indicate some capacity of these cells to mature on exposure to phorbol esters. These myeloma pre-B cells may represent the stem cell or self-renewal component in myeloma. Our establishment of these cells in long-term culture offers a considerable asset in studying the immature cells, which may be critical to the immortalization of myeloma.

The myelinated fiber loss in the corpus callosum of mouse model of schizophrenia induced by MK-801.

PubMed

Xiu, Yun; Kong, Xiang-ru; Zhang, Lei; Qiu, Xuan; Gao, Yuan; Huang, Chun-xia; Chao, Feng-lei; Wang, San-rong; Tang, Yong

2015-04-01

Previous magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) investigations have shown that the white matter volume and fractional anisotropy (FA) were decreased in schizophrenia (SZ), which indicated impaired white matter integrity in SZ. However, the mechanism underlying these abnormalities has been less studied. The current study was designed to investigate the possible reasons for white matter abnormalities in the mouse model of SZ induced by NMDA receptor antagonist using the unbiased stereological methods and transmission electron microscope technique. We found that the mice treated with MK-801 demonstrated a series of schizophrenia-like behaviors including hyperlocomotor activity and more anxiety. The myelinated fibers in the corpus callosum (CC) of the mice treated with MK-801 were impaired with splitting lamellae of myelin sheaths and segmental demyelination. The CC volume and the total length of the myelinated fibers in the CC of the mice treated with MK-801 were significantly decreased by 9.4% and 16.8% when compared to those of the mice treated with saline. We further found that the loss of the myelinated fibers length was mainly due to the marked loss of the myelinated nerve fibers with the diameter of 0.4-0.5 μm. These results indicated that the splitting myelin sheaths, demyelination and the loss of myelinated fibers with small diameter might provide one of the structural bases for impaired white matter integrity of CC in the mouse model of SZ. These results might also provide a baseline for further studies searching for the treatment of SZ through targeting white matter. Copyright © 2015 Elsevier Ltd. All rights reserved.

The efficacy and safety of pomalidomide in relapsed/refractory multiple myeloma in a "real-world" study: Polish Myeloma Group experience.

PubMed

Charlinski, Grzegorz; Grzasko, Norbert; Jurczyszyn, Artur; Janczarski, Mariusz; Szeremet, Agnieszka; Waszczuk-Gajda, Anna; Bernatowicz, Paweł; Swiderska, Alina; Guzicka-Kazimierczak, Renata; Lech-Maranda, Ewa; Szczepaniak, Andrzej; Wichary, Ryszard; Dmoszynska, Anna

2018-06-08

Patients with relapsed/refractory multiple myeloma (RRMM) have poor prognosis. Pomalidomide is an immunomodulatory compound that has demonstrated activity in MM patients with disease refractory to lanlidomide and bortezomib. Participants of clinical trials are highly selected populations; therefore, the aim of this study was to present observations from real practice that might provide important information for practitioners. We analyzed retrospectively 50 patients treated with pomalidomide in 12 Polish sites between 2014 and 2017. Median age was 63 years, median time since diagnosis 4.5 years and median number of prior regimens 4. The overall response rate was 39.1%. Median progression-free survival (PFS) and overall survival (OS) were 10.0 and 14.0 months, respectively. Previous treatment with immunomodulatory drugs, bortezomib or stem cell transplant had no impact on PFS and OS. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia 24.0%, thrombocytopenia 10.0%, anemia 8.0%). Most common grade 3/4 non-hematologic toxicities were respiratory tract infection (14.0%) and neuropathy (4.0%). This real-world data have confirmed that pomalidomide is an active drug in RRMM and support results of published clinical trials and other real-world studies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells

PubMed Central

Brito, Jose L.R.; Walker, Brian; Jenner, Matthew; Dickens, Nicholas J.; Brown, Nicola J.M.; Ross, Fiona M.; Avramidou, Athanasia; Irving, Julie A.E.; Gonzalez, David; Davies, Faith E.; Morgan, Gareth J.

2009-01-01

Background The recurrent immunoglobulin translocation, t(4;14)(p16;q32) occurs in 15% of multiple myeloma patients and is associated with poor prognosis, through an unknown mechanism. The t(4;14) up-regulates fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET) genes. The involvement of MMSET in the pathogenesis of t(4;14) multiple myeloma and the mechanism or genes deregulated by MMSET upregulation are still unclear. Design and Methods The expression of MMSET was analyzed using a novel antibody. The involvement of MMSET in t(4;14) myelomagenesis was assessed by small interfering RNA mediated knockdown combined with several biological assays. In addition, the differential gene expression of MMSET-induced knockdown was analyzed with expression microarrays. MMSET gene targets in primary patient material was analyzed by expression microarrays. Results We found that MMSET isoforms are expressed in multiple myeloma cell lines, being exclusively up-regulated in t(4;14)-positive cells. Suppression of MMSET expression affected cell proliferation by both decreasing cell viability and cell cycle progression of cells with the t(4;14) translocation. These findings were associated with reduced expression of genes involved in the regulation of cell cycle progression (e.g. CCND2, CCNG1, BRCA1, AURKA and CHEK1), apoptosis (CASP1, CASP4 and FOXO3A) and cell adhesion (ADAM9 and DSG2). Furthermore, we identified genes involved in the latter processes that were differentially expressed in t(4;14) multiple myeloma patient samples. Conclusions In conclusion, dysregulation of MMSET affects the expression of several genes involved in the regulation of cell cycle progression, cell adhesion and survival. PMID:19059936

Cellular Proliferation by Multiplex Immunohistochemistry Identifies High-Risk Multiple Myeloma in Newly Diagnosed, Treatment-Naive Patients.

PubMed

Ely, Scott; Forsberg, Peter; Ouansafi, Ihsane; Rossi, Adriana; Modin, Alvin; Pearse, Roger; Pekle, Karen; Perry, Arthur; Coleman, Morton; Jayabalan, David; Di Liberto, Maurizio; Chen-Kiang, Selina; Niesvizky, Ruben; Mark, Tomer M

2017-12-01

Therapeutic options for multiple myeloma (MM) are growing, yet clinical outcomes remain heterogeneous. Cytogenetic analysis and disease staging are mainstays of risk stratification, but data suggest a complex interplay between numerous abnormalities. Myeloma cell proliferation is a metric shown to predict outcomes, but available methods are not feasible in clinical practice. Multiplex immunohistochemistry (mIHC), using multiple immunostains simultaneously, is universally available for clinical use. We tested mIHC as a method to calculate a plasma cell proliferation index (PCPI). By mIHC, marrow trephine core biopsy samples were costained for CD138, a plasma cell-specific marker, and Ki-67. Myeloma cells (CD138 + ) were counted as proliferating if coexpressing Ki-67. Retrospective analysis was performed on 151 newly diagnosed, treatment-naive patients divided into 2 groups on the basis of myeloma cell proliferation: low (PCPI ≤ 5%, n = 87), and high (PCPI > 5%, n = 64). Median overall survival (OS) was not reached versus 78.9 months (P = .0434) for the low versus high PCPI groups. Multivariate analysis showed that only high-risk cytogenetics (hazard ratio [HR] = 2.02; P = .023), International Staging System (ISS) stage > I (HR = 2.30; P = .014), and PCPI > 5% (HR = 1.70; P = .041) had independent effects on OS. Twenty-three (36%) of the 64 patients with low-risk disease (ISS stage 1, without high-risk cytogenetics) were uniquely reidentified as high risk by PCPI. PCPI is a practical method that predicts OS in newly diagnosed myeloma and facilitates broader use of MM cell proliferation for risk stratification. Copyright © 2017 Elsevier Inc. All rights reserved.

Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma.

PubMed

Liu, Huan; Liu, Zhiqiang; Du, Juan; He, Jin; Lin, Pei; Amini, Behrang; Starbuck, Michael W; Novane, Nora; Shah, Jatin J; Davis, Richard E; Hou, Jian; Gagel, Robert F; Yang, Jing

2016-08-24

Myelomatous bone disease is characterized by the development of lytic bone lesions and a concomitant reduction in bone formation, leading to chronic bone pain and fractures. To understand the underlying mechanism, we investigated the contribution of myeloma-expressed thymidine phosphorylase (TP) to bone lesions. In osteoblast progenitors, TP up-regulated the methylation of RUNX2 and osterix, leading to decreased bone formation. In osteoclast progenitors, TP up-regulated the methylation of IRF8 and thereby enhanced expression of NFATc1 (nuclear factor of activated T cells, cytoplasmic 1 protein), leading to increased bone resorption. TP reversibly catalyzes thymidine into thymine and 2-deoxy-d-ribose (2DDR). Myeloma-secreted 2DDR bound to integrin αVβ3/α5β1 in the progenitors, activated PI3K (phosphoinositide 3-kinase)/Akt signaling, and increased DNMT3A (DNA methyltransferase 3A) expression, resulting in hypermethylation of RUNX2, osterix, and IRF8 This study elucidates an important mechanism for myeloma-induced bone lesions, suggesting that targeting TP may be a viable approach to healing resorbed bone in patients. Because TP overexpression is common in bone-metastatic tumors, our findings could have additional mechanistic implications. Copyright © 2016, American Association for the Advancement of Science.

Cytogenetics in the management of multiple myeloma: an update by the Groupe francophone de cytogénétique hématologique (GFCH).

PubMed

Daudignon, Agnès; Quilichini, Benoît; Ameye, Geneviève; Poirel, Hélène; Bastard, Christian; Terré, Christine

2016-10-01

Cytogenetics of multiple myeloma has evolved in recent years by the emergence of Interphasic fluorescence in situ hybridization (FISH) performed on sorted plasma cells detecting abnormalities independently of a proliferative and infiltrative index. Cytogenetic analysis plays a major part in the risk stratification of myeloma diagnosis due to prognostic impact of various cytogenetic abnormalities as well as to the association between emerging therapeutic approaches in MM. Thus, practice guidelines now recommend interphasic FISH or alternative molecular technics as the initial analysis for multiple myeloma. The Groupe francophone de cytogénétique hématologique (GFCH) proposes in this issue an update of managing multiple myeloma cytogenetics.

Efficacy and safety of bortezomib-based retreatment at the first relapse in multiple myeloma patients: A retrospective study.

PubMed

Oriol, Albert; Giraldo, Pilar; Kotsianidis, Ioannis; Couturier, Catherine; Olie, Robert; Angermund, Ralf; Corso, Alessandro

2015-08-01

Multiple myeloma remains incurable and retreatment with available therapies is of substantial interest. This retrospective observational study included data from 35 patients treated initially and at the first relapse with bortezomib-containing regimens. Bortezomib retreatment provided a similar depth and time to response as first-line therapy; however, as could be expected, the duration of response was shorter with retreatment. The tolerability profile was similar with bortezomib as the first- and second-line therapy, with no evidence of cumulative toxicity. These findings support bortezomib retreatment after a treatment-free interval of ≥6 months in patients who achieved at least a partial response to the first-line bortezomib-based therapy.

Acquired cutis laxa following urticarial vasculitis associated with IgA myeloma.

PubMed

Turner, Ryan B; Haynes, Harley A; Granter, Scott R; Miller, Danielle M

2009-06-01

Cutis laxa (CL) is an inherited or acquired connective tissue disorder characterized clinically by loosely hanging skin folds. There is often preceding cutaneous inflammatory eruption (ie, urticaria, eczema, erythema multiforme), and there is frequently internal organ involvement of the gastrointestinal, urogenital, pulmonary, and cardiovascular systems. Histologically, there are degenerative changes in the dermal elastic fibers. Of the few reports on this rare disorder, authors have speculated about an immune-mediated destruction of elastic fibers, and monoclonal gammopathies, such as multiple myeloma or heavy chain deposition disease, have a recognized association with CL. We report an unusual case of rapidly progressing acquired CL associated with leukocytoclastic vasculitis, IgA myeloma, and an immune complex-mediated glomerulonephritis. Light microscopy of the lax skin revealed complete absence of elastic fibers in areas of vasculitis.

Salicylic Acid-Regulated Antioxidant Mechanisms and Gene Expression Enhance Rosemary Performance under Saline Conditions

PubMed Central

El-Esawi, Mohamed A.; Elansary, Hosam O.; El-Shanhorey, Nader A.; Abdel-Hamid, Amal M. E.; Ali, Hayssam M.; Elshikh, Mohamed S.

2017-01-01

Salinity stress as a major agricultural limiting factor may influence the chemical composition and bioactivity of Rosmarinus officinallis L. essential oils and leaf extracts. The application of salicylic acid (SA) hormone may alleviate salinity stress by modifying the chemical composition, gene expression and bioactivity of plant secondary metabolites. In this study, SA was applied to enhance salinity tolerance in R. officinallis. R. officinallis plants were subjected to saline water every 2 days (640, 2,000, and 4,000 ppm NaCl) and 4 biweekly sprays of SA at 0, 100, 200, and 300 ppm for 8 weeks. Simulated salinity reduced all vegetative growth parameters such as plant height, plant branches and fresh and dry weights. However, SA treatments significantly enhanced these plant growth and morphological traits under salinity stress. Salinity affected specific major essential oils components causing reductions in α-pinene, β-pinene, and cineole along with sharp increases in linalool, camphor, borneol, and verbenone. SA applications at 100–300 ppm largely reversed the effects of salinity. Interestingly, SA treatments mitigated salinity stress effects by increasing the total phenolic, chlorophyll, carbohydrates, and proline contents of leaves along with decline in sodium and chloride. Importantly, this study also proved that SA may stimulate the antioxidant enzymatic mechanism pathway including catalase (CAT), superoxide dismutase (SOD), and ascorbate peroxidase (APX) as well as increasing the non-enzymatic antioxidants such as free and total ascorbate in plants subjected to salinity. Quantitative real-time PCR analysis revealed that APX and 3 SOD genes showed higher levels in SA-treated rosemary under salinity stress, when compared to non-sprayed plants. Moreover, the expression level of selected genes conferring tolerance to salinity (bZIP62, DREB2, ERF3, and OLPb) were enhanced in SA-treated rosemary under salt stress, indicating that SA treatment resulted in the

Body Mass Index and Physical Activity at Different Ages and Risk of Multiple Myeloma in the NIH-AARP Diet and Health Study

PubMed Central

Hofmann, Jonathan N.; Moore, Steven C.; Lim, Unhee; Park, Yikyung; Baris, Dalsu; Hollenbeck, Albert R.; Matthews, Charles E.; Gibson, Todd M.; Hartge, Patricia; Purdue, Mark P.

2013-01-01

Several studies have reported an increased risk of multiple myeloma associated with excess body weight. We investigated the risk of multiple myeloma in relation to separate measures of adiposity and energy balance at different ages in the National Institutes of Health-AARP Diet and Health Study, a large prospective cohort study in the United States. Participants completed a baseline questionnaire (1995–1996; n = 485,049), and a subset of participants completed a second questionnaire (1996–1997; n = 305,618) in which we solicited more detailed exposure information. Hazard ratios and 95% confidence intervals were estimated for the risk of multiple myeloma (overall, n = 813; subset, n = 489) in relation to several measures of obesity and leisure time physical activity. Multiple myeloma risk was associated with increasing body mass index (BMI) at cohort entry (per 5-kg/m2 increase, hazard ratio (HR) = 1.10, 95% confidence interval (CI): 1.00, 1.22); similar associations were observed for BMI at age 50 years (HR = 1.14, 95% CI: 1.02, 1.28), age 35 years (HR = 1.20, 95% CI: 1.05, 1.36), and age 18 years (HR = 1.13, 95% CI: 0.98, 1.32) without adjustment for baseline BMI. Risk of multiple myeloma was not associated with physical activity level at any age. These findings support the hypothesis that excess body weight, both in early adulthood and later in life, is a risk factor for multiple myeloma and suggest that maintaining a healthy body weight throughout life may reduce multiple myeloma risk. PMID:23543160

[Multiple myeloma : What has been confirmed in therapy?

PubMed

Baertsch, M-A; Goldschmidt, H

2017-12-01

Multiple myeloma (MM) is a malignancy of terminally differentiated B cells/plasma cells and is primarily located in the bone marrow. Symptomatic multiple myeloma typically presents with osteolyses, anemia, reduced renal function, and/or hypercalcemia. In the case of such MM-related end organ damage, urgent systemic treatment is indicated. In order to prevent end organ damage, current guidelines now recommend treatment initiation already when certain biomarkers are met. Current first-line treatment is based on proteasome inhibition and immunomodulation. Eligible patients still benefit from the addition of high-dose chemotherapy and autologous stem cell transplantation. Radiotherapy and orthopedic interventions play an important role in the treatment of localized skeletal complications. For relapsed MM, five novel agents have been approved in Europe during the last two years. These are second-generation proteasome inhibitors (carfilzomib, ixazomib) as well as first-in-class monoclonal antibodies (daratumumab, elotuzumab) and a histone deacetylase inhibitor (panobinostat). Triple combinations based on the established regimens lenalidomide/dexamethasone and bortezomib/dexamethasone plus one of the novel agents have been shown to significantly prolong progression-free survival. Median overall survival of patients with MM has doubled since the turn of the millennium.

Multiple myeloma can be accurately diagnosed in acute kidney injury patients using a rapid serum free light chain test.

PubMed

Heaney, Jennifer L J; Campbell, John P; Yadav, Punit; Griffin, Ann E; Shemar, Meena; Pinney, Jennifer H; Drayson, Mark T

2017-07-20

Acute kidney injury (AKI) is common in patients with multiple myeloma (MM). Whether serum free light chain (sFLC) measurements can distinguish between myeloma and other causes of AKI requires confirmation to guide early treatment. A rapid and portable sFLC test (Seralite®) is newly available and could reduce delays in obtaining sFLC results and accelerate diagnosis in patients with unexplained AKI. This study evaluated the accuracy of Seralite® to identify MM as the cause of AKI. sFLCs were retrospectively analysed in patients with AKI stage 3 as per KDIGO criteria (i.e. serum creatinine ≥354 μmol/L or those on dialysis treatment) (n = 99); 45/99 patients had a confirmed MM diagnosis. The Seralite® κ:λ FLC ratio accurately diagnosed all MM patients in the presence of AKI: a range of 0.14-2.02 returned 100% sensitivity and specificity for identifying all non-myeloma related AKI patients. The sFLC difference (dFLC) also demonstrated high sensitivity (91%) and specificity (100%): an optimal cut-off of 399 mg/L distinguished between myeloma and non-myeloma AKI patients. We propose a pathway of patient screening and stratification in unexplained AKI for use of Seralite® in clinical practice, with a κ:λ ratio range of 0.14-2.02 and dFLC 400 mg/L as decision points. Seralite® accurately differentiates between AKI due to MM and AKI due to other causes in patients considered at risk of myeloma. This rapid test can sensitively screen for MM in patients with AKI and help inform early treatment intervention.

Understanding what matters most to people with multiple myeloma: a qualitative study of views on quality of life

PubMed Central

2014-01-01

Background Multiple myeloma is an incurable haematological cancer that affects physical, psychological and social domains of quality of life (QOL). Treatment decisions are increasingly guided by QOL issues, creating a need to monitor QOL within clinical practice. The development of myeloma-specific QOL questionnaires has been limited by a paucity of research to fully characterise QOL in this group. Aims of the present study are to (1) explore the issues important to QOL from the perspective of people with multiple myeloma, and (2) explore the views of patients and clinical staff on existing QOL questionnaires and their use in clinical practice. Methods The ‘Issues Interviews’ were semi-structured qualitative interviews to explore the issues important to QOL in a purposive sample of myeloma patients (n = 20). The ‘Questionnaire Interviews’ were semi-structured qualitative interviews in a separate purposive sample of myeloma patients (n = 20) to explore views on existing QOL questionnaires and their clinical use. Two patient focus groups (n = 7, n = 4) and a focus group of clinical staff (n = 6) complemented the semi-structured interviews. Thematic content analysis resulted in the development of a theoretical model of QOL in myeloma. Results Main themes important to QOL were Biological Status, Treatment Factors, Symptoms Status, Activity & Participation, Emotional Status, Support Factors, Expectations, Adaptation & Coping and Spirituality. Symptoms had an indirect effect on QOL, only affecting overall QOL if they impacted upon Activity & Participation, Emotional Status or Support Factors. This indirect relationship has implications for the design of QOL questionnaires, which often focus on symptom status. Health-service factors emerged as important but are often absent from QOL questionnaires. Sexual function was important to patients and difficult for clinicians to discuss, so inclusion in clinical QOL tools may flag hidden problems and

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

PubMed

Rand, Kristin A; Song, Chi; Dean, Eric; Serie, Daniel J; Curtin, Karen; Sheng, Xin; Hu, Donglei; Huff, Carol Ann; Bernal-Mizrachi, Leon; Tomasson, Michael H; Ailawadhi, Sikander; Singhal, Seema; Pawlish, Karen; Peters, Edward S; Bock, Cathryn H; Stram, Alex; Van Den Berg, David J; Edlund, Christopher K; Conti, David V; Zimmerman, Todd; Hwang, Amie E; Huntsman, Scott; Graff, John; Nooka, Ajay; Kong, Yinfei; Pregja, Silvana L; Berndt, Sonja I; Blot, William J; Carpten, John; Casey, Graham; Chu, Lisa; Diver, W Ryan; Stevens, Victoria L; Lieber, Michael R; Goodman, Phyllis J; Hennis, Anselm J M; Hsing, Ann W; Mehta, Jayesh; Kittles, Rick A; Kolb, Suzanne; Klein, Eric A; Leske, Cristina; Murphy, Adam B; Nemesure, Barbara; Neslund-Dudas, Christine; Strom, Sara S; Vij, Ravi; Rybicki, Benjamin A; Stanford, Janet L; Signorello, Lisa B; Witte, John S; Ambrosone, Christine B; Bhatti, Parveen; John, Esther M; Bernstein, Leslie; Zheng, Wei; Olshan, Andrew F; Hu, Jennifer J; Ziegler, Regina G; Nyante, Sarah J; Bandera, Elisa V; Birmann, Brenda M; Ingles, Sue A; Press, Michael F; Atanackovic, Djordje; Glenn, Martha J; Cannon-Albright, Lisa A; Jones, Brandt; Tricot, Guido; Martin, Thomas G; Kumar, Shaji K; Wolf, Jeffrey L; Deming Halverson, Sandra L; Rothman, Nathaniel; Brooks-Wilson, Angela R; Rajkumar, S Vincent; Kolonel, Laurence N; Chanock, Stephen J; Slager, Susan L; Severson, Richard K; Janakiraman, Nalini; Terebelo, Howard R; Brown, Elizabeth E; De Roos, Anneclaire J; Mohrbacher, Ann F; Colditz, Graham A; Giles, Graham G; Spinelli, John J; Chiu, Brian C; Munshi, Nikhil C; Anderson, Kenneth C; Levy, Joan; Zonder, Jeffrey A; Orlowski, Robert Z; Lonial, Sagar; Camp, Nicola J; Vachon, Celine M; Ziv, Elad; Stram, Daniel O; Hazelett, Dennis J; Haiman, Christopher A; Cozen, Wendy

2016-12-01

Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10 -7 ) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR. ©2016 American Association for Cancer Research.

Gender-Dependent Effects of Maternal Immune Activation on the Behavior of Mouse Offspring

PubMed Central

Xuan, Ingrid C. Y.; Hampson, David R.

2014-01-01

Autism spectrum disorders are neurodevelopmental disorders characterized by two core symptoms; impaired social interactions and communication, and ritualistic or repetitive behaviors. Both epidemiological and biochemical evidence suggests that a subpopulation of autistics may be linked to immune perturbations that occurred during fetal development. These findings have given rise to an animal model, called the “maternal immune activation” model, whereby the offspring from female rodents who were subjected to an immune stimulus during early or mid-pregnancy are studied. Here, C57BL/6 mouse dams were treated mid-gestation with saline, lipopolysaccharide (LPS) to mimic a bacterial infection, or polyinosinic:polycytidylic acid (Poly IC) to mimic a viral infection. Autism-associated behaviors were examined in the adult offspring of the treated dams. Behavioral tests were conducted to assess motor activity, exploration in a novel environment, sociability, and repetitive behaviors, and data analyses were carried independently on male and female mice. We observed a main treatment effect whereby male offspring from Poly IC-treated dams showed reduced motor activity. In the marble burying test of repetitive behavior, male offspring but not female offspring from both LPS and Poly IC-treated mothers showed increased marble burying. Our findings indicate that offspring from mothers subjected to immune stimulation during gestation show a gender-specific increase in stereotyped repetitive behavior. PMID:25111339

The Effects of In-Hospital Intravenous Cold Saline in Postcardiac Arrest Patients Treated with Targeted Temperature Management.

PubMed

Suppogu, Nissi; Panza, Gregory A; Kilic, Sena; Gowdar, Shreyas; Kallur, Kamala R; Jayaraman, Ramya; Lundbye, Justin; Fernandez, Antonio B

2018-03-01

Recent data suggest that rapid infusion of intravenous (IV) cold saline for Targeted Temperature Management (TTM) after cardiac arrest is associated with higher rates of rearrest, pulmonary edema, and hypoxia, with no difference in neurologic outcomes or survival when administered by Emergency Medical Services. We sought to determine the effects of IV cold saline administration in the hospital setting in postcardiac arrest patients to achieve TTM and its effect on clinical parameters and neurologic outcomes. A cohort of 132 patients who completed TTM after cardiac arrest in a single institution was retrospectively studied. Patients who did not receive cold saline were matched by age, gender, Glasgow coma scale, downtime, and presenting rhythm to patients who received cold saline. Demographics, cardiac rearrest, diuretic use, time to target temperature, and Cerebral Performance Category (CPC) scores were recorded among other variables. Patients who received cold saline achieved target temperature sooner (280 vs. 345 minutes, p = 0.05), had lower lactate levels on day 1 (4.2 ± 3.5 mM vs. 6.0 ± 4.9 mM, p = 0.019) and day 2 (1.3 ± 2.2 mM vs. 2.2 ± 3.2 mM, p = 0.046), increased incidence of pulmonary edema (51.5% vs. 31.8%, p = 0.006), and increased diuretic utilization (63.6% vs. 42.4%, p = 0.014). There was no significant difference in cardiac rearrest, arterial oxygenation, and CPC scores (ps > 0.05). Infusion of IV cold saline is associated with shorter time to target temperature, increased incidence of pulmonary edema, and diuretic use, with no difference in cardiac rearrest, survival, and neurologic outcomes.

A beam-walking apparatus to assess behavioural impairments in MPTP-treated mice: pharmacological validation with R-(-)-deprenyl.

PubMed

Quinn, Leann P; Perren, Marion J; Brackenborough, Kim T; Woodhams, Peter L; Vidgeon-Hart, Martin; Chapman, Helen; Pangalos, Menelas N; Upton, Neil; Virley, David J

2007-08-15

A beam-walking apparatus has been evaluated for its ability to detect motor impairments in mice acutely treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, s.c., single or double administration). Mice subjected to MPTP lesioning showed deficits in motor performance on the beam-walking task, for up to 6 days post-MPTP administration, as compared to saline-treated controls. In addition, MPTP-treated mice were detected to have a marked depletion in striatal dopamine levels and a concomitant reduction in substantia nigra (SN) tyrosine hydroxylase (TH) immunoreactivity, at 7 days post-MPTP administration, indicative of dopaminergic neuronal loss. Pre-administration of the potent MAO-B inhibitor R-(-)-deprenyl at 3 or 10 mg/kg, 30 min, s.c, significantly inhibited the MPTP-induced reduction in SN TH-immunoreactivity, striatal dopamine depletions and impairments in mouse motor function. The data described in the present study provides further evidence that functional deficits following an acute MPTP dosing schedule in mice can be quantified and are related to nigro-striatal dopamine function.

A kinetic approach to evaluate salinity effects on carbon mineralization in a plant residue-amended soil*

PubMed Central

Nourbakhsh, Farshid; Sheikh-Hosseini, Ahmad R.

2006-01-01

The interaction of salinity stress and plant residue quality on C mineralization kinetics in soil is not well understood. A laboratory experiment was conducted to study the effects of salinity stress on C mineralization kinetics in a soil amended with alfalfa, wheat and corn residues. A factorial combination of two salinity levels (0.97 and 18.2 dS/m) and four levels of plant residues (control, alfalfa, wheat and corn) with three replications was performed. A first order kinetic model was used to describe the C mineralization and to calculate the potentially mineralizable C. The CO2-C evolved under non-saline condition, ranged from 814.6 to 4842.4 mg CO2-C/kg in control and alfalfa residue-amended soils, respectively. Salinization reduced the rates of CO2 evolution by 18.7%, 6.2% and 5.2% in alfalfa, wheat and corn residue-amended soils, respectively. Potentially mineralizable C (C 0) was reduced significantly in salinized alfalfa residue-treated soils whereas, no significant difference was observed for control treatments as well as wheat and corn residue-treated soils. We concluded that the response pattern of C mineralization to salinity stress depended on the plant residue quality and duration of incubation. PMID:16972320

Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma.

PubMed

Walker, Brian A; Mavrommatis, Konstantinos; Wardell, Christopher P; Ashby, T Cody; Bauer, Michael; Davies, Faith E; Rosenthal, Adam; Wang, Hongwei; Qu, Pingping; Hoering, Antje; Samur, Mehmet; Towfic, Fadi; Ortiz, Maria; Flynt, Erin; Yu, Zhinuan; Yang, Zhihong; Rozelle, Dan; Obenauer, John; Trotter, Matthew; Auclair, Daniel; Keats, Jonathan; Bolli, Niccolo; Fulciniti, Mariateresa; Szalat, Raphael; Moreau, Philippe; Durie, Brian; Stewart, A Keith; Goldschmidt, Hartmut; Raab, Marc S; Einsele, Hermann; Sonneveld, Pieter; San Miguel, Jesus; Lonial, Sagar; Jackson, Graham H; Anderson, Kenneth C; Avet-Loiseau, Herve; Munshi, Nikhil; Thakurta, Anjan; Morgan, Gareth J

2018-06-08

Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1,273 newly diagnosed patients with multiple myeloma we identify 63 driver genes, some of which are novel including IDH1 , IDH2 , HUWE1 , KLHL6 , and PTPN11 Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more mutations in driver genes are associated with a worse outcome, as are those with identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in FGFR3 , DIS3 and PRKD2 ; t(11;14) with mutations in CCND1 and IRF4 ; t(14;16) with mutations in MAF , BRAF , DIS3 and ATM ; and hyperdiploidy with gain 11q, mutations in FAM46C and MYC rearrangements. These associations indicate that the genomic landscape of myeloma is pre-determined by the primary events upon which further dependencies are built, giving rise to a non-random accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens. Copyright © 2018 American Society of Hematology.

Drug discovery in prostate cancer mouse models.

PubMed

Valkenburg, Kenneth C; Pienta, Kenneth J

2015-01-01

The mouse is an important, though imperfect, organism with which to model human disease and to discover and test novel drugs in a preclinical setting. Many experimental strategies have been used to discover new biological and molecular targets in the mouse, with the hopes of translating these discoveries into novel drugs to treat prostate cancer in humans. Modeling prostate cancer in the mouse, however, has been challenging, and often drugs that work in mice have failed in human trials. The authors discuss the similarities and differences between mice and men; the types of mouse models that exist to model prostate cancer; practical questions one must ask when using a mouse as a model; and potential reasons that drugs do not often translate to humans. They also discuss the current value in using mouse models for drug discovery to treat prostate cancer and what needs are still unmet in field. With proper planning and following practical guidelines by the researcher, the mouse is a powerful experimental tool. The field lacks genetically engineered metastatic models, and xenograft models do not allow for the study of the immune system during the metastatic process. There remain several important limitations to discovering and testing novel drugs in mice for eventual human use, but these can often be overcome. Overall, mouse modeling is an essential part of prostate cancer research and drug discovery. Emerging technologies and better and ever-increasing forms of communication are moving the field in a hopeful direction.

Oxidative stress responses in gills of tilapia (Oreochromis niloticus) at different salinities

NASA Astrophysics Data System (ADS)

Handayani, Kiki Syaputri; Novianty, Zahra; Saputri, Miftahul Rohmah; Irawan, Bambang; Soegianto, Agoes

2017-08-01

The objective of present study is to evaluate the impact of different salinities on the levels of CAT, GSH and MDA of the gills of Nile tilapia (Oreochromis niloticus). Nile tilapia was treated by exposure to salinities concentration 0 ‰, 5 ‰ and 10 ‰. Research models were weakened and sacrificed, then took the left and right sides of the gills. The result of gills homogenity was centrifuged for supernatan, then supernatan was proceed with testing levels of CAT, GSH and MDA by ELISA assay methods. The levels of CAT in gills were significantly higher at 10 ‰ than at 5 ‰ and 0 ‰. The levels of GSH in gills were significantly higher at 0 ‰ than 5 ‰. The levels of GSH in gills at 5 ‰ and 10 ‰ salinities were not significantly different. The levels of MDA in gills at salinity 10 ‰ and 5 ‰ were higher than in control gills at 0 ‰ salinities. This occurs because the salinity of 10 ‰ salinity was optimal for live of fish tilapia. In conclusion, salinity impact the increasing of CAT, GSH, and MDA levels in gills of Nile tilapia.

PI3K/Akt inhibitor LY294002 potentiates homoharringtonine antimyeloma activity in myeloma cells adhered to stromal cells and in SCID mouse xenograft.

PubMed

Chen, Ping; Wen, Xiaofang; Wang, Bin; Hou, Diyu; Zou, Hong; Yuan, Qin; Yang, Hui; Xie, Jieqiong; Huang, Huifang

2018-05-01

Homoharringtonine (HHT) is a known anti-leukemia drug that inhibits multiple myeloma (MM) cells both in vitro and in vivo. Our prior study demonstrated that the potency of HHT in MM cells was compromised significantly when myeloma cells were co-cultured with BM stromal cells. This study aimed to investigate whether PI3K/Akt inhibitor LY294002 could potentiate the antimyeloma activity of HHT against MM cells adhered to BM stromal cells and in vivo xenograft models. A co-culture system composed of MM cells and human stromal cells was employed to mimic MM cells in bone marrow niche. The inhibitory and pro-apoptotic effect of HHT and LY294002 was determined by CCK-8 assay or flow cytometry. Expression of PI3K/Akt signaling molecules and anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) was assessed by western blot analysis and/or reverse transcription real-time quantitative PCR (RT-qPCR). MM xenografts were used to evaluate antitumor effect of combined therapy with HHT and LY294002. Adhesion to BM stromal cells rendered MM cells resistant to HHT whereas silencing Mcl-1 partly reversed the resistance. LY294002 induced apoptosis in MM cells and potentiated the antimyeloma effects of HHT by inhibiting the PI3K/Akt signal pathway which was abnormally activated during adhesion. LY294002 also enhanced the antimyeloma effect of HHT in in vivo xenograft models. These findings suggest that activation of PI3K/Akt signal pathway was responsible for the resistance to HHT in MM cells adhered to stromal cells. LY294002 can potentiate the antimyeloma activity of HHT both in vitro and in vivo, which may represent a new clinical treatment in MM.

A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Multiple Myeloma.

PubMed

Raju, G K; Gurumurthi, Karthik; Domike, Reuben; Kazandjian, Dickran; Landgren, Ola; Blumenthal, Gideon M; Farrell, Ann; Pazdur, Richard; Woodcock, Janet

2018-01-01

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision-making about new drugs to treat multiple myeloma (MM). MM assessments have been based on endpoints such as time to progression (TTP), progression-free survival (PFS), and objective response rate (ORR) which are different than benefit-risk analysis based on overall survival (OS). Twenty-three FDA decisions on MM drugs submitted to FDA between 2003 and 2016 were identified and analyzed. The benefits and risks were quantified relative to comparators (typically the control arm of the clinical trial) to estimate whether the median benefit-risk was positive or negative. A sensitivity analysis was demonstrated using ixazomib to explore the magnitude of uncertainty. FDA approval decision outcomes were consistent and logical using this benefit-risk framework. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Mechanism of immunomodulatory drugs' action in the treatment of multiple myeloma

PubMed Central

Chang, Xiubao; Zhu, Yuanxiao; Shi, Changxin; Stewart, A. Keith

2014-01-01

Although immunomodulatory drugs (IMiDs), such as thalidomide, lenalidomide, and pomalidomide, are widely used in the treatment of multiple myeloma (MM), the molecular mechanism of IMiDs' action is largely unknown. In this review, we will summarize recent advances in the application of IMiDs in MM cancer treatment as well as their effects on immunomodulatory activities, anti-angiogenic activities, intervention of cell surface adhesion molecules between myeloma cells and bone marrow stromal cells, anti-inflammatory activities, anti-proliferation, pro-apoptotic effects, cell cycle arrest, and inhibition of cell migration and metastasis. In addition, the potential IMiDs' target protein, IMiDs' target protein's functional role, and the potential molecular mechanisms of IMiDs resistance will be discussed. We wish, by presentation of our naive discussion, that this review article will facilitate further investigation in these fields. PMID:24374776

A prospective, randomized study of cryotherapy during administration of high-dose melphalan to decrease the severity and duration of oral mucositis in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation.

PubMed

Lilleby, K; Garcia, P; Gooley, T; McDonnnell, P; Taber, R; Holmberg, L; Maloney, D G; Press, O W; Bensinger, W

2006-06-01

Forty patients with multiple myeloma scheduled to receive melphalan 200 mg/m(2) followed by autologous stem cell transplantation were randomly assigned to receive oral cryotherapy or room temperature normal saline rinses 30 min before and for 6 h after high-dose therapy. Patients were evaluated for the development of mucositis using the National Cancer Institute grading system as well as evaluation of secondary measures such as days of total parenteral nutrition (TPN), narcotic use, hospitalization, weight loss and resumption of oral caloric intake for 28 days after transplant. Patients self-scored their pain, swallowing, drinking, eating, sleeping and taste alterations for 28 days. The primary end point of this trial was the incidence of grades 3-4 mucositis. Compared to the normal saline group, patients using cryotherapy experienced less grade 3-4 mucositis, 14 vs 74%, P=0.0005. Patients receiving cryotherapy also had statistically lower uses of narcotics and TPN, although there were no differences in length of hospitalization or weight loss. Patient-reported pain was significantly lower and activities were significantly better in the cryotherapy group.

The potentiality of Trichoderma harzianum in alleviation the adverse effects of salinity in faba bean plants.

PubMed

Abd El-Baki, G K; Mostafa, Doaa

2014-12-01

The interaction between sodium chloride and Trichoderma harzianum (T24) on growth parameters, ion contents, MDA content, proline, soluble proteins as well as SDS page protein profile were studied in Vicia faba Giza 429. A sharp reduction was found in fresh and dry mass of shoots and roots with increasing salinity. Trichoderma treatments promoted the growth criteria as compared with corresponding salinized plants. The water content and leaf area exhibited a marked decrease with increasing salinity. Trichoderma treatments induced a progressive increase in both parameters. Both proline and MDA contents were increased progressively as the salinity rose in the soil. Trichoderma treatments considerably retarded the accumulation of both parameters in shoots and roots. Both Na+ and K+ concentration increased in both organs by enhancing salinity levels. The treatment with Trichoderma harzianum enhanced the accumulation of both ions. Exposure of plants to different concentrations of salinity, or others treated with Trichoderma harzianum produced marked changes in their protein pattern. Three types of alterations were observed: the synthesis of certain proteins declined significantly, specific synthesis of certain other proteins were markedly observed and synthesis of a set specific protein was induced de novo in plant treated with Trichoderma harzianum.

Development of a mouse-feline chimeric antibody against feline tumor necrosis factor-alpha.

PubMed

Doki, Tomoyoshi; Takano, Tomomi; Hohdatsu, Tsutomu

2016-10-01

Feline infectious peritonitis (FIP) is a fatal inflammatory disease caused by FIP virus infection. Feline tumor necrosis factor (fTNF)-alpha is closely involved in the aggravation of FIP pathology. We previously described the preparation of neutralizing mouse anti-fTNF-alpha monoclonal antibody (mAb 2-4) and clarified its role in the clinical condition of cats with FIP using in vitro systems. However, administration of mouse mAb 2-4 to cat may lead to a production of feline anti-mouse antibodies. In the present study, we prepared a mouse-feline chimeric mAb (chimeric mAb 2-4) by fusing the variable region of mouse mAb 2-4 to the constant region of feline antibody. The chimeric mAb 2-4 was confirmed to have fTNF-alpha neutralization activity. Purified mouse mAb 2-4 and chimeric mAb 2-4 were repeatedly administered to cats, and the changes in the ability to induce feline anti-mouse antibody response were investigated. In the serum of cats treated with mouse mAb 2-4, feline anti-mouse antibody production was induced, and the fTNF-alpha neutralization effect of mouse mAb 2-4 was reduced. In contrast, in cats treated with chimeric mAb 2-4, the feline anti-mouse antibody response was decreased compared to that of mouse mAb 2-4-treated cats.

Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma.

PubMed

Mateos, María-Victoria; Granell, Miguel; Oriol, Albert; Martinez-Lopez, Joaquin; Blade, Joan; Hernandez, Miguel T; Martín, Jesus; Gironella, Mercedes; Lynch, Mark; Bleickardt, Eric; Paliwal, Prashni; Singhal, Anil; San-Miguel, Jesus

2016-11-01

Elotuzumab is an immunostimulatory, humanized immunoglobulin G1 monoclonal antibody that selectively targets and kills signalling lymphocytic activation molecule family member 7-expressing myeloma cells. We evaluated the safety and tolerability of elotuzumab 10 mg/kg combined with thalidomide 50-200 mg and dexamethasone 40 mg (with/without cyclophosphamide 50 mg) in patients with relapsed/refractory multiple myeloma (RRMM). The primary endpoint was the proportion of grade ≥3 non-haematological adverse events (AEs); other endpoints included the number of dose reductions/discontinuations and efficacy. Forty patients were treated, who had a median of three previous therapies, including bortezomib (98%) and lenalidomide (73%). Grade ≥3 non-haematological AEs were reported in 63% of patients, most commonly asthenia (35%) and peripheral oedema (25%). Six (15%) patients had an infusion reaction. Twenty-six (65%) patients had ≥1 dose reduction/discontinuation due to an AE, none related to elotuzumab. Overall response rate was 38%; median progression-free survival was 3·9 months. Median overall survival was 16·3 months and the 1-year survival rate was 63%. Minimal incremental toxicity was observed with addition of elotuzumab to thalidomide/dexamethasone with or without cyclophosphamide, and efficacy data suggest clinical benefit in a highly pre-treated population. Elotuzumab combined with thalidomide may provide an additional treatment option for patients with RRMM. © 2016 John Wiley & Sons Ltd.

Coexistence of chronic myelogenous leukemia and multiple myeloma. Case report and review of the literature.

PubMed

Tanaka, M; Kimura, R; Matsutani, A; Zaitsu, K; Oka, Y; Oizumi, K

1998-01-01

A case report of simultaneous presentation of chronic myelogenous leukemia (CML) and multiple myeloma (MM) in a 72-year-old female is described. Our case was typical of Ph1-positive and chimeric bcr-abl messenger RNA-positive CML. Furthermore, a marked IgG (kappa-type) paraproteinemia was present. Fluorescence in situ hybridization showed that 97% of marrow nucleated cells were positive for bcr-abl fusion signal, when myeloma cells in the bone marrow amounted to 19.0%. In the literature survey, 4 similar cases with coexistence of CML and MM have been identified.

New techniques to control salinity-wastewater reuse interactions in golf courses of the Mediterranean regions

NASA Astrophysics Data System (ADS)

Beltrao, J.; Costa, M.; Rosado, V.; Gamito, P.; Santos, R.; Khaydarova, V.

2003-04-01

Due to the lack water around the Mediterranean regions, potable water luxurious uses - as in golf courses - are increasingly contested. In order to solve this problem, non conventional water resources (effluent, gray, recycled, reclaimed, brackish), like treated wastewater, for irrigation gained increasing role in the planning and development of additional water supplies in golf courses. In most cases, the intense use of effluent for irrigation attracted public awareness in respect of contaminating pathogens and heavy metals. The contaminating effect of salinity in soil and underground water is very often neglected. The objective of this work is to present the conventional techniques to control salinity of treated wastewater and to present some results on new clean techniques to solve this problem, in the framework of the INCO-COPERNICUS project (no. IC-15CT98-0105) "Adaptation of Efficient Water Use Criteria in Marginal Regions of Europe and Middle Asia with Scarce Sources Subject to Environmental Control, Climate Change and Socio-Economic Development" and of the INCO-DC project (no. IC18-CT98-0266) "Control of Salination and Combating Desertification Effects in the Mediterranean Region. Phase II". Saline water is the most common irrigation water in arid climates. Moreover, for each region treated wastewater is always more saline than tap water, and therefore, when treated wastewater is reused in golf courses, more salinity problems occur. Conventional techniques to combat the salination process in golf courses can be characterized by four generations: 1) Problem of root zone salination by soil leaching - two options can occur - when there is an impermeable layer, salts will be concentrated above this layer; on the other hand, when there is no impermeable layer, aquifers contamination can be observed; 2) Use of subsurface trickle irrigation - economy of water, and therefore less additional salts; however the problem of groundwater contamination due to natural rain

Influence of intramuscular granisetron on experimentally induced muscle pain by acidic saline.

PubMed

Louca, S; Ernberg, M; Christidis, N

2013-06-01

The aim of this study was to investigate whether intramuscular administration of the 5-HT(3) receptor antagonist granisetron reduces experimental muscle pain induced by repeated intramuscular injections of acidic saline into the masseter muscles. Twenty-eight healthy and pain-free volunteers, fourteen women and fourteen men participated in this randomized, double-blind and placebo-controlled study. After a screening examination and registration of the baseline pressure-pain threshold (PPT), the first simultaneous bilateral injections of 0·5 mL acidic saline (9 mg mL(-1) , pH 3·3) into the masseter muscles were performed. Two days later, PPT and pain (VAS) were re-assessed. The masseter muscle was then pre-treated with 0·5 mL granisetron (Kytril(®) 1 mg mL(-1) pH 5·3) on one side and control substance (isotonic saline, 9 mg mL(-1) pH 6) on the contralateral side. Two minutes thereafter a bilateral simultaneous injection of 0·5 mL acidic saline followed. The evoked pain intensity, pain duration, pain area and PPT were assessed. The volunteers returned 1 week later to re-assess VAS and PPT. On the side pre-treated with granisetron, the induced pain had significantly lower intensity and shorter duration (P < 0·05) compared with the side pre-treated with control. A subgroup analysis showed that the effect of granisetron on pain duration was significant only in women (P < 0·001), while the effect on peak pain and pain area were significant in both sexes. The results showed no significant change in PPT. In conclusion, these results indicate that granisetron has a pain-reducing effect on experimentally induced muscle pain by repeated acidic saline injection. © 2013 John Wiley & Sons Ltd.

Proteasome 20S in multiple myeloma: comparison of concentration and chymotrypsin-like activity in plasma and serum.

PubMed

Romaniuk, Wioletta; Kalita, Joanna; Ostrowska, Halina; Kloczko, Janusz

2018-03-05

The ubiquitin-proteasome system is relevant in the pathobiology of many haematological malignancies, including multiple myeloma. The assessment of proteasome concentration and chymotrypsin-like (ChT-L) activity might constitute a new approach to diagnosis, prognosis and monitoring of anticancer treatment of patients with haematological malignancies and other diseases. The aim of our study was to determine which material, plasma or serum, is better for measuring chymotrypsin-like (ChT-L) activity and proteasome concentration. We analysed proteasome concentration and chymotrypsin-like (ChT-L) activity in 70 plasma and serum samples drawn from 28 patients at different treatment stages for multiple myeloma (MM) and 31 healthy volunteers. Proteasome ChT-L activity and concentration in multiple myeloma patients were significantly higher in plasma compared to serum. In this group we observed significant and positive correlations both between the plasma and serum proteasome ChT-L activity and plasma and serum proteasome concentration. The higher values of proteasome concentration and ChT-L activity in plasma than in serum and their better correlations with parameters of tumour load and prognosis suggest that plasma constitutes a better biological material for measuring ChT-L activity and proteasome concentration than serum in multiple myeloma patients.

Reassessment of the relationship between M-protein decrement and survival in multiple myeloma.

PubMed

Palmer, M; Belch, A; Hanson, J; Brox, L

1989-01-01

The relationship between percentage M-protein decrement and survival is assessed in 134 multiple myeloma patients. The correlation did not achieve statistical significance (P = 0.069). Multivariate analysis using the Cox proportional hazards model, including a number of previously recognised prognostic factors, showed only percentage M-protein decrement, creatinine and haemoglobin to be significantly correlated with survival. However, the R'-statistic for each of these variables was low, indicating that their prognostic power is weak. We conclude that neither the percentage M-protein decrement nor the response derived from it can be used as an accurate means of assessing the efficacy of treatment in myeloma. Mature survival data alone should be used for this purpose.

Reassessment of the relationship between M-protein decrement and survival in multiple myeloma.

PubMed Central

Palmer, M.; Belch, A.; Hanson, J.; Brox, L.

1989-01-01

The relationship between percentage M-protein decrement and survival is assessed in 134 multiple myeloma patients. The correlation did not achieve statistical significance (P = 0.069). Multivariate analysis using the Cox proportional hazards model, including a number of previously recognised prognostic factors, showed only percentage M-protein decrement, creatinine and haemoglobin to be significantly correlated with survival. However, the R'-statistic for each of these variables was low, indicating that their prognostic power is weak. We conclude that neither the percentage M-protein decrement nor the response derived from it can be used as an accurate means of assessing the efficacy of treatment in myeloma. Mature survival data alone should be used for this purpose. PMID:2757916

Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma.

PubMed

Mateos, María-Victoria; Dimopoulos, Meletios A; Cavo, Michele; Suzuki, Kenshi; Jakubowiak, Andrzej; Knop, Stefan; Doyen, Chantal; Lucio, Paulo; Nagy, Zsolt; Kaplan, Polina; Pour, Ludek; Cook, Mark; Grosicki, Sebastian; Crepaldi, Andre; Liberati, Anna M; Campbell, Philip; Shelekhova, Tatiana; Yoon, Sung-Soo; Iosava, Genadi; Fujisaki, Tomoaki; Garg, Mamta; Chiu, Christopher; Wang, Jianping; Carson, Robin; Crist, Wendy; Deraedt, William; Nguyen, Huong; Qi, Ming; San-Miguel, Jesus

2018-02-08

The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival. At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 10 5 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab-associated infusion-related reactions occurred in 27

Hemostatic Abnormalities in Multiple Myeloma Patients

PubMed Central

Gogia, Aarti; Sikka, Meera; Sharma, Satender; Rusia, Usha

2018-01-01

Background: Multiple myeloma (MM) is a neoplastic plasma cell disorder characterized by clonal proliferation of plasma cells in the bone marrow. Diverse hemostatic abnormalities have been reported in patients with myeloma which predispose to bleeding and also thrombosis. Methods: Complete blood count, biochemical parameters and parameters of hemostasis i.e. platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), factor VIII assay results, plasma fibrinogen, D-dimer and lupus anticoagulant, were assessed in 29 MM patients and 30 age matched controls. Results: The most frequent abnormal screening parameter was APTT. Of the six indicative of a bleeding tendency i.e. thrombocytopenia, prolonged PT, APTT, TT, reduced plasma fibrinogen and factor VIII, at least one was abnormal in 8 (27.6%) patients. Of the four prothrombotic markers, lupus anticoagulant, D-dimer, elevated factor VIII and plasma fibrinogen, one or more marker was present in 24 (82.7%). D-dimer was the most common prothrombotic marker, being elevated in 22 (75.9%) patients. One or more laboratory parameter of hemostasis was abnormal in all 29 (100%) patients. Though thrombotic complications are reported to be less frequent as compared to hemorrhagic manifestations, one or more marker of thrombosis was present in 24 (82.7%) patients. Conclusion: This study provided laboratory evidence of hemostatic dysfunction which may be associated with thrombotic or bleeding complications at diagnosis in all MM patients. Hence, screening for these abnormalities at the time of diagnosis should help improved prognosis in such cases. PMID:29373903

Treatment of aggressive multiple myeloma by high-dose chemotherapy and total body irradiation followed by blood stem cells autologous graft

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fermand, J.P.; Levy, Y.; Gerota, J.

1989-01-01

Eight patients with stage III aggressive multiple myeloma, refractory to current chemotherapy in six cases, were treated by high-dose chemotherapy (nitrosourea, etoposide, and melphalan) (HDC) and total body irradiation (TBI), followed by autografting with blood stem cells. These cells were previously collected by leukapheresis performed during hematologic recovery following cytotoxic drug-induced bone marrow aplasia. Seven patients were alive 9 to 17 months after HDC-TBI and graft. One died at day 40 from cerebral bleeding. All living patients achieved a 90% or greater reduction in tumor mass. In two cases, a complete remission (CR) has persisted at a follow-up of 15more » and 16 months. Three patients have been well and off therapy with stable minimal residual disease (RD) since 10, 11, and 17 months, respectively. A patient in apparent CR and another with RD have relapsed 9 to 12 months posttreatment. Autologous blood-derived hematopoietic stem cells induced successful and sustained engraftment in all living patients. These results, although still preliminary, indicate that HDC and TBI, followed by blood stem cells autograft, which has both practical and theoretical interest over allogeneic or autologous bone marrow transplantation, deserve consideration in selected patients with multiple myeloma.« less

Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma.

PubMed