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

Science.gov (United States)

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 plasmacytomas

International Nuclear Information System (INIS)

Mill, W.B.; Wasserman, T.H.

1987-01-01

Radiation therapy is the primary modality of treatment in the management of solitary plasmacytomas. The dose of radiation recommended is 5500 to 6000 cGy in 6 to 8 weeks. Disseminated myeloma is primarily treated with chemotherapy, which frequently includes melphalan and prednisone. Other drugs that are active in this disease are cyclophophamide, vincristine, procarbazine, BCNU, and doxorubicin. Adjuvant radiation therapy is indicated for painful bone lesions, for prevention and treatment of pathologic features of long bones, for spinal cord compression, and to relieve pressure from soft tissue masses. Myeloma is a relatively radiosensitive tumor requiring only 1000 to 2000 cGy in 1 to 2 weeks to relieve most painful lesions

Myelomatous ascites as an initial manifestation of extramedullary involvement of multiple myeloma

Energy Technology Data Exchange (ETDEWEB)

Choi, Seo Youn; Lee, Hae Kyung; Yi, Boem Ha; Lee, Min Hee; Kim, Hee Kyung; Park, Seong Kyu [Soonchunhyang University Bucheon Hospital, Bucheon (Korea, Republic of)

2017-03-15

Multiple myeloma is a common hematological malignancy. Aggressive myeloma invades the organs outside the bone marrow, lymph, or reticuloendothelial systems. Among the extramedullary involvements of multiple myeloma, myelomatous ascites are extremely rare and are associated with a poor prognosis. We describe a case of myelomatous ascites as an initial manifestation of extramedullary involvement of multiple myeloma in 39-year-old patient. The patient was treated with high-dose chemotherapy, but extensive extramedullary involvement progressed, and the patient expired approximately five months after the initial detection of ascites.

Multiple myeloma with extramedullary disease.

Science.gov (United States)

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.

Evaluation of serial bone X-ray examination in multiple myeloma

Energy Technology Data Exchange (ETDEWEB)

Wahlin, A.; Holm, J.; Osterman, G.; Norberg, B. (University Hospital, Umeaa (Sweden). Dept. of Internal Medicine and Diagnostic Radiology I)

1982-01-01

Fifteen patients with multiple myeloma stage III were treated with a combination of cytostatics and plasmapheresis in a sequential trial running for 60 weeks. Thirteen patients showed clinical improvement and ten a reduction of thieir myeloma protein by at least 50%. Bone X-ray examination was performed every 15 weeks. Progression of bone lesions was seen in one patient, whereas the radiographic picture was unchanged in the others. It is concluded that bone X-ray, although essential in the diagnosis and staging of multiple myeloma, is not suitable for the monitoring of patients during treatment.

Transcatheter shunt embolotherapy in multiple myeloma with high output heart failure

Energy Technology Data Exchange (ETDEWEB)

Kim, Jeong Ho [Wonkwang University School of Medicine, Iksan (Korea, Republic of); Ko, Gi Young; Yoon, Hyun Ki; Sung, Kyu Bo [Ulsan University College of Medicine, Seoul (Korea, Republic of)

2002-12-01

High-output heart failure may be fairly common in patients with multiple myeloma and is associated with severe bone involvement. In this report, we describe the case of a 67-year-old man with multiple myeloma who presented with high output heart failure subsequently treated by transcatheter arterial embolization.

Transcatheter shunt embolotherapy in multiple myeloma with high output heart failure

International Nuclear Information System (INIS)

Kim, Jeong Ho; Ko, Gi Young; Yoon, Hyun Ki; Sung, Kyu Bo

2002-01-01

High-output heart failure may be fairly common in patients with multiple myeloma and is associated with severe bone involvement. In this report, we describe the case of a 67-year-old man with multiple myeloma who presented with high output heart failure subsequently treated by transcatheter arterial embolization

Comparison of Thromboemboli Prophylactic Effect of Aspirin and Low Dose Warfarin in Standard Risk Multiple Myeloma Patients that Treated with Regimens Containing Thalidomide

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Seyed Amir Dadkhahi

2017-05-01

Full Text Available Abstract Background: Most of the current regimens in the treatment of multiple myeloma include thalidomide. Thalidomide is a modulator of the immune system and according to several studies, its main complication is thromboembolism. The aim of this study is to compare the thromboemboli prophylactic effect of aspirin and low dose warfarin in standard risk multiple myeloma patients that treated with regimens containing thalidomide. Materials and Methods: In this double- blind clinical trial study, sixty-six patients with multiple myeloma under treatment with thalidomide-containing regimens with standard risk for thromboembolism who were admitted to Khansari hospital, entered the study according to inclusion and exclusion criteria. The incidence of thromboembolism in these patients was evaluated. Results: Five patients in the warfarin group and 2 patients in the aspirin group had thromboemboli. Chi square analyses showed no significant difference between groups (p=0.635. Conclusion: The results showed that both drugs are effective in preventing thromboembolism and can be used as a prophylactic treatment.

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

OpenAIRE

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 plu...

Osteoclastome-like giant cell thyroid carcinoma controlled by intensive radiation and adriamycin, in a patient with meningioma and multiple myeloma treated by radiation and cytoxan

International Nuclear Information System (INIS)

Vizel-Schwartz, M.

1981-01-01

The eighth cases of osteoclastome-like giant cell carcinoma of the thyroid, and the first one to be treated with adriamycin in addition to surgery and radiation, is reported. This rare variant of anaplastic thyroid carcinoma appeared in a patient operated on for meningioma and treated for multiple myeloma with cranial radiation and chronic administration of cytoxan

Pharmacovigilance of patients with multiple myeloma being treated with bortezomib and/or thalidomide

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T.B.M. Castro

2016-01-01

Full Text Available In order to evaluate the main adverse effects of drug protocols using bortezomib and/or thalidomide for the treatment of multiple myeloma, we conducted a prospective study. Data were collected through interviews, clinical observation, and from hospital records. A total of 59 patients were included. There was a predominance of females, 36 (61% vs 23 (39% males, and of whites, 49 (83.1% vs 10 (16.9% blacks. Age ranged from 40 to 94 years, with a median of 65 years (SD=11.6. Regarding staging at diagnosis, 27 (45.7% patients were in stage III-A, with 12 (20.3% patients having serum creatinine ≥2 mg/dL. The main adverse effects in the bortezomib treatment group (n=40 were: neutropenia (42.5%, diarrhea (47.5%, and peripheral neuropathy in 60% of cases, with no difference between the iv (n=26 and sc (n=14 administration routes (P=0.343. In the group treated with thalidomide (n=19, 31.6% had neutropenia, 47.4% constipation, and 68.4% peripheral neuropathy. Neutropenia was associated with the use of alkylating agents (P=0.038. Of the 3 patients who received bortezomib in combination with thalidomide, only 1 presented peripheral neuropathy (33.3%. Peripheral neuropathy was the main adverse effect of the protocols that used bortezomib or thalidomide, with a higher risk of neutropenia in those using alkylating agents. Improving the identification of adverse effects is critical in multiple myeloma patient care, as the patient shows improvements during treatment, and requires a rational and safe use of medicines.

Introduction: multiple myeloma.

Science.gov (United States)

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.

Stages of Plasma Cell Neoplasms (Including Multiple Myeloma)

Science.gov (United States)

... cancer treatment is also called biotherapy or immunotherapy. Immunomodulators are a type of biologic therapy. Thalidomide , lenalidomide , and pomalidomide are immunomodulators used to treat multiple myeloma and other plasma ...

Comparative analysis of CD138 antigen targeting for the treatment of multiple myeloma with bismuth-213 and Melphalan chemotherapy

International Nuclear Information System (INIS)

Gouard, S.; Gaschet, J.; Maurel, C.; Barbet, J.; Davodeau, F.; Pallardy, A.; Faivre-Chauvet, A.; Kraeber-Bodere, F.; Bruchertseifer, F.; Morgenstern, A.; Cherel, M.

2015-01-01

Full text of publication follows. Aim: multiple myeloma (MM) is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow, with the presence of a monoclonal immunoglobulin in serum and/or urine and development of osteolytic bone lesions in human. Despite intense research to develop new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) has been shown to be effective in vivo in a multiple myeloma model and seems particularly suited for disseminated tumour cells or small clusters of tumour cells. CD138 (Syndecan-1) is found mainly in epithelial cells, but has been shown to be expressed by most myeloma cells, both in human and in mouse. In order to define where alpha RIT stands in MM treatment, the aim of this study was to compare Melphalan, MM standard treatment, with alpha RIT using a bismuth-213-labelled anti-mouse CD138 rat antibody in a syngeneic mouse MM model. Material and Methods: C57BL/KaLwRij mice were grafted with 10 6 5T33 cells (murine myeloma cells). Luciferase transfected 5T33 were used for in vivo localization of the cells during the course of disease. The first step of the study was to assess the dose-response of Melphalan (100, 200 et 300 μg/mouse), 21 days after engraftment. The second step consisted in therapeutic association: Melphalan followed by RIT at d22 et d25 after engraftment. Toxicity (animal weight, blood cell counts) and treatment efficacy were studied in animals receiving no treatment, injected with Melphalan alone (200 μg), RIT alone at d22 and d25 (3.7 MBq of 213 Bi-anti-CD138) and Melphalan combined with alpha RIT. Results: fifty percent of untreated mice died by d64 after MM engraftment. In mice treated with Melphalan alone, only the 200 μg dose improved median survival. No animal was cured after Melphalan treatment whereas 60% of the mice survived with RIT alone at d22 after tumour engraftment. However, the therapeutic window seems to be narrow, indeed no effect was observed with

Apoptotic Effect of Anti myeloma Polyclonal Antibodies on The Growth of Myeloma Cells

International Nuclear Information System (INIS)

Abd El-Ghany, I.Y.; El-Kolaly, M.T.; Moustafa, K.A.; El-Shershaby, H.M.; Sayed, A.A.; Borai, I.H.; El-Lahloby, N.M.

2013-01-01

Multiple myeloma (MM) is a malignancy characterized by proliferation of plasma cells. Cancer immunotherapy is a major branch of biological therapy that utilizes living cells and their products. The aim of this study is to produce and evaluate the antiproliferative effect of anti myeloma polyclonal antibodies (with and without labelling with radioactive isotopes) against the growth of myeloma cells. The production of polyclonal antibodies (PAb) was generated by immunizing five healthy female mature white New-Zealand rabbits with myeloma cells (SP2/OR) through primary injection and five booster doses. The preparation of labelled anti myeloma antibodies was carried out using chloramine-T method and it was purified using PD-10 chromatographic column. The results obtained revealed that anti myeloma polyclonal antibodies inhibited proliferation and induced apoptosis of myeloma cell lines in vitro and induced apoptosis after serial intraperitoneal injection of PAb in ascites bearing mice in vivo. The present study suggested that the effect of labelled anti myeloma antibodies on myeloma cells growth inhibition was more effective than that of anti myeloma antibodies without labelling which is due to the cytotoxic effect of ionizing radiation. Apoptosis triggered by PAb was confirmed by flow cytometry, caspase -8 and -9 and β2-microglobulin.

Technetium-99m Sestamibi in Multiple Myeloma

International Nuclear Information System (INIS)

Saber, R.A.

2002-01-01

Technetium-99m 2-methoxy - isobutyl - isonitrile (99mTc-MIBI) has been reported to be useful in evaluating patients with multiple myeloma. The aim of this study is to evaluate the role of technetium-99m sestamibi (99mTc-MIBI) scintigraphy in the diagnosis. staging and follow-up of patients with multiple myeloma. Methods and Materials: twenty-five consecutive patients with multiple myeloma were studied using 99mTc- MIBI. Of the 25 patients included in this study, 6 were in stage I, II in stage II and 8 in stage III. Anterior and posterior whole-body imaging were obtained 20 min after I.V. injection of 740 MBq of 99mTc-MIBI. Four different MIBI patterns could be described in our patients: physiological (P), diffuse (D), focal (F) and combined diffuse and focal (D+F). All patients in stages II and III as well as 3 patients in stage I were treated with chemotherapy (cyclophosphamide and prednisone) then 99mTc-MlBI scans were repeated after 6 courses. Results: in comparison to conventional X-ray skeletal survey, 99mTc-MIBI scans showed a higher number of myeloma bone disease at diagnosis. All patients with stage II and III multiple myeloma were positive with 99mTc-MlBl scans at diagnosis. The pattern of positive MIBI accumulation was diffuse in 13 (52%) patients, focal in 4 (16%) and combined focal and diffuse in 6 (24%) patients. The intensity of 99mTc-MIBI correlated with disease activity as determined by lactate dehydrogenase (LDH), number of plasma cells in bone marrow and serum electrophoresis. There was a direct correlation between 99mTc-MIBI scan result and clinical outcome of patients following 6 courses of chemotherapy. Sensitivity and specificity of 99mTc-MIBI scintigraphy in detecting myeloma bone lesions were 92% and 90% respectively. Conclusion: 99mTc-MIBI scintigraphy is a reliable method to evaluate bone marrow activity in patients with multiple myeloma and follow-up of myeloma bone lesions

Sequential hemi-body radiotherapy in advanced multiple myeloma

International Nuclear Information System (INIS)

Jaffe, J.P.; Bosch, A.; Raich, P.C.

1979-01-01

Eleven patients with advanced multiple myeloma refractory to standard chemotherapy were treated with a regimen of sequential hemi-body radiotherapy consisting of 800 rad midplane in a single dose to each half. 9/10 patients experienced significant relief of skeletal pain and there were 5/11 objective tumor responses with one complete remission. Treatment-related morbidity was significant and consisted primarily of nausea and emesis, bone marrow suppression, and pneumonitis. This therapy is helpful in the management of advanced myeloma, and should be studied earlier in the course of the disease

Treatment Options for Plasma Cell Neoplasms (Including Multiple Myeloma)

Science.gov (United States)

... cancer treatment is also called biotherapy or immunotherapy. Immunomodulators are a type of biologic therapy. Thalidomide , lenalidomide , and pomalidomide are immunomodulators used to treat multiple myeloma and other plasma ...

Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study

NARCIS (Netherlands)

Lokhorst, Henk M.; van der Holt, Bronno; Cornelissen, Jan J.; Kersten, Marie-José; van Oers, Marinus; Raymakers, Reinier; Minnema, Monique C.; Zweegman, Sonja; Janssen, Jeroen J.; Zijlmans, Mark; Bos, Gerard; Schaap, Nicolaas; Wittebol, Shulamiet; de Weerdt, Okke; Ammerlaan, Rianne; Sonneveld, Pieter

2012-01-01

To prospectively evaluate allogeneic stem cell transplantation (allo-SCT) for myeloma as part of first-line therapy, a donor versus no-donor analysis was performed of patients treated in the HOVON-50 study, a study that was originally designed to examine thalidomide combined with intensive therapy.

Updated survivals and prognostic factor analysis in myeloma treated by a staged approach use of bortezomib/thalidomide/dexamethasone in transplant eligible patients

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Chim Chor

2010-11-01

Full Text Available Abstract Background Bortezomib, an NFkB inhibitor, is an active agent for the treatment of myeloma (MM. We have reported a promising complete remission (CR rate for newly diagnosed myeloma patients treated by a staged approach, in which chemosensitive patients underwent autologous haematopoietic stem cell transplantation (auto-HSCT while less chemosensitive patients received salvage therapy with bortezomib/thalidomide/dexamethasone prior to auto-HSCT. Methods Herein, with an additional 13 months of follow-up, we reported the updated survivals, and examined potential prognostic factors impacting event-free (EFS and overall survival (OS. Results With a median follow-up of 30 months, the projected OS was 73% and EFS was 50.2%. Age, gender, clinical stage and DAPK methylation could not account for the differential chemosensitivity. Advanced ISS stage and DAPK methylation adversely impacted OS whereas oligoclonal reconstitution predicted superior EFS. Conclusions Our staged approach illustrated an economical use of expensive targeted agents while preserving a good CR rate and OS. The comparable survivals of chemosensitive and less chemosensitive patients suggested the staged approach might have abolished the adverse prognostic impact of suboptimal chemosensitivity. Finally, the adverse impact of DAPK methylation and favorable impact of oligoclonal reconstitution in myeloma warrants further study.

Neovascular niche for human myeloma cells in immunodeficient mouse bone.

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Hirono Iriuchishima

Full Text Available The interaction with bone marrow (BM plays a crucial role in pathophysiological features of multiple myeloma (MM, including cell proliferation, chemoresistance, and bone lesion progression. To characterize the MM-BM interactions, we utilized an in vivo experimental model for human MM in which a GFP-expressing human MM cell line is transplanted into NOG mice (the NOG-hMM model. Transplanted MM cells preferentially engrafted at the metaphyseal region of the BM endosteum and formed a complex with osteoblasts and osteoclasts. A subpopulation of MM cells expressed VE-cadherin after transplantation and formed endothelial-like structures in the BM. CD138(+ myeloma cells in the BM were reduced by p53-dependent apoptosis following administration of the nitrogen mustard derivative bendamustine to mice in the NOG-hMM model. Bendamustine maintained the osteoblast lining on the bone surface and protected extracellular matrix structures. Furthermore, bendamustine suppressed the growth of osteoclasts and mesenchymal cells in the NOG-hMM model. Since VE-cadherin(+ MM cells were chemoresistant, hypoxic, and HIF-2α-positive compared to the VE-cadherin(- population, VE-cadherin induction might depend on the oxygenation status. The NOG-hMM model described here is a useful system to analyze the dynamics of MM pathophysiology, interactions of MM cells with other cellular compartments, and the utility of novel anti-MM therapies.

Multiple myeloma on polycythemia vera following radioactive phosphorus therapy

International Nuclear Information System (INIS)

West, W.O.

1976-01-01

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 3 / 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

Nephrogenic Diabetes Insipidus: A Rare Presentation in Multiple Myeloma

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Mehdi Dehghani

2012-04-01

Full Text Available We report a case of multiple myeloma that presented with anorexia, fatigue, high erythrocyte sedimentation rate, bone marrow plasmacytosis of more than 30%, polyuria,and low urine specific gravity. This unusual presentation was diagnosed as nephrogenic diabetes insipidus secondary to a proximal tubular dysfunction. The tubular functional disturbance appeared to be related to thepresence of lambda-type light chains. The patient was treated withdesmopressine without response. After one month of treatment with thalidomide and dexamethasone for myeloma there was a dramatic response with decreased urine output.

Inhibition of fatty acid metabolism reduces human myeloma cells proliferation.

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José Manuel Tirado-Vélez

Full Text Available 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.

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

Science.gov (United States)

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

Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation

DEFF Research Database (Denmark)

Boissy, Patrice; Andersen, Thomas L; Abdallah, Basem M

2005-01-01

, a challenge for treating multiple myeloma is discovering drugs targeting not only myeloma cells but also osteoclasts and osteoblasts. Because resveratrol (trans-3,4',5-trihydroxystilbene) is reported to display antitumor activities on a variety of human cancer cells, we investigated the effects...... of this natural compound on myeloma and bone cells. We found that resveratrol reduces dose-dependently the growth of myeloma cell lines (RPMI 8226 and OPM-2) by a mechanism involving cell apoptosis. In cultures of human primary monocytes, resveratrol inhibits dose-dependently receptor activator of nuclear factor......RNA and cell surface protein levels and a decrease of NFATc1 stimulation and NF-kappaB nuclear translocation, whereas the gene expression of c-fms, CD14, and CD11a is up-regulated. Finally, resveratrol promotes dose-dependently the expression of osteoblast markers like osteocalcin and osteopontin in human bone...

Emerging therapies in multiple myeloma.

Science.gov (United States)

El-Amm, Joelle; Tabbara, Imad A

2015-06-01

The treatment of multiple myeloma has evolved significantly over the past 2 decades due to the use of high-dose chemotherapy and autologous stem cell transplantation, and the subsequent introduction of the immunomodulatory agents (thalidomide and lenalidomide) and the proteasome inhibitor (bortezomib). The median overall survival of multiple myeloma patients has increased significantly with patients younger than age 50 years experiencing a 10-year survival rate of around 40%. However, despite the increased effectiveness of the first-line agents, the majority of patients will eventually relapse and become drug resistant. Promising novel therapies have recently emerged and are being used to treat relapsed and refractory patients. This review will cover the clinical data regarding these emergent therapies that include new generation of proteasome inhibitors (carfilzomib, ixazomib, oprozomib, and marizomib), immunomodulatory drugs (pomalidomide), monoclonal antibodies (elotuzumab and daratumumab), signal transduction modulator (perifosine), and histone deacetylase inhibitors (vorinostat and panobinostat).

Multiple myeloma: Results of radiotherapy in skeletal lesions

International Nuclear Information System (INIS)

Budach, V.; Hueltenschmidt, B.; Stuschke, M.; Stueben, G.; Sack, H.; Bamberg, M.

1991-01-01

In this retrospective study the records of 157 patients with the diagnosis of multiple myeloma were evaluated with regard to subjective pain relief after a series of radiation therapy at 389 local sites. The most frequently treated region was the spine (50.2%), followed by the thoracic wall (17.9%) and the upper and lower extremities (17.8%). The median survival after diagnosis of all patients was 36 months. 88.4% of all treated sites showed good to moderate response in terms of pain remission after irradiation. It is shown that pain relief is significantly dependent on the total dose but independent of the dose per fraction. A total dose of 30 Gy in two weeks (5x3 Gy/week) is recommended as a well tolerated and reasonable treatment option to achieve maximum palliation and minimum hospitalization time for patients in whom multiple myeloma is diagnosed. (orig.) [de

Immune Recovery after Cyclophosphamide Treatment in Multiple Myeloma: Implication for Maintenance Immunotherapy

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Amir Sharabi

2011-01-01

Full Text Available Multiple myeloma (MM is a progressive B-lineage neoplasia characterized by clonal proliferation of malignant plasma cells. Increased numbers of regulatory T cells (Tregs were determined in mouse models and in patients with MM, which correlated with disease burden. Thus, it became rational to target Tregs for treating MM. The effects of common chemotherapeutic drugs on Tregs are reviewed with a focus on cyclophosphamide (CYC. Studies indicated that selective depletion of Tregs may be accomplished following the administration of a low-dose CYC. We report that continuous nonfrequent administrations of CYC at low doses block the renewal of Tregs in MM-affected mice and enable the restoration of an efficient immune response against the tumor cells, thereby leading to prolonged survival and prevention of disease recurrence. Hence, distinctive time-schedule injections of low-dose CYC are beneficial for breaking immune tolerance against MM tumor cells.

Palliative radiotherapy in plasma cell myeloma

International Nuclear Information System (INIS)

Adamietz, I.A.; Schoeber, C.; Schulte, R.W.M.; Renner, K.; Peest, D.

1991-01-01

Pain symptoms caused by bone lesions of multiple myeloma can be relieved by a local irradiation treatment. To estimate the influence of systemic treatment on the palliative effect of local radiotherapy the records of 70 myeloma patients treated with chemotherapy combined with or followed by local irradiation were reviewed. The local response rate, defined as complete pain relief at the irradiated site, was 80 percent in patients receiving irradiation during chemotherapy (melphalan and prednisone) and this palliative effect endured 31.8+-3.6 months. If irradiation was started in the period without systemic treatment the local response rate was 39.6 percent and lasted 24.8+-17.9 months. In sites treated with more than one radiotherapy course 94 percent response after the 1st treatment, 56 percent after the 2nd and no response after the 3rd was achieved. The duration of local pain control was positively related to the applied radiation dose. It is concluded that irradiation during concomitant chemotherapy is superior to radiotherapy performed in a period without systemic treatment. Local long-term palliation can only be achieved by a sufficient high radiation dose. (author). 24 refs.; 2 figs.; 2 tabs

Effects of radiotherapy in the treatment of multiple myeloma

International Nuclear Information System (INIS)

Ochtrop, Thomas Alexander

2015-01-01

Palliative irradiation of osteolytic lesions is a considerable component in the treatment for patients with multiple myeloma. In this study, we analyzed the efficacy of irradiation in these patients. Patients and methods: We retrospectively analyzed 153 patients with multiple myeloma who were admitted to our department between 1989 and 2013. According to the staging system of Durie and Salmon 116 patients were classified as stage III. 107/153 patients were treated with radiotherapy of at least one and up to 6 bony lesions at different times. In order to evaluate the effect of local radiotherapy on pain relief and bone recalcification a uni- and multivariate analysis was performed using a binary logistic regression model to correct for multiple measurements. Complete information on dose, fractionation and volume of radiotherapy was available from 81 patients treated in 136 target volumes for pain relief, and from 69 patients treated in 108 target volumes for recalcification. Total radiation doses varied between 8 Gy to 50 Gy (median dose 25 Gy in 2.5 Gy fractions, 5 times a week). Results: Radiotherapy resulted in complete local pain relief in 31% and partial local pain relief in 54% of the patients. In the univariate analysis, higher total radiation doses (p = 0.023) and higher age (p = 0.014) at the time of radiotherapy were significantly associated with a higher likelihood of pain relief, whereas no significant association was detected for concurrent systemic treatment, type and stage of myeloma and location of bone lesions. The same variables were independent predictors for pain relief in the multivariate analysis. Recalcification was observed in 48% of irradiated bone lesions. In the uni- and multivariate analysis higher radiation doses were significantly associated (p = 0.048) with an increased likelihood of recalcification. Side effects of radiotherapy were generally mild. Conclusions: Higher total biological radiation doses were associated with better pain

Paclitaxel-Fe3O4 nanoparticles inhibit growth of CD138–  CD34– tumor stem-like cells in multiple myeloma-bearing mice

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Yang C

2013-04-01

Full Text Available Cuiping Yang,1,3,* Jing Wang,2,* Dengyu Chen,1,* Junsong Chen,1 Fei Xiong,4 Hongyi Zhang,1 Yunxia Zhang,2 Ning Gu,4 Jun Dou11Department of Pathogenic Biology and Immunology, Medical School, 2Department of Gynecology and Obstetrics, Zhongda Hospital, Southeast University, Nanjing, 3Department of Pathogenic Biology and Immunology, School of Basic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 4School of Biological Science and Medical Engineering, Southeast University, Nanjing, People’s Republic of China*These authors contributed equally to this workBackground: There is growing evidence that CD138– CD34– cells may actually be tumor stem cells responsible for initiation and relapse of multiple myeloma. However, effective drugs targeted at CD138– CD34– tumor stem cells are yet to be developed. The purpose of this study was to investigate the inhibitory effect of paclitaxel-loaded Fe3O4 nanoparticles (PTX-NPs on CD138– CD34– tumor stem cells in multiple myeloma-bearing mice.Methods: CD138– CD34– cells were isolated from a human U266 multiple myeloma cell line using an immune magnetic bead sorting method and then subcutaneously injected into mice with nonobese diabetic/severe combined immunodeficiency to develop a multiple myeloma-bearing mouse model. The mice were treated with Fe3O4 nanoparticles 2 mg/kg, paclitaxel 4.8 mg/kg, and PTX-NPs 0.64 mg/kg for 2 weeks. Tumor growth, pathological changes, serum and urinary interleukin-6 levels, and molecular expression of caspase-3, caspase-8, and caspase-9 were evaluated.Results: CD138– CD34– cells were found to have tumor stem cell characteristics. All the mice developed tumors in 40 days after injection of 1 × 106 CD138– CD34– tumor stem cells. Tumor growth in mice treated with PTX-NPs was significantly inhibited compared with the controls (P <  0.005, and the groups that received nanoparticles alone (P < 0.005 or paclitaxel alone (P < 0.05. In addition

Cost-effectiveness analysis of treating transplant-eligible multiple myeloma patients in Macedonia

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Qerimi V

2018-06-01

Full Text Available Vjollca Qerimi,1,2 Aleksandra Kapedanovska Nestorovska,1 Zoran Sterjev,1 Sonja Genadieva-Stavric,3 Ljubica Suturkova1 1Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia; 2Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT – University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria; 3Medical Faculty, University Hematology Clinic, Skopje, Macedonia Purpose: A decision-analytic model was developed to study the impact of induction regimens vincristine, adriamycin, dexamethasone (VAD; thalidomide, dexamethasone (TD; and bortezomib, dexamethasone (BorD, followed by autologous stem cell transplantation (ASCT for treating multiple myeloma (MM patients in Macedonia. Additionally, a cost-effectiveness analysis (CEA of treatment sequences to predict health effects and costs of different treatment sequences was performed.Methods: Model strategies were based on a previously published study for treating patients with MM in Macedonia. The data on disease progression and treatment effectiveness were obtained from the published reports of randomized clinical trials (GIMEMA M-B02005, IFM 2005-01. Utility parameters were extracted from the literature. To compare treatment combinations, a decision tree model was developed. Additionally, a cost analysis for one-time per-protocol costs was performed from a Macedonian national health care perspective. The incremental cost-effectiveness ratios (ICERs/quality-adjusted life years (QALYs gained for 1-, 10-, and 20-year time horizons were determined. Costs and health outcomes were discounted to evaluate the effects of time in the model.Results: The one-time costs of BorD (EUR 5,656 were higher compared to VAD (EUR 303 and TD (EUR 329, increasing the overall costs for BorD. Thus, the BorD combination dominated in the baseline

Localized cutaneous mucinosis associated with multiple myeloma: A rare presentation

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Parvaiz Anwar Rather

2014-01-01

Full Text Available Lichen myxoedematosus (LM, a form of primary cutaneous mucinosis, may present either as localized less severe form called papular mucinosis or diffuse more severe form called scleromyxoedema. The diffuse form is almost always associated with monoclonal gammopathy, whereas localized form is not. We report an atypical case of localized form of LM associated with multiple myeloma in a 66-year-old male, who presented with asymptomatic waxy papular eruption on extremities, which on histopathological examination confirmed the diagnosis of cutaneous mucinosis. After initially being put on steroids and hydroxychloroquine with minimal improvement, patient subsequently presented with encephalopathy and on evaluation revealed hypernatremia, hypercalcemia, hypergammaglobulinemia, reversal of albumin-globulin (A/G ratio, azotemia, and lytic lesions in skull X-ray. Bone marrow aspiration and biopsy confirmed multiple myeloma. Patient was successfully treated with standard treatment regimen for multiple myeloma with bortezumib and dexamethasone and his skin lesions subsided completely.

Immunomodulation of multiple myeloma.

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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.

Conventional chemotherapy and long-term survival in multiple myeloma patients

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Kraj, M; Poglod, R.; Sokolowska, U.; Kruk, B.; Maj, S.

2010-01-01

Objectives. The study was especially focused on the estimation of real frequency of long-term survivals in patients with multiple myeloma and finding common clinical and laboratory features present in long-term surviving patients as possible good prognostic factors. Material and methods. The survey was carried out on 600 multiple myeloma patients diagnosed before the year 2000 and treated with conventional chemotherapy in the Institute of Hematology and Transfusion Medicine in Warsaw in the years 1962-2009. All patients who had fulfilled the requirement of more than seven years of survival from the diagnosis and beginning of treatment for myeloma were included into the study group. Results. Out of 600 studied patients with multiple myeloma 88 (14.7%) survived over 7 years including 45 (7.5%) over 10 years, 11 (1.8 %) over 15 years and 7 (1.1%) over 20 years from the disease diagnosis and beginning of antitumor treatment. Patients with long survival were younger (median age 55 years) at the time of diagnosis than the whole studied group and had normal serum creatinine, calcium and beta2-microglobulin levels. Sixty eight percent of these patients had stage I or II clinical progression, 60% presented with IgG monoclonal protein and 58% with osteolysis. Treatment with melphalan only was given to 18 patients, 30 were treated with melphalan, followed by vincristine, cyclophosphamide, BCNU, doxorubicin and prednisone or dexamethasone. Polychemotherapy was given from the time of the diagnosis to 16 patients, 15 received radiotherapy or 60C o irradiation besides chemotherapy and 9 received new agents: thalidomide, bortezomib, lenalidomide. In 66% of the evaluated cases response to treatment was good and in another 34% stabilization of the proliferative process was achieved. The mean duration of treatment till the achievement of partial response was 10 months, range: 2 - 89 months. The mean duration of good therapeutic response was 70 months. Twelve patients are alive and

Palliative radiation therapy for multiple myeloma

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Minowa, Yasushi; Sasai, Keisuke; Ishigaki, Takashi; Nagata, Yasushi; Hiraoka, Masahiro

1996-01-01

Radiation therapy is a useful palliative modality for refractory lesions of multiple myeloma. It has been reported that total doses of 10 to 20 Gy are usually adequate to obtain some degree of pain relief. However, there are many patients who need additional doses to obtain sufficient pain relief. In this study. we retrospectively analyzed the records of patients with multiple myeloma irradiated at our department, in an attempt to develop an effective treatment policy for this disease. Twenty-nine patients with 53 lesions were treated between 1968 and 1993. Total irradiation doses were 4 to 60 Gy (median 40 Gy) with daily fractions of 2 Gy or less, and 16 to 51 Gy (median 30 Gy) with daily fractions greater than 2 Gy. Evaluated were 59 symptoms, including pain (68%), neurological abnormalities (15%), and masses (28%). Symptomatic remission was obtained in 33 of 36 (92%) lesions with pain, 6 of 8 (75%) with neurological abnormalities, and 13 of 15 (87%) mass lesions. Pain was partially relieved at a median TDF of 34, and completely at a median TDF of 66 (equivalent to 40-42 Gy with daily fractions of 2 Gy). Radiation therapy is an effective and palliative treatment method for symptomatic multiple myeloma. However, the treatment seems to require higher radiation doses than those reported to obtain adequate relief of symptoms. (author)

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

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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.

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

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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.

AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model

International Nuclear Information System (INIS)

Yao, H; Ashihara, E; Strovel, J W; Nakagawa, Y; Kuroda, J; Nagao, R; Tanaka, R; Yokota, A; Takeuchi, M; Hayashi, Y; Shimazaki, C; Taniwaki, M; Strand, K; Padia, J; Hirai, H; Kimura, S; Maekawa, T

2011-01-01

Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery

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

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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.

Multiple myeloma

International Nuclear Information System (INIS)

Sohn, Jeong Ick; Ha, Choon Ho; Choi, Karp Shik

1994-01-01

Multiple myeloma is a malignant plasma cell tumor that is thought to originate proliferation of a single clone of abnormal plasma cell resulting production of a whole monoclonal paraprotein. The authors experienced a case of multiple myeloma with severe mandibular osteolytic lesions in 46-year-old female. As a result of careful analysis of clinical, radiological, histopathological features, and laboratory findings, we diagnosed it as multiple myeloma, and the following results were obtained. 1. Main clinical symptoms were intermittent dull pain on the mandibular body area, abnormal sensation of lip and pain due to the fracture on the right clavicle. 2. Laboratory findings revealed M-spike, reversed serum albumin-globulin ratio, markedly elevated ESR and hypercalcemia. 3. Radiographically, multiple osteolytic punched-out radiolucencies were evident on the skull, zygoma, jaw bones, ribs, clavicle and upper extremities. Enlarged liver and increased uptakes on the lesional sites in RN scan were also observed. 4. Histopathologically, markedly hypercellular marrow with sheets of plasmoblasts and megakaryocytes were also observed.

Case Report: Multiple Myeloma with Gangrene of Extremities

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N Gharahi

2009-07-01

Full Text Available Introduction: Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone and it results in bone pain or fracture, renal failure, susceptibility to infections, anemia and hypercalcemia. The hyper viscosity syndrome is rare. Cryoglobulins are immunoglubulins that precipitate at temperatures less than 37degrees Celsius. Monoclonal cryoglobulins are usually present along with a specific hematologic disorder and are often asymptomatic. We report a second case of multiple myeloma with gangrene of all four extremities. Case: The Patient was a 77 year–old farmer with a 2 weeks history of coldness, pain and discoloration of the fingers of both the extremities which had extended to the mid forearm and shin regions. It was accompanied by skin erosions of the lower extremities, dark spots on the ear auricles and discoloration of the tip of the nose. On physical examination, quadrigangrene associated with ischemia of the auricles and tip of nose was seen. Serum proteins electrophoresis demonstrated monoclonal gammopathy and serum was positive for cryoglobulin, Bone marrow study showed neoplastic plasma cells infiltration. The patient was diagnosed as cryoglobulinemia based on multiple myeloma and treated accordingly.

Multiple Myeloma: Patient Handbook

Science.gov (United States)

... information about myeloma in a caring and compassionate man- ner. IMF InfoLine specialists can be reached at InfoLine@myeloma.org, or 800-452-CURE (2873) or 818-487-7455. Terms and definitions Albumin (ALB): Simple water-soluble protein that is ...

Establishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation.

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Marilène Binsfeld

Full Text Available Multiple myeloma (MM is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT remains controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD.Balb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received an allogeneic (B10.D2 donor or autologous (Balb/cJ donor transplant 30 days later. We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. Lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect. In addition, the treated mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggested the involvement of effector memory CD4 and CD8 T cells associated with the GvM response. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR Vβ spectratyping analysis identified Vβ families within CD4 and CD8 T cells, which were associated with both GvM effects and GvHD, whereas other Vβ families within CD4 T cells were associated exclusively with either GvM or GvHD responses.We successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first murine GvM model using immunocompetent mice that develop MM which closely resembles human MM disease and that are treated after disease establishment with an allo-SCT. Importantly, using TCR Vβ spectratyping, we also demonstrated the presence of GvM unique responses

In vitro sensitization of human lymphocytes to a myeloma cell-related antigen

International Nuclear Information System (INIS)

Whitson, M.E.; Griffin, G.D.; Novelli, G.D.; Solomon, A.

1981-01-01

Peripheral blood lymphocytes from normal human donors were cocultivated with cells from two established human multiple myeloma cell lines, RPMI 8226 and K-737, and with lymphoblastoid cells from a third B cell line, RAMM. After a comparison of three methods of lymphocyte sensitization, a 6-day incubation protocol with equal numbers of normal lymphocytes and mitomycin C-treated tumor cells was selected. Cells fom the RPMI 8226 myeloma line stimulated the differentiation of lymphocytes into cytotoxic effector cells as measured by 51 Cr release from labeled target cells. The RPMI 8226-sensitized lymphocytes were cytotoxic for myeloma cells (RPMI 8226 and K-737) and for lymphoblastoid cells (RAMM) but not for cells from human lung tumor lines (A549, A427, MB9812), a breast carcinoma line (ALAB), a normal diploid fibroblast line (HSBP), or normal lymphocytes

In vitro sensitization of human lymphocytes to a myeloma cell-related antigen

Energy Technology Data Exchange (ETDEWEB)

Whitson, M.E. (Univ. of South Carolina, Columbia); Griffin, G.D.; Novelli, G.D.; Solomon, A.

1981-01-01

Peripheral blood lymphocytes from normal human donors were cocultivated with cells from two established human multiple myeloma cell lines, RPMI 8226 and K-737, and with lymphoblastoid cells from a third B cell line, RAMM. After a comparison of three methods of lymphocyte sensitization, a 6-day incubation protocol with equal numbers of normal lymphocytes and mitomycin C-treated tumor cells was selected. Cells fom the RPMI 8226 myeloma line stimulated the differentiation of lymphocytes into cytotoxic effector cells as measured by /sup 51/Cr release from labeled target cells. The RPMI 8226-sensitized lymphocytes were cytotoxic for myeloma cells (RPMI 8226 and K-737) and for lymphoblastoid cells (RAMM) but not for cells from human lung tumor lines (A549, A427, MB9812), a breast carcinoma line (ALAB), a normal diploid fibroblast line (HSBP), or normal lymphocytes.

Genetic variants and multiple myeloma risk

DEFF Research Database (Denmark)

Martino, Alessandro; Campa, Daniele; Jurczyszyn, Artur

2014-01-01

BACKGROUND: Genetic background plays a role in multiple myeloma susceptibility. Several single-nucleotide polymorphisms (SNP) associated with genetic susceptibility to multiple myeloma were identified in the last years, but only a few of them were validated in independent studies. METHODS...... with multiple myeloma risk (P value range, 0.055-0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women. CONCLUSIONS: We can exclude that the selected polymorphisms are major multiple myeloma risk factors. IMPACT: Independent validation studies are crucial to identify true genetic risk...

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

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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.

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

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Yong-sheng Tu

2017-10-01

Full Text Available 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.

Safe and tolerable one-hour pamidronate infusion for multiple myeloma patients

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Dimitrios Chantzichristos

2008-09-01

Full Text Available Dimitrios Chantzichristos, Andréasson Björn, Johansson PeterDepartment of Internal Medicine, Uddevalla Hospital, Uddevalla, SwedenBackground: Once a month, patients with multiple myeloma received an infusion of bisphosphonates, principally to reduce osteoclastic bone resorption. Recommended infusion time for pamidronate is 2 hours in the US and 4 hours in Europe because of its potential nephrotoxicity. From 2003, a 90 mg infusion of pamidronate was provided over 1 hour to patients with no pre-existing renal impairment, in the Daily Care Unit at Uddevalla Hospital.Method: Retrospective analysis of the renal deterioration, serum calcium, and adverse effects in patients with multiple myeloma treated with 1-hour pamidronate 90 mg infusion from January 2003 to April 2007.Results: Seventy-nine patients provided valuable data. A total number of 846 infusions were given and the median number of infusion to each patient was 11. Significant creatinine elevation was seen in 7 patients (8.9%, after 19 infusions (2.2%. Renal deterioration occurred in 5 of these 7 patients, which was related to progress of the myeloma or opportunistic infections. Prevalence of infusion-related events was 0.8% and the mean total S-Ca was 0.05 mmol/L lower than the baseline.Conclusion: Few events of renal deterioration, hypocalcemia, or other adverse effects resulted from a 1-hour pamidronate 90 mg infusion for multiple myeloma patients with no pre-existing renal impairment.Keywords: bisphosphonates, pamidronate, multiple myeloma, infusion time

Epigenetic Activity of Peroxisome Proliferator-Activated Receptor Gamma Agonists Increases the Anticancer Effect of Histone Deacetylase Inhibitors on Multiple Myeloma Cells.

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Nassera Aouali

Full Text Available Epigenetic modifications play a major role in the development of multiple myeloma. We have previously reported that the PPARγ agonist pioglitazone (PIO enhances, in-vitro, the cytotoxic effect of the Histone deacetylase inhibitor (HDACi, valproic acid (VPA, on multiple myeloma cells. Here, we described the development of a new multiple myeloma mouse model using MOLP8 cells, in order to evaluate the effect of VPA/PIO combination on the progression of myeloma cells, by analyzing the proliferation of bone marrow plasma cells. We showed that VPA/PIO delays the progression of the disease and the invasion of myeloma cells in the bone marrow. Mechanistically, we demonstrated that VPA/PIO increases the cleavage of caspase 3 and PARP, and induces the acetylation of Histone 3 (H3. Furthermore, we provided evidence that PPARγ agonist is able to enhance the action of other HDACi such as Vorinostat or Mocetinostat. Using PPARγ antagonist or siPPARγ, we strongly suggest that, as described during adipogenesis, PIO behaves as an epigenetic regulator by improving the activity of HDACi. This study highlights the therapeutic benefit of PIO/VPA combination, compared to VPA treatment as a single-arm therapy on multiple myeloma and further highlights that such combination may constitute a new promising treatment strategy which should be supported by clinical trials.

Value of the free light chain analysis in the clinical evaluation of response in multiple myeloma patients receiving anti-myeloma therapy

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Toftmann Hansen, Charlotte; Pedersen, Per T.; Jensen, Bo Amdi

Value of the free light chain analysis in the clinical evaluation of response in multiple myeloma patients receiving anti-myeloma therapy.......Value of the free light chain analysis in the clinical evaluation of response in multiple myeloma patients receiving anti-myeloma therapy....

Whole bone marrow irradiation for the treatment of multiple myeloma

International Nuclear Information System (INIS)

Coleman, M.; Saletan, S.; Wolf, D.; Nisce, L.; Wasser, J.; McIntyre, O.R.; Tulloh, M.

1982-01-01

Nine patients with multiple myeloma were treated with whole bone marrow irradiation. Six had heavily pretreated disease refractory to chemotherapy. Three had stable disease lightly pretreated by chemotherapy. A modification of the ''three and two'' total nodal radiation technique was employed. Although varying and often severe treatment related cytopenia occurred, infectious complications, clinical bleeding, and nonhematalogic complications were minimal. Five of nine patients showed a decrease in monoclonal protein components, and one showed an increase during treatment. These preliminary results indicate that a reduction of tumor cell burden may occur in patients following whole bone marrow irradiation and that the technique is feasible. Whole bone marrow irradiation combined with chemotherapy represents a new conceptual therapeutic approach for multiple myeloma

Hemibody irradiation in stage III multiple myeloma: results of 20 patients

International Nuclear Information System (INIS)

Troussard, X.; Reman, O.; Macro, M.; Leporrier, M.; Roussel, A.

1988-01-01

The advanced forms of multiple myeloma of bone, stage III, or those with a large tumoral mass, characterized by a considerable number of myelomacells, pose difficult problems in treatment. Little progress has been made since the introduction of the alkylating agents, and combined chemotherapy does not seem to be any more effective in terms of survival. It is these severe forms that culminate in painful symptoms which are often difficult to eliminate. The radiosensitivity of myeloma led us to treat 20 patients affected by severe forms of the disease by total body irradiation in two stages, and we analyze here the effects of treatment and the tolerance for this technique

Zicam-induced damage to mouse and human nasal tissue.

Directory of Open Access Journals (Sweden)

Jae H Lim

Full Text Available Intranasal medications are used to treat various nasal disorders. However, their effects on olfaction remain unknown. Zicam (zinc gluconate; Matrixx Initiatives, Inc, a homeopathic substance marketed to alleviate cold symptoms, has been implicated in olfactory dysfunction. Here, we investigated Zicam and several common intranasal agents for their effects on olfactory function. Zicam was the only substance that showed significant cytotoxicity in both mouse and human nasal tissue. Specifically, Zicam-treated mice had disrupted sensitivity of olfactory sensory neurons to odorant stimulation and were unable to detect novel odorants in behavioral testing. These findings were long-term as no recovery of function was observed after two months. Finally, human nasal explants treated with Zicam displayed significantly elevated extracellular lactate dehydrogenase levels compared to saline-treated controls, suggesting severe necrosis that was confirmed on histology. Our results demonstrate that Zicam use could irreversibly damage mouse and human nasal tissue and may lead to significant smell dysfunction.

Cerebral metastases from multiple myeloma

International Nuclear Information System (INIS)

Norum, J.; Wist, E.; Dahl, I.M.; University Hospital, Tromsoe

1991-01-01

The authors report a patient with multiple intracerebral lesions from myeloma. The case also demonstrates that myeloma is a radiosensitive tumour and that radiotherapy is important to keep in mind when intracranial lesions are revealed. (orig.)

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

Science.gov (United States)

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.

Local control and survival in spinal cord compression from lymphoma and myeloma

International Nuclear Information System (INIS)

Wallington, M.; Mendis, S.; Premawardhana, U.; Sanders, P.; Shahsavar-Haghighi, K.

1997-01-01

Background: Between 1979 and 1989, 48 cases of extradural spinal cord and cauda equina compression in patients with lymphoma (24) and myeloma (24) received local radiation therapy for control of cord compression. Twenty five (52%) of the cases were treated by surgical decompression prior to irradiation. Thirty five (73%) of the cases received chemotherapy following the diagnosis of spinal cord compression. Post-treatment outcome was assessed at a minimum follow-up of 24 months to determine the significant clinical and treatment factors following irradiation. Results: Seventeen (71%) of the lymphoma and 15 (63%) of the myeloma patients achieved local control, here defined as improvement to, or maintenance of ambulation with minimal or no assistance for 3 months from the start of radiotherapy. At a median follow-up of 30 (2-98) for the lymphoma and 10 (1-87) months for the myeloma patients, the results showed that survival following local radiation therapy for cord compression was independently influenced by the underlying disease type in favour of lymphoma compared to myeloma (P<0.01). The median duration of local control and survival figures were 23 and 48 months for the lymphomas compared to 4.5 and 10 months for the myeloma cases. Survival was also independently influenced by preservation of sphincter function at initial presentation (P<0.02) and the achievement of local control following treatment (P<0.01). Discussion: We conclude that while disease type independently impacts on outcome following treatment of spinal cord compression in lymphoma and myeloma, within both of these disease type the achievement of local control of spinal cord compression is an important management priority, for without local control survival may be adversely affected

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

Science.gov (United States)

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.

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

NARCIS (Netherlands)

F. Ross (F.); H. Avet-Loiseau; G. Ameye (Geneviève); N. Gutierrez (Norma); G. Liebisch (Gerhard); S. O'Connor (Sheila); K. Dalva (Klara); F. Fabris (Federica Margherita); A.M. Testi (Adele); M. Jarosova (M.); C. Hodkinson (Clare); A. Collin (Anna); G. Kerndrup (Gitte); P. Kuglik (Petr); D. Ladon (Dariusz); P. Bernasconi (Paolo); B. Maes (Bart); Z. Zemanova (Zuzana); K. Michalova (Kyra); L. Michau (Lucienne); K. Neben (Kai); N.E.U. Hermansen (N. Emil); K. Rack (Katrina); A. Rocci (Alberto); R. Protheroe (Rebecca); L. Chiecchio (Laura); H.A. Poirel (Hélène A); P. Sonneveld (Pieter); M. Nyegaard (M.); H.E. Johnsen (Hans)

2012-01-01

textabstractThe 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

Therapeutic advancements in multiple myeloma

Directory of Open Access Journals (Sweden)

Alessandro eGozzetti

2014-09-01

Full Text Available Multiple myeloma survival has significantly improved in latest years, due to a broad spectrum of novel agents available for treatment. The introduction of thalidomide, bortezomib and lenalidomide together with autologous stem cell transplantation has dramatically prolonged complete remissions rate, progression free survivals resulting ultimately in prolonged survivals in myeloma patients. Moreover, novel strategies of treatment such as consolidation and maintenance are being used to implement responses. A number of new drugs such as carfilzomib and pomalidomide are already in clinical practice, and new kids on the block are entering, making the future of myeloma patients brighter.

PET/CT and MR imaging in myeloma

Energy Technology Data Exchange (ETDEWEB)

Mulligan, Michael E. [University of Maryland Medical Center, Department of Radiology, Baltimore, MD (United States); Badros, Ashraf Z. [University of Maryland, Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD (United States)

2007-01-15

Myeloma is the most common primary bone malignancy. It accounts for 10% of all hematological malignancies and 1% of all cancers. In the United States, there are an estimated 16,000 new cases and over 11,000 deaths yearly due to myeloma. Plasma cell dyscrasias manifest themselves in a variety of forms that range from MGUS (monoclonal gammopathy of undetermined significance) and smoldering myeloma that require no therapy, to the ''malignant'' form of multiple myeloma. The role of imaging in the management of myeloma includes: an assessment of the extent of intramedullary bone disease, detection of any extramedullary foci, and severity of the disease at presentation; the identification and characterization of complications; subsequent assessment of disease status. This review will focus on the use of PET/CT and MR imaging for myeloma patients at the time of initial diagnosis and for follow-up management, based on current reports in the literature and our practice at the Marlene and Stewart Greenebaum Cancer Center, University of Maryland Medical Center in Baltimore, USA. (orig.)

The impact of comorbidity on mortality in multiple myeloma

DEFF Research Database (Denmark)

Gregersen, Henrik; Vangsted, Annette Juul; Abildgaard, Niels

2017-01-01

To describe the prevalence of comorbidity and its impact on survival in newly diagnosed multiple myeloma patients compared with population controls. Cases of newly diagnosed symptomatic multiple myeloma during the 2005-2012 period were identified in the Danish National Multiple Myeloma Registry....... For each myeloma patient, 10 members of the general population matched by age and sex were chosen from the national Civil Registration System. Data on comorbidity in the myeloma patients and the general population comparison cohort were collected by linkage to the Danish National Patient Registry (DNPR......). Cox proportional hazards regression models were used to evaluate the prognostic significance of comorbidity. The study included 2190 cases of multiple myeloma and 21,900 population controls. The comorbidity was increased in multiple myeloma patients compared with population controls, odds ratio (OR) 1...

Histone deacetylase inhibitors in multiple myeloma

Directory of Open Access Journals (Sweden)

Sarah Deleu

2009-06-01

Full Text Available Novel drugs such as bortezomib and high dose chemotherapy combined with stem cell transplantation improved the outcome of multiple myeloma patients in the past decade. However, multiple myeloma often remains incurable due to the development of drug resistance governed by the bone marrow micro-environment. Therefore targeting new pathways to overcome this resistance is needed. Histone deacetylase (HDAC inhibitors represent a new class of anti-myeloma agents. Inhibiting HDACs results in histone hyperacetylation and alterations in chromatine structure, which, in turn, cause growth arrest differentiation and/or apoptosis in several tumor cells. Here we summarize the molecular actions of HDACi as a single agent or in combination with other drugs in different in vitro and in vivo myeloma models and in (preclinical trials.

A concise revised myeloma comorbidity index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients

NARCIS (Netherlands)

M. Engelhardt (Monika); Domm, A.-S. (Anne-Saskia); Dold, S.M. (Sandra Maria); G. Ihorst (Gabriele); Reinhardt, H. (Heike); Zober, A. (Alexander); Hieke, S. (Stefanie); Baayen, C. (Corine); Müller, S.J. (Stefan Jürgen); H. Einsele (Hermann); P. Sonneveld (Pieter); O. Landgren; M. Schumacher (M.); R. Wäsch (Ralph)

2017-01-01

textabstractWith growing numbers of elderly multiple myeloma patients, reliable tools to assess their vulnerability are required. The objective of the analysis herein was to develop and validate an easy to use myeloma risk score (revised Myeloma Comorbidity Index) that allows for risk prediction of

Hypercalcaemia : myeloma

International Nuclear Information System (INIS)

Naude, F; Venter, E.K.; Meyer, B.J.

2004-01-01

Full text: Introduction: A hypercalcaemic patient was referred to the Department of Nuclear Medicine to localise a parathyroid adenoma pre-operatively. Instead of an adenoma, multiple myeloma was diagnosed - comprimed histologically. Conclusion: Many conditions are associated with hypercalcaemia. Principal causes are primary hyperparathyroidism, advanced secondary hyperparathyroidism, milk alkali syndrome, vitamin D intoxication, Vit A intoxication, thiazide diuretic treatment, malignancy. Primary hyperparathyroidism (pHPT) is the most common cause in ambulatory adult patients, and malignancy the leading cause in hospitalised patients. Radioscintigraphic imaging of the parathyroids is one of the procedures used to localise the site of parathyroid adenomas. Currently 99mTc-sestamibi is the radioactive agent of choice. Hypercalcaemia is a relative frequent phenomenon in many malignant disorders, but seems to be insufficiently recognised. Various patterns of 99mTc-sestamibi uptake in the bone marrow of multiple myeloma patients have been reported: normal (negative), focal. diffuse and combined focal and diffuse. Diffuse and/or focal 99mTc-sestamibi uptake in the bone marrow is almost diagnostic of multiple myeloma. The distribution and intensity of 99mTc-sestamibi uptake are related to both the clinical status and stage of the disease, and can be used to estimate the success of therapy; a negative sestamibi study in patients receiving therapy indicates remission. (author)

Osteoclast nuclei of myeloma patients show chromosome translocations specific for the myeloma cell clone: a new type of cancer-host partnership?

DEFF Research Database (Denmark)

Levin Andersen, Thomas; Boissy, Patrice; Sondergaard, T E

2007-01-01

through fusion between myeloma cells and osteoclasts. In conclusion, malignant cells contribute significantly to the formation of bone-resorbing osteoclasts in multiple myeloma. Osteoclast-myeloma clone hybrids reflect a previously unrecognized mechanism of bone destruction in which malignant cells...

The novel immunotoxin HM1.24-ETA′ induces apoptosis in multiple myeloma cells

International Nuclear Information System (INIS)

Staudinger, M; Glorius, P; Burger, R; Kellner, C; Klausz, K; Günther, A; Repp, R; Klapper, W; Gramatzki, M; Peipp, M

2014-01-01

Despite new treatment modalities, the clinical outcome in a substantial number of patients with multiple myeloma (MM) has yet to be improved. Antibody-based targeted therapies for myeloma patients could make use of the HM1.24 antigen (CD317), a surface molecule overexpressed on malignant plasma cells and efficiently internalized. Here, a novel immunotoxin, HM1.24-ETA′, is described. HM1.24-ETA′ was generated by genetic fusion of a CD317-specific single-chain Fv (scFv) antibody and a truncated variant of Pseudomonas aeruginosa exotoxin A (ETA′). HM1.24-ETA′ inhibited growth of interleukin 6 (IL-6)-dependent and -independent myeloma cell lines. Half-maximal growth inhibition was observed at concentrations as low as 0.3 nM. Target cell killing occurred via induction of apoptosis and was unaffected in co-culture experiments with bone marrow stromal cells. HM1.24-ETA′ efficiently triggered apoptosis of freshly isolated/cryopreserved cells of patients with plasma cell leukemia and MM and was active in a preclinical severe combined immunodeficiency (SCID) mouse xenograft model. Importantly, HM1.24-ETA′ was not cytotoxic against CD317-positive cells from healthy tissue (monocytes, human umbilical vein endothelial cells). These results indicate that CD317 may represent a promising target structure for specific and efficient immunotoxin therapy for patients with plasma cell tumors

A murine model of human myeloma bone disease

NARCIS (Netherlands)

Garrett, I.R.; Dallas, S.; Radl, J.; Mundy, G.R.

1997-01-01

Myeloma causes a devastating and unique form of osteolytic bone disease. Although osteoclast activation is responsible for bone destruction, the precise mechanisms by which myeloma cells increase osteoclast activity have not been defined. An animal model of human myeloma bone disease mould help in

New Genetic Insights and Therapy in Multiple Myeloma

NARCIS (Netherlands)

K.L. Wu

2007-01-01

textabstractIn the last decade, several significant advances in myeloma therapy have occurred with the pace of change accelerated with the introduction of new anti-myeloma agents. The approach to the treatment of multiple myeloma has become more complex with an array of therapeutic options,

A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts.

Directory of Open Access Journals (Sweden)

Maiko Matsushita

Full Text Available Despite the recent advances in the treatment of multiple myeloma (MM, MM patients with high-risk cytogenetic changes such as t(4;14 translocation or deletion of chromosome 17 still have extremely poor prognoses. With the goal of helping these high-risk MM patients, we previously developed a novel phthalimide derivative, TC11. Here we report the further characterization of TC11 including anti-myeloma effects in vitro and in vivo, a pharmacokinetic study in mice, and anti-osteoclastogenic activity. Intraperitoneal injections of TC11 significantly delayed the growth of subcutaneous tumors in human myeloma-bearing SCID mice. Immunohistochemical analyses showed that TC11 induced apoptosis of MM cells in vivo. In the pharmacokinetic analyses, the Cmax was 2.1 μM at 1 h after the injection of TC11, with 1.2 h as the half-life. TC11 significantly inhibited the differentiation and function of tartrate-resistant acid phosphatase (TRAP-positive multinucleated osteoclasts in mouse osteoclast cultures using M-CSF and RANKL. We also revealed that TC11 induced the apoptosis of myeloma cells accompanied by α-tubulin fragmentation. In addition, TC11 and lenalidomide, another phthalimide derivative, directly bound to nucleophosmin 1 (NPM1, whose role in MM is unknown. Thus, through multiple molecular interactions, TC11 is a potentially effective drug for high-risk MM patients with bone lesions. The present results suggest the possibility of the further development of novel thalidomide derivatives by drug designing.

Sequential hemi-body radiotherapy in advanced multiple myeloma. [Side effects of indicated x-ray therapy

Energy Technology Data Exchange (ETDEWEB)

Jaffe, J.P.; Bosch, A.; Raich, P.C.

1979-01-01

Eleven patients with advanced multiple myeloma refractory to standard chemotherapy were treated with a regimen of sequential hemi-body radiotherapy consisting of 800 rad midplane in a single dose to each half. 9/10 patients experienced significant relief of skeletal pain and there were 5/11 objective tumor responses with one complete remission. Treatment-related morbidity was significant and consisted primarily of nausea and emesis, bone marrow suppression, and pneumonitis. This therapy is helpful in the management of advanced myeloma, and should be studied earlier in the course of the disease.

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

OpenAIRE

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

2012-01-01

Abstract Introduction 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. Case 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 w...

Salinization and Saline Environments

Science.gov (United States)

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.

Science.gov (United States)

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.

Endocarditis due to Gemella haemolysans in a newly diagnosed multiple myeloma patient

Directory of Open Access Journals (Sweden)

Dongyan Liu

2016-09-01

Full Text Available An 87-year-old Caucasian woman with hypertension, diabetes mellitus type 2, and COPD was admitted with 1-week duration of back pain and weight gain. The physical examination revealed jugular venous distention, rales in the left lower lung field, and severe pitting edema over lower extremities. As workup for leukocytosis, blood cultures grew Gemella haemolysans. Subsequently, a transthoracic echocardiogram revealed vegetation on the non-coronary aortic leaflet and mild aortic stenosis. She was treated with ampicillin and gentamicin. After further investigation, the patient was diagnosed with plasma cell myeloma, the monoclonal lambda type. This is the first reported case of G. haemolysans endocarditis in a multiple myeloma patient.

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

Science.gov (United States)

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 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.

Minocycline Reduces Spontaneous Hemorrhage in Mouse Models of Cerebral Amyloid Angiopathy

Science.gov (United States)

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

CARs in the Lead Against Multiple Myeloma

DEFF Research Database (Denmark)

Ormhøj, Maria; Bedoya, Felipe; Frigault, Matthew J.

2017-01-01

The recent clinical success of CD19-directed chimeric antigen receptor (CAR) T cell therapy in chronic and acute leukemia has led to increased interest in broadening this technology to other hematological malignancies and solid tumors. Now, advances are being made using CAR T cell technology...... to target myeloma antigens such as B cell maturation antigen (BCMA), CD138, and kappa-light chain as well as CD19 on putative myeloma stem cells. To date, only a limited number of multiple myeloma patients have received CAR T cell therapy but preliminary results have been encouraging. In this review, we...... summarize the recently reported results of clinical trials conducted utilizing CAR T cell therapy in multiple myeloma (MM)....

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

Directory of Open Access Journals (Sweden)

Claudia Zelle-Rieser

2016-11-01

Full Text Available Abstract Background Multiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments. In addition, T cell function concerning proliferation and expression of T-bet, IL-2, IFNγ, and CD107a was investigated after in vitro stimulation by CD3/CD28. Finally, data was compared to healthy, age-matched donor T cells from both compartments. Methods Multicolor flow cytometry was utilized for the analyses of surface molecules, intracellular staining of cytokines was also performed by flow cytometry, and proliferation was assessed by 3H-thymidine incorporation. Statistical analyses were performed utilizing unpaired T test and Mann-Whitney U test. Results We observed enhanced T cell exhaustion and senescence especially at the tumor site. CD8+ T cells expressed several molecules associated with T cell exhaustion (PD-1, CTLA-4, 2B4, CD160 and T cell senescence (CD57, lack of CD28. This phenotype was associated with lower proliferative capacity and impaired function. Despite a high expression of the transcription factor T-bet, CD8+ T cells from the tumor site failed to produce IFNγ after CD3/CD28 in vitro restimulation and displayed a reduced ability to degranulate in response to T cell stimuli. Notably, the percentage of senescent CD57+CD28− CD8+ T cells was significantly lower in treated myeloma patients when compared to untreated patients. Conclusions T cells from the bone marrow of myeloma

Multiple myeloma.

LENUS (Irish Health Repository)

Collins, Conor D

2012-02-01

Advances in the imaging and treatment of multiple myeloma have occurred over the past decade. This article summarises the current status and highlights how an understanding of both is necessary for optimum management.

Nucleotide excision repair is a potential therapeutic target in multiple myeloma

Science.gov (United States)

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

Can dentists detect multiple myeloma through oral manifestations?

Directory of Open Access Journals (Sweden)

Thaís Miranda Xavier de Almeida

2018-01-01

Full Text Available Objective: To review published data on oral manifestations of multiple myeloma. Methods: An electronic database search was performed of articles published from 1971 to November 2016 in order to identify studies that reported oral manifestations of patients with multiple myeloma. Case reports and case series with oral manifestations of multiple myeloma in English were included in the study. An additional search was performed of the references of the selected articles. Results: Thirty-seven articles that reported 81 patients with oral manifestations of multiple myeloma were selected: 30 case reports (82% and seven case series (18%. The most common clinical features in the dental cavity were swelling (65.4%, bone pain (33.3%, paresthesia (27.1% and amyloidosis lesions (11.1%. Osteolytic lesions detected on imaging exams were reported in the majority of the patients (90.1% as plasmacytomas or ‘punched-out’ lesions. Conclusions: Swelling and osteolytic lesions represent the most common clinical and radiographic signs of the jaws relating to multiple myeloma, respectively. Keywords: Multiple Myeloma, Oral Manifestations, Mouth, Jaws

Skeletal surveys in multiple myeloma

International Nuclear Information System (INIS)

Sebes, J.I.; Niell, H.B.; Palmieri, G.M.A.; Reidy, T.J.

1986-01-01

Thirty-three patients with multiple myeloma were studied with serial skeletal surveys, serum immunoglobulin levels, and postabsorptive urinary hydroxyproline (Spot-HYPRO) determinations. Twenty receiving chemotherapy were also followed with skeletal surveys in order to evaluate bone response to treatment. A close association was found between skeletal findings and changes in immunoglubulin levels with positive correlation in 71% of the patients. A similar association was found between skeletal disease and Spot-HYPRO level changes in 65%. Five of 12 patients (42%) with partial or complete clinical response to chemotherapy, demonstrated improvement in the appearance of skeletal lesions. Positive correlation between the roentgenographic changes and clinical markers of myeloma as well as therapeutic response, indicates that skeletal surveys are useful and effective in monitoring patients with multiple myeloma. (orig.)

Abnormal radiological features in a multiple myeloma patient: a case report and radiological review of myelomas

DEFF Research Database (Denmark)

Ghosh, Sujoy; Wadhwa, P; A, Kumar

2011-01-01

and porotic changes. Primary sclerotic manifestations are rare and occur in only 3% of cases. Although exceptional, multiple myeloma must be borne in mind in the presence of bone sclerosis. This report presents a patient with multiple myeloma with a sunburst/hair-on-end pattern on the radiograph and sclerotic...

Intratibial injection of human multiple myeloma cells in NOD/SCID IL-2Rγ(null mice mimics human myeloma and serves as a valuable tool for the development of anticancer strategies.

Directory of Open Access Journals (Sweden)

Julia Schueler

Full Text Available BACKGROUND: We systematically analyzed multiple myeloma (MM cell lines and patient bone marrow cells for their engraftment capacity in immunodeficient mice and validated the response of the resulting xenografts to antimyeloma agents. DESIGN AND METHODS: Using flow cytometry and near infrared fluorescence in-vivo-imaging, growth kinetics of MM cell lines L363 and RPMI8226 and patient bone marrow cells were investigated with use of a murine subcutaneous bone implant, intratibial and intravenous approach in NOD/SCID, NOD/SCID treated with CD122 antibody and NOD/SCID IL-2Rγ(null mice (NSG. RESULTS: Myeloma growth was significantly increased in the absence of natural killer cell activity (NSG or αCD122-treated NOD/SCID. Comparison of NSG and αCD122-treated NOD/SCID revealed enhanced growth kinetics in the former, especially with respect to metastatic tumor sites which were exclusively observed therein. In NSG, MM cells were more tumorigenic when injected intratibially than intravenously. In NOD/SCID in contrast, the use of juvenile long bone implants was superior to intratibial or intravenous cancer cell injection. Using the intratibial NSG model, mice developed typical disease symptoms exclusively when implanted with human MM cell lines or patient-derived bone marrow cells, but not with healthy bone marrow cells nor in mock-injected animals. Bortezomib and dexamethasone delayed myeloma progression in L363- as well as patient-derived MM cell bearing NSG. Antitumor activity could be quantified via flow cytometry and in vivo imaging analyses. CONCLUSIONS: Our results suggest that the intratibial NSG MM model mimics the clinical situation of the disseminated disease and serves as a valuable tool in the development of novel anticancer strategies.

Coexisting multiple myeloma, lymphoma, and non-small cell lung cancer: a case report and review of the literature

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Khade P

2017-11-01

Full Text Available Parth Khade, Srinivas Devarakonda Department of Internal Medicine, Louisiana State University Health, Shreveport, LA, USA Abstract: Multiple myeloma is a plasma cell dyscrasia characterized by neoplastic proliferation of plasma cells, producing a monoclonal immunoglobulin. Small lymphocytic lymphoma (SLL is a neoplasm consisting of monoclonal B-cell lymphocyte proliferation. We present an extremely rare case of coexisting multiple myeloma, SLL, and squamous cell carcinoma of the lung in a 74-year-old female patient. She initially presented with a midline mass with pain in the lumbar area. Debulking surgery was performed, and pathology showed plasmacytoma. Further evaluation revealed coexistent IgG kappa myeloma. Imaging revealed extensive abdominal lymphadenopathy, and mesenteric lymph node biopsy confirmed the presence of SLL. The patient was also found to have a mass in the left lower lobe of the lung; biopsy showed squamous cell carcinoma. This patient was treated with lenalidomide and dexamethasone for multiple myeloma, and stereotactic body radiotherapy for limited stage lung cancer. Due to the more indolent course of SLL, watchful waiting was applied. Keywords: coexisting, multiple myeloma, lung cancer, non-Hodgkin’s lymphoma

Economic and clinical impact of multiple myeloma to managed care.

Science.gov (United States)

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

Clinical Application of 18F-FDG PET in Multiple Myeloma

International Nuclear Information System (INIS)

Lee, Su Jin; Choi, Joon Young

2009-01-01

This review focuses on the clinical use of 18 F-FDG PET to evaluate multiple myeloma. 18 F-FDG PET is useful for diagnosis, staging of multiple myeloma and differential diagnosis of myeloma related disease such as monoclonal gammopathy of undetermined significance or plasmacytoma. For therapy response, 18 F-FDG PET may be effective after chemotherapy for multiple myeloma and radiotherapy for plasmacytoma

Myeloma: making sense of a complex blood cancer.

LENUS (Irish Health Repository)

Kelly, Mary B

2012-01-31

Myeloma is a challenging blood cancer characterized by bone destruction, hypercalcaemia, renal insufficiency and anaemia. Although myeloma remains incurable, recent advancements in treatments have resulted in significant improvements in morbidity. The use of immunomodulatory drugs-thalidomide, lenalidomide, pomalidomide (in clinical trials)-and the proteasome inhibitor, bortezomib, in conjunction with conventional chemotherapy and supportive therapies, have resulted in a significant shift in approaches to treatment and an improvement in patients\\' quality of life. Nurses must remain up-to-date with current treatments for myeloma and their related side-effects. In addition, nurses play a key role in the coordination of a multidisciplinary approach to care for myeloma patients.

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

Science.gov (United States)

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.

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

Directory of Open Access Journals (Sweden)

Vigo Federica

2012-08-01

Full Text Available Abstract Introduction 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. Case 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. Conclusion 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.

A prospective study of percutaneous vertebroplasty in patients with myeloma and spinal metastases

International Nuclear Information System (INIS)

Chew, C.; Ritchie, M.; O’Dwyer, P.J.; Edwards, R.

2011-01-01

Aim: To assess patient outcome in a consecutive series of patients with myeloma and spinal metastases who underwent percutaneous vertebroplasty. Materials and methods: Data were gathered prospectively on all patients undergoing percutaneous vertebroplasty between June 2001 and June 2010. Outcome measures included visual analogue pain scores (VAS) and Roland–Morris Questionnaire (RMQ) in patients treated since 2005 as well as complications and long-term outcome in all patients. Results: One hundred and twenty-eight patients underwent percutaneous vertebroplasty for myeloma (n = 41) or spinal metastases (n = 87) over a 9 year period. VAS scores fell from 7.75 ± 1.88 pre-vertebroplasty to 4.77 ± 2.69 post-vertebroplasty (p = 0.001). RDQ scores improved from 18.55 ± 4.79 to 13.5 ± 6.96 (p = 0.001). Complications were recorded in three patients: cement extension to vena cava (n = 1), local haematoma (n = 1), and loss of sensation over T1 dermatome (n = 1). The Kaplan–Meier estimate of 5 year survival post-vertebroplasty was 40% for patients with myeloma and 25% for those with metastases. Conclusion: This large prospective study demonstrates percutaneous vertebroplasty reduces pain and improves disability in patients from intractable pain from myeloma or spinal metastases and now forms an important part of the multimodality treatment for these patients.

The orally available multikinase inhibitor regorafenib (BAY 73-4506) in multiple myeloma.

Science.gov (United States)

Breitkreutz, Iris; Podar, Klaus; Figueroa-Vazquez, Vianihuini; Wilhelm, Scott; Hayden, Patrick J; Anderson, Kenneth C; Raab, Marc S

2018-05-01

A promising approach to the treatment of multiple myeloma (MM) involves agents that target not only the myeloma cells directly, but also the tumor microenvironment which promotes tumor cell growth, angiogenesis, and MM bone disease. Here we investigate the orally available multikinase inhibitor, regorafenib (BAY 73-4506), for its therapeutic efficacy in MM. Regorafenib is a potent inhibitor of angiogenic (VEGFR 1-3, PDGFR-b) as well as oncogenic (c-KIT, RET, FGFR, Raf) kinases. We show that regorafenib induces apoptosis in all MM cell lines at below clinically achievable concentrations. Regorafenib overcomes the growth advantage conferred by a stroma cell MM and an endothelial cell MM, co-culture systems, and abrogates growth factor-stimulated MEK, ERK, and AKT phosphorylation at nanomolar to micromolar concentrations. Moreover, it inhibits endothelial cell growth and tubule formation, abrogates both VEGF secretion and VEGF-induced MM cell migration, inhibits osteoclastogenesis, and shows synergistic cytotoxicity with dexamethasone, the immunomodulatory drug pomalidomide, and the p110δ inhibitor idelalisib. Most importantly, regorafenib significantly delays tumor growth in a xenograft mouse model of human MM. These results provide the rationale for further clinical evaluation of regorafenib, alone and in combination, in the treatment of MM.

Sexual dysfunction in multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board.

Science.gov (United States)

Richards, Tiffany A; Bertolotti, Page A; Doss, Deborah; McCullagh, Emily J

2011-08-01

The World Health Organization describes sexuality as a "central aspect of being human throughout life and encompasses sex, gender identities and roles, sexual orientation, eroticism, pleasure, intimacy, and reproduction. Sexuality is influenced by the interaction of biological, psychological, social, economic, political, cultural, ethical, legal, historical, religious, and spiritual factors." Currently, no research has been conducted regarding sexual dysfunction in patients with multiple myeloma; therefore, information related to the assessment and evaluation of sexual dysfunction is gleaned from other malignancies and diseases. In this article, members of the International Myeloma Foundation's Nurse Leadership Board discuss the definition, presentation, and causes of sexual dysfunction; provide recommendations for sexual assessment practices; and promote discussion among patients with multiple myeloma, their healthcare providers, and their partners.

The Danish National Multiple Myeloma Registry

DEFF Research Database (Denmark)

Gimsing, Peter; Holmström, Morten Orebo; Klausen, Tobias Wirenfelt

2016-01-01

AIM: The Danish National Multiple Myeloma Registry (DMMR) is a population-based clinical quality database established in January 2005. The primary aim of the database is to ensure that diagnosis and treatment of plasma cell dyscrasia are of uniform quality throughout the country. Another aim...... diagnosed patients with multiple myeloma (MM), smoldering MM, solitary plasmacytomas, and plasma cell leukemia in Denmark are registered annually; ~350 patients. Amyloid light-chain amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome......), monoclonal gammopathy of undetermined significance and monoclonal gammopathy of undetermined significance with polyneuropathy have been registered since 2014. MAIN VARIABLES: The main registered variables at diagnosis are patient demographics, baseline disease characteristics, myeloma-defining events...

Immunoparesis in newly diagnosed Multiple Myeloma patients

DEFF Research Database (Denmark)

Sorrig, Rasmus; Klausen, Tobias W.; Salomo, Morten

2017-01-01

Immunoparesis (hypogammaglobulinemia) is associated to an unfavorable prognosis in newly diagnosed Multiple myeloma (MM) patients. However, this finding has not been validated in an unselected population-based cohort. We analyzed 2558 newly diagnosed MM patients in the Danish Multiple Myeloma...

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

Science.gov (United States)

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.

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

DEFF Research Database (Denmark)

Ross, Fiona M; Avet-Loiseau, Hervé; Ameye, Geneviève

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...

Immune resistance of Multiple Myeloma : the role of the microenvironment

NARCIS (Netherlands)

de Haart, SJ

2017-01-01

Immunotherapeutic strategies in Multiple Myeloma are under development. In this thesis we present a new perspective in optimizing immunotherapy in Multiple Myeloma patient. We propose that currently, immunotherapy is limited in efficacy through interactions of Multiple Myeloma cells with the bone

Expression of RAN, ZHX-2, and CHC1L genes in multiple myeloma patients and in myeloma cell lines treated with HDAC and Dnmts inhibitors

Czech Academy of Sciences Publication Activity Database

Legartová, Soňa; Harničarová, Andrea; Bártová, Eva; Hájek, R.; Pour, L.; Kozubek, Stanislav

2010-01-01

Roč. 57, č. 5 (2010), s. 482-487 ISSN 0028-2685 R&D Projects: GA MŠk ME 919; GA ČR(CZ) GAP302/10/1022 Grant - others:GA MŠk(CZ) LC06027; GA MŠk(CZ) LC535 Program:LC; LC Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : multiple myeloma * RAN * ZHX-2 Subject RIV: BO - Biophysics Impact factor: 1.449, year: 2010

Case report 383: Multiple myeloma

International Nuclear Information System (INIS)

Kouwenberg, J.J.; Simons, A.J.

1986-01-01

A unique and obviously extremely rare example of multiple myeloma has been presented, affecting the peripheral appendicular skeleton and not the hematopoietic system of the axial skeleton, radiologically and probably pathologically. Only one other similar case has been described. The radiological features were confirmed by the pathological studies: a biopsy specimen obtained from a large osteolytic lesion in a patella showed the typical stigma of multiple myeloma; a biopsy from the iliac creast showed no abnormality. (orig./SHA)

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

DEFF Research Database (Denmark)

Lokhorst, Henk M; Plesner, Torben; Laubach, Jacob P

2015-01-01

BACKGROUND: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODS: In part 1...... interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen...

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

Science.gov (United States)

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.

Autologous Graft versus Host Disease: An Emerging Complication in Patients with Multiple Myeloma

Directory of Open Access Journals (Sweden)

Anu Batra

2014-01-01

Full Text Available Autologous graft versus host disease (autoGVHD is a rare transplant complication with significant morbidity and mortality. It has been hypothesized that patients with multiple myeloma might be predisposed to autoGVHD through dysregulation of the immune response resulting from either their disease, the immunomodulatory agents (IMiDs used to treat it, or transplant conditioning regimen. Hematopoietic progenitor cell (HPC products were available from 8 multiple myeloma patients with biopsy-proven autoGVHD, 16 matched multiple myeloma patients who did not develop autoGVHD, and 7 healthy research donors. The data on number of transplants prior to developing autoGVHD, mobilization regimens, exposure to proteasome inhibitors, use of IMiDs, and class I human leukocyte antigen types (HLA A and B were collected. The HPC products were analyzed by flow cytometry for expression of CD3, CD4, CD8, CD25, CD56, and FoxP3. CD3+ cell number was significantly lower in autoGVHD patients compared to unaffected controls (P=0.047. On subset analysis of CD3+ cells, CD8+ cells (but not CD4+ cells were found to be significantly lower in patients with autoGVHD (P=0.038. HLA-B55 expression was significantly associated with development of autoGVHD (P=0.032. Lower percentages of CD3+ and CD8+ T-cells and HLA-B55 expression may be predisposing factors for developing autoGVHD in myeloma.

Implications of Heterogeneity in Multiple Myeloma

Directory of Open Access Journals (Sweden)

Sanjay de Mel

2014-01-01

Full Text Available Multiple myeloma is the second most common hematologic malignancy in the world. Despite improvement in outcome, the disease is still incurable for most patients. However, not all myeloma are the same. With the same treatment, some patients can have very long survival whereas others can have very short survival. This suggests that there is underlying heterogeneity in myeloma. Studies over the years have revealed multiple layers of heterogeneity. First, clinical parameters such as age and tumor burden could significantly affect outcome. At the genetic level, there are also significant heterogeneity ranging for chromosome numbers, genetic translocations, and genetic mutations. At the clonal level, there appears to be significant clonal heterogeneity with multiple clones coexisting in the same patient. At the cell differentiation level, there appears to be a hierarchy of clonally related cells that have different clonogenic potential and sensitivity to therapies. These levels of complexities present challenges in terms of treatment and prognostication as well as monitoring of treatment. However, if we can clearly delineate and dissect this heterogeneity, we may also be presented with unique opportunities for precision and personalized treatment of myeloma. Some proof of concepts of such approaches has been demonstrated.

Stimulation of Toll-like receptor-1/2 combined with Velcade increases cytotoxicity to human multiple myeloma cells

International Nuclear Information System (INIS)

Abdi, J; Mutis, T; Garssen, J; Redegeld, F

2013-01-01

An increasing body of evidence supports the important role of adhesion to bone marrow microenvironment components for survival and drug resistance of multiple myeloma (MM) cells. Previous studies suggested that stimulation of Toll-like receptors by endogenous ligands released during inflammation and tissue damage may be pro-tumorigenic, but no studies have been performed in relation to modulation of cell adhesion and drug cytotoxicity. Here, we investigated the effect of TLR1/2 activation on adhesion of human myeloma cells to fibronectin, and their sensitivity to the proteasome inhibitor Velcade. It was found that TLR1/2 activation with Pam3CSK4 increased the cytotoxicity of Velcade in L363, OPM-2 and U266 human myeloma cells. This effect was not related to a decreased adhesion of the cells to fibronectin, but TLR1/2 activation stimulated the caspase-3 activity in Velcade-treated myeloma cells, which may be responsible for the enhanced cell death. Inhibitors of NF-κB and MAPK reduced the stimulatory effect. These findings indicate that TLR activation of MM cells could bypass protective effects of cell adhesion and suggest that TLR signaling may also have antitumorigenic potential

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

DEFF Research Database (Denmark)

Andersen, Thomas L; Søe, Kent; Søndergaard, Teis Esben

2010-01-01

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...

Clinical Application of {sup 18}F-FDG PET in Multiple Myeloma

Energy Technology Data Exchange (ETDEWEB)

Lee, Su Jin; Choi, Joon Young [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

2009-12-15

This review focuses on the clinical use of {sup 18}F-FDG PET to evaluate multiple myeloma. {sup 18}F-FDG PET is useful for diagnosis, staging of multiple myeloma and differential diagnosis of myeloma related disease such as monoclonal gammopathy of undetermined significance or plasmacytoma. For therapy response, {sup 18}F-FDG PET may be effective after chemotherapy for multiple myeloma and radiotherapy for plasmacytoma.

Palliative radiotherapy for multiple myeloma

International Nuclear Information System (INIS)

Furusawa, Mitsuhiro; Baba, Yuji; Murakami, Ryuji; Yokoyama, Toshimi; Nishimura, Ryuichi; Uozumi, Hideaki; Takada, Chitose; Takahashi, Mutsumasa

1995-01-01

This study reviews the experience of palliative radiotherapy to patients with multiple myeloma to define the optimal dose for pain relief. The records of 31 patients (66 sites) with multiple myeloma irradiated for palliation at Kumamoto University hospital between 1985 and 1994 were reviewed. Total dose ranged from 8 to 50 Gy, with a mean of 32.2 Gy. Symptoms included pain (78.1%), neurological abnormalities (28.1%), and palpable masses (34.3%). Symptomatic remission was obtained in 45 of 46 evaluable sites (97.8%). Complete remission of symptoms were obtained in 28.3%, and partial remission in 69.6%. According to fraction size, there was no significant difference between 3-5 Gy and 1.8-2 Gy. The incidence of complete remission increased when a total dose of more than 20 Gy was given. When the quality of life is considered, hypofractionation was recommended for the palliative radiation therapy of multiple myeloma. (author)

A case of multiple myeloma presenting as a bullous dermatosis

Directory of Open Access Journals (Sweden)

Gul Ulker

2008-01-01

Full Text Available Multiple myeloma is a malignant plasma cell proliferative disorder that produces a monoclonal immunoglobulin protein. The skin involvement and the development of bullous disease are rarely seen features in multiple myeloma. We present a 55-year-old man with a longstanding, large, tense bullous eruption and hypertrophic scars over his body accompanied recently with weight loss and fatique. He had no response to the previous treatments, which included oral glucocorticoids and dapsone. Histologic examination of the lesions revealed subepidermal bullae, while no immunoflourescence staining was observed. In a further detailed labarotory examination, multiple myeloma was detected. After the treatment of multiple myeloma with chemotherapy, the lesions regressed. Patients with longstanding, recurrent, unusual bullous eruption should be investigated for the development of multiple myeloma.

Effects of Radiotherapy in the treatment of multiple myeloma: a retrospective analysis of a Single Institution

International Nuclear Information System (INIS)

Matuschek, Christiane; Ochtrop, Thomas A; Bölke, Edwin; Ganswindt, Ute; Fenk, Roland; Gripp, Stephan; Kröpil, Patric; Gerber, Peter Arne; Kammers, Kai; Hamilton, Jackson; Orth, Klaus; Budach, Wilfried

2015-01-01

Palliative irradiation of osteolytic lesions is a considerable component in the treatment for patients with multiple myeloma. In this study, we analyzed the efficacy of irradiation in these patients. We retrospectively analyzed 153 patients with multiple myeloma who were admitted to our department between 1989 and 2013. According to the staging system of Durie & Salmon 116 patients were classified as stage III. 107/153 patients were treated with radiotherapy of at least one and up to 6 bony lesions at different times. In order to evaluate the effect of local radiotherapy on pain relief and bone recalcification a uni- and multivariate analysis was performed using a binary logistic regression model to correct for multiple measurements. Complete information on dose, fractionation and volume of radiotherapy was available from 81 patients treated in 136 target volumes for pain relief, and from 69 patients treated in 108 target volumes for recalcification. Total radiation doses varied between 8 Gy to 50 Gy (median dose 25 Gy in 2.5 Gy fractions, 5 times a week). Radiotherapy resulted in complete local pain relief in 31% and partial local pain relief in 54% of the patients. In the univariate analysis, higher total radiation doses (p = 0.023) and higher age (p = 0.014) at the time of radiotherapy were significantly associated with a higher likelihood of pain relief, whereas no significant association was detected for concurrent systemic treatment, type and stage of myeloma and location of bone lesions. The same variables were independent predictors for pain relief in the multivariate analysis. Recalcification was observed in 48% of irradiated bone lesions. In the uni- and multivariate analysis higher radiation doses were significantly associated (p = 0.048) with an increased likelihood of recalcification. Side effects of radiotherapy were generally mild. Higher total biological radiation doses were associated with better pain relief and recalcification in this

Radiation therapy for the palliation of multiple myeloma

International Nuclear Information System (INIS)

Leigh, B.R.; Kurtts, T.A.; Mack, C.F.; Matzner, M.B.; Shimm, D.S.

1993-01-01

This study reviews the experience at the University of Arizona in an effort to define the minimum effective radiation dose for durable pain relief in the majority of patients with symptomatic multiple myeloma. The records of 101 patients with multiple myeloma irradiated for palliation at the University of Arizona between 1975 and 1990 were reviewed. Three hundred sixteen sites were treated. Ten sites were asymptomatic, including six hemibody fields with advanced disease unresponsive to chemotherapy and four local fields with impending pathological fractures. Three hundred six evaluable symptomatic sites remained. The most common symptom was bone pain. Other symptoms included neurological impairment with a palpable mass. Total tumor dose ranged from 3.0 to 60 Gy, with a mean of 25 Gy. Symptom relief was obtained in 297 of 306 evaluable symptomatic sites (97%). Complete relief of symptoms was obtained in 26% and partial relief in 71%. Symptom relief was obtained in 92% of sites receiving a total dose less than 10 Gy (n = 13) and 98% of sites receiving 10 Gy or more (n = 293). No dose-response could be demonstrated. The likelihood of symptom relief was not influenced by the location of the lesion or the use of concurrent chemotherapy. Of the 297 responding sites, 6% (n = 19) relapsed after a median symptom-free interval of 16 months. Neither the probability of relapse nor the time to relapse was related to the radiation dose. Retreatment of relapsing sites provided effective palliation in all cases. Radiation therapy is effective in palliating local symptoms in multiple myeloma. A total dose of 10 Gy should provide durable symptom relief in the majority of patients. 16 refs., 3 figs., 4 tabs

Radiotherapy for solitary plasmacytoma and multiple myeloma

International Nuclear Information System (INIS)

Schmaus, M.C.; Neuhof, D.

2014-01-01

Solitary plasmacytoma and multiple myeloma require a differentiated radiotherapy. The irradiation for plasmacytoma with an adequate total dose (medullary 40-50 Gy or extramedullary 50-60 Gy) leads to a high degree of local control with a low rate of side effects. In cases of multiple myeloma radiotherapy will achieve effective palliation, both in terms of recalcification as well as reduction of neurological symptoms and analgesia. In terms of analgesia the rule is the higher the single dose fraction the faster the reduction of pain. As part of a conditioning treatment prior to stem cell transplantation radiotherapy contributes to the establishment of a graft versus myeloma effect (GVM). (orig.) [de

Positive findings on bone scan in multiple myeloma

International Nuclear Information System (INIS)

Lin Lin

2004-01-01

We report a case of multiple myeloma in which the CT only shows osteolytic lesions and MRI only shows compressive fractrue, but the scan shows some interesting imaging that make us to think of multiple myeloma. (authors)

Hemibody irradiation in multiple myeloma

International Nuclear Information System (INIS)

Tobias, J.S.; Richards, J.D.M.; Blackman, G.M.; Joannides, T.; Trask, C.W.L.; Nathan, J.I.

1985-01-01

Eighteen patients with multiple myeloma were treated by hemibody irradiation using large single fractions, usually to a dose of 10 Gy (lower half) and 7.5 GY (upper half). All except one patient had previously been treated by multiple courses of conventional chemotherapy with melphalan and prednisone, and were considered to be resistant to further chemotherapy. In most cases, local field irradiation had also been given for symptomatic bone pain. Of the 13 patients who had symptoms at the start of hemibody irradiation, 11 improved sufficiently for their analgesia requirement to be reduced. In eight patients, there was a significant fall in circulating immunoglobulin but no patient with Bence-Jones proteinuria had complete resolution of this biochemical abnormality. Although thrombocytopenia and neutropenia were common, only two patients required platelet transfusion and the treatment was in general extremely well tolerated. Survival following hemibody irradiation was similar to the survival reported from the use of 'second-line' chemotherapy and we feel that hemibody irradiation is a more acceptable alternative for most patients. (orig.)

Imaging spectrum in sclerotic myelomas: an experience of three cases

International Nuclear Information System (INIS)

Grover, S.B.; Dhar, A.

2000-01-01

The classic radiographic presentation of multiple myeloma is lytic skeletal lesions. Primary sclerotic manifestations are rare and occur only in 3 % of cases. The imaging spectrum in three cases of multiple myeloma with primary osteosclerosis is described. The first patient had spiculated sclerosis of the orbit, which is an uncommon site for myeloma. The second patient with POEMS syndrome had multiple, scattered, skeletal lesions with sclerotic margins. The third patient presented with a chest wall mass and had an expansile thick spiculated sclerosis in the rib. The wide imaging spectrum possible in sclerotic myelomas and their relevant differential diagnosis is emphasized. (orig.)

Noninvasive imaging of multiple myeloma using near infrared fluorescent molecular probe

Science.gov (United States)

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.

Whole body MR in patients with multiple myeloma

International Nuclear Information System (INIS)

Piekarek, A.; Sosnowski, P.; Nowicki, A.; Komarnicki, M.

2009-01-01

Background: Multiple myeloma is a cancer of plasma cells which leads to bone marrow infiltration. Aim: Whole-body MR is the most sensitive imaging method available to detect multiple myeloma lesions. Ma terial and methods: MR scans were performed in 100 patients with multiple myeloma who were receiving treatment in the Haematology Clinic in Poznan in the years 2005 - 2006. Whole-body MR scans were performed with general coil 1.0 T in STIR sequences and T1 sequences, in coronal and sagittal planes with scanning area covering the head, neck, trunk and the limbs (FOV for specific regions was 36 -48 cm). The bone lesions were classified as focal (monofocal/multifocal lesions), infiltrative, mixed and 'salt and pepper' type. Depending on the size of the lesions the patients were included in one of three groups according to Salmon-Durie Plus classification. Results: Four main types of multiple myeloma were distinguished based on MR scans: focal (48 patients; monofocal in 10 patients), infiltrative (17 patients), mixed type (19 patients) and 'salt and pepper' type (4 patients). The remaining 12 patients had no multiple myeloma lesions in the bone marrow. Additionally, in 18% of patients a soft tissue mass could be observed. According to Salmon-Durie Plus categorisation 27 subjects were classified as having stage I, 16 patients stage and 57 patients stage III disease. In 12% of patients MR data changed the disease staging. Conclusions: WB MR is a sensitive and effective diagnostic method with an important impact on staging and further treatment of multiple myeloma. (authors)

Myeloma: Patient accounts of their pathways to diagnosis

Science.gov (United States)

Hart, Ruth I.; Smith, Alexandra G.; Macleod, Una; Patmore, Russell; Cook, Gordon; Roman, Eve

2018-01-01

Background Pathways to myeloma diagnosis can be prolonged, and are often preceded by multiple GP consultations and emergency presentation. This is the first qualitative study to examine events leading to diagnosis by asking patients about their experiences during this time. Methods Set within a UK population-based cohort, semi-structured interviews were conducted with 20 myeloma patients with varying characteristics and pathways, 12 of whom invited their relatives to take part. Interviews were audio-recorded and qualitative analysis undertaken. Results Pre-diagnostic awareness of myeloma was minimal. Disease onset was typically described as gradual, and health changes vague but progressive, with increasing loss of function. A wide range of symptoms was reported, with the similarity of these to self-limiting conditions failing to raise suspicion of myeloma among patients and GPs. Patients tended to normalise symptoms at first, although all eventually sought GP advice. GPs often initially suggested benign diagnoses, which were sometimes only revised after multiple consultations with persistent/worsening symptoms. Referrals were made to various hospital specialities, and haematology if associated with abnormal blood tests suggestive of myeloma. Once in secondary care, progress towards diagnosis was generally rapid. Conclusions Accounts confirmed that pathways to diagnosis could be difficult, largely due to the way myeloma presents, and how symptoms are interpreted and managed by patients and GPs. Recognition of ‘normal’ health and consultation patterns for the individual could promote appropriate help-seeking and timely referral when changes occur, and may be more effective than raising awareness about the myriad of potential symptoms associated with this disease. PMID:29617390

Novel human multiple myeloma cell line UHKT-893

Czech Academy of Sciences Publication Activity Database

Uherková, L.; Vančurová, I.; Vyhlídalová, I.; Pleschnerová, M.; Špička, I.; Mihalová, R.; Březinová, J.; Hodný, Zdeněk; Čermáková, K.; Polanská, V.; Marinov, I.; Jedelský, P.L.; Kuželová, K.; Stöckbauer, P.

2013-01-01

Roč. 37, č. 3 (2013), s. 320-326 ISSN 0145-2126 Institutional support: RVO:68378050 Keywords : human myeloma cell line * human multiple myeloma * plasma cell * IL-6 dependence * immunoglobulin * free light chain Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.692, year: 2013

Multiple myeloma in a captive lion (Panthera leo

Directory of Open Access Journals (Sweden)

Adrian S.W. Tordiffe

2013-09-01

Full Text Available Multiple myeloma is a rare, systemic proliferation of neoplastic plasma cells. A case was reported in an 11-year-old male captive lion (Panthera leo at the National Zoological Gardens of South Africa, Pretoria. The classic features of symptomatic multiple myeloma were all evident in this case; namely osteolytic lesions, monoclonal gammopathy in the serum with excretion of monoclonal proteins in the urine, neoplastic plasma cells in the bone marrow and associated renal failure and anaemia. In addition, similar to the common pattern of this disease in domestic felids, at least three extramedullary tumours were found and several organs were infiltrated by neoplastic plasma cells. The cytoplasm of approximately 50%of the neoplastic round cells, including a few giant myeloma cells, stained weakly to strongly using immunohistochemical stains for B-lymphocytes (CD79a. The normal haematological parameters and lack of any osteolytic lesions in the lion at the time of the first evaluation suggest that the primary neoplastic cells could have originated from one of the extramedullary tumour sites. Only two cases of multiple myeloma have previously been reported in captive wild felids. To the authors’ knowledge, there are no case reports of multiple myeloma in lions.

The Role of Immunotherapy in Multiple Myeloma

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Mehmet Kocoglu

2016-01-01

Full Text Available Multiple myeloma is the second most common hematologic malignancy. The treatment of this disease has changed considerably over the last two decades with the introduction to the clinical practice of novel agents such as proteasome inhibitors and immunomodulatory drugs. Basic research efforts towards better understanding of normal and missing immune surveillence in myeloma have led to development of new strategies and therapies that require the engagement of the immune system. Many of these treatments are under clinical development and have already started providing encouraging results. We, for the second time in the last two decades, are about to witness another shift of the paradigm in the management of this ailment. This review will summarize the major approaches in myeloma immunotherapies.

Multiple myeloma of an extremity: must the whole bone be irradiated?

International Nuclear Information System (INIS)

Catell, Donna; Kogen, Zeev; Donahue, Bernadine; Steinfeld, Alan

1996-01-01

Purpose/Objective: Radiation of the entire shaft of a long bone affected by multiple myeloma is often advocated to prevent recurrent disease in the bone remote from the symptomatic site. Our standard of care has been to irradiate only the symptomatic area. We investigated the pattern of recurrence in patients treated in this manner. Materials and Methods: 163 patients with multiple myeloma were treated between 1971 and 1994. Twenty-seven patients received treatment to a long bone with 43 sites irradiated (17 humeri, 24 femurs, 1 radius, 1 ulna.) The most common long bone treated was the femur. All patients were treated with megavoltage therapy. The symptomatic lesion, plus a margin of 1-2 cm was treated with no attempt to treat the entire shaft. Mean radiation dose was 2782 cGy (range 600-4480 cGy). The length of the field was measured in centimeters and expressed as both an absolute (AL) and relative (RL) length (i.e. percentage of total length of bone). Results: The mean total AL and RL for femur fields was 18 cm and 42% respectively. For the humerus, the AL and RL were 20 cm and 68% respectively. Only 4 patients developed progressive disease in the same bone but outside the previously irradiated field. In 3 of the 4 patients the RL was between 20 and 30%. The dose of radiation given to these patients was 1250, 2100, 3000 and 3500 cGy. In all of these 4 cases, treatment of progressive disease in adjacent sites provided effective palliation of symptoms. Conclusion: Radiation therapy to the symptomatic portion of a long bone affected by MM is effective for palliation. Symptomatic recurrence out of the irradiated field is uncommon and can be effectively treated. Potential benefits of this approach include irradiation of less normal marrow and elimination of use of pairs of fields or extended distance treatment to cover the entire femur

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

Science.gov (United States)

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 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 proliferation index and plasmablastic morphological features were predictive of a short time to recurrence

Bismuth adjuvant ameliorates adverse effects of high-dose chemotherapy in patients with multiple myeloma and malignant lymphoma undergoing autologous stem cell transplantation

DEFF Research Database (Denmark)

Hansen, Per Boye; Penkowa, Milena

2017-01-01

show for the first time that bismuth significantly reduces grade 2 stomatitis, febrile neutropenia and infections caused by melphalan in multiple myeloma, where adverse effects also were significantly linked to gender. In lymphoma patients, bismuth significantly reduces diarrhoea relative to placebo......PURPOSE: High-dose chemotherapy prior to autologous stem cell transplantation (ASCT) leads to adverse effects including mucositis, neutropenia and bacteremia. To reduce the toxicity, we treated myeloma and lymphoma patients with peroral bismuth as an adjuvant to chemotherapy to convey...

Detection of Extramedullary Multiple Myeloma in Liver by FDG-PET/CT

International Nuclear Information System (INIS)

Kim, Daeweung; Kim, Woo Hyoung; Kim, Myoung Hyoun; Choi, Keum Ha; Kim, Chang Guhn

2014-01-01

We present the case of a 42-year-old man with a painful mass lesion in the right shoulder that was detected by contrast-enhanced computed tomography (CT) and 18 F-fluoro-2-deoxyglucose ( 18 F-FDG) positron emission tomography (PET)/CT. Excisional biopsy revealed infiltration of plasma cells with anaplastic features, consistent with solitary plasmacytoma (PC). Serum analysis showed elevation of serum free lambda light chain levels (27.78 mg/l), with an abnormally high kappa:lambda ratio (2.33) and high total proteins (10.4 g/dl). Serum protein electrophoresis revealed an M spike in the gamma-globulin region (56.1 %=5.8 g/dl). Subsequently, 18 F-FDG PET/CT revealed another hypermetabolic mass in the right lobe of the liver. CT-guided biopsy of the liver lesion revealed plasma cell myeloma, consistent with multiple myeloma. Multiple myeloma presenting as nodular liver masses is very rare in clinical practice. In a retrospective review of more than 2,000 patients, Talamo et al. reported only nine cases where there was nodular involvement of the liver by multiple myeloma. The organ most commonly involved was the liver, followed by pancreas, stomach, peritoneum with malignant ascites, colon, rectum, duodenum and ileum. Therefore, the literature published thus far has been limited to a few reports and case series. Among these reports, some had demonstrated the PET or PET/CT findings of nodular liver involvement of multiple myeloma. About 10 % of the solitary myelomas appeared as extramedullary PC or solitary PC of bone. In spite of the advances in therapy, the treatment of multiple myeloma is still palliative. However, solitary PC could be cured by resection or radiation therapy. Thus, differentiation between PC and multiple myeloma is essential in making a decision for the appropriate therapeutic regimen. 18 F-FDG PET/CT has the unique ability to detect and characterize malignant lesions in one single examination. Schirrmeister et al. reported that 18 F-FDG PET revealed

Immunogenic Targets for Specific Immunotherapy in Multiple Myeloma

Directory of Open Access Journals (Sweden)

Lu Zhang

2012-01-01

Full Text Available Multiple myeloma remains an incurable disease although the prognosis has been improved by novel therapeutics and agents recently. Relapse occurs in the majority of patients and becomes fatal finally. Immunotherapy might be a powerful intervention to maintain a long-lasting control of minimal residual disease or to even eradicate disseminated tumor cells. Several tumor-associated antigens have been identified in patients with multiple myeloma. These antigens are expressed in a tumor-specific or tumor-restricted pattern, are able to elicit immune response, and thus could serve as targets for immunotherapy. This review discusses immunogenic antigens with therapeutic potential for multiple myeloma.

Guidelines for supportive care in multiple myeloma 2011.

Science.gov (United States)

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.

A Pictorial Review on Extraosseous Manifestations of Multiple Myelomas

International Nuclear Information System (INIS)

Seo, Jung Min; Lee, Kyung Soo; Yi, Chin A; Kim, Seong Hyun; Park, Byung Kwan; Han, Boo Kyung; Kim, Hyung Jin

2011-01-01

Extraosseous involvement of multiple myelomas can be seen clinically or radiologically in approximately 10-20% of patients at the time of initial diagnosis and may develop in an additional 15% of patients over the course of the disease. The condition can arise in any tissue of the body and its presence has been associated with more aggressive disease, a guarded prognosis, or high-dose chemotherapy. Imaging findings of extraosseous multiple myelomas are diverse. They usually show high enhancement on contrast-medium enhanced CT scans, exhibit iso-signal intensity on both T1- and T2- weighted images, and variable 18F-fluorine deoxyglucose (FDG) uptake at PET. The disease may simulate an infectious condition since it may be concurrent with underlying multiple myelomas per se or it may occur during myeloma treatment including stem cell transplantation.

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

Science.gov (United States)

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

Directory of Open Access Journals (Sweden)

Atsushi Kasamatsu

2015-01-01

Full Text Available 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.

Maxillary Swelling as the First Evidence of Multiple Myeloma

Science.gov (United States)

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

Hemibody irradiation. An effective second-line therapy in drug-resistance multiple myeloma

International Nuclear Information System (INIS)

Singer, C.R.; Tobias, J.S.; Giles, F.; Rudd, G.N.; Blackman, G.M.; Richards, J.D.

1989-01-01

The authors report the results of treatment of 41 patients with melphalan-resistant multiple myeloma using single half-body irradiation (HBI) or double half-body irradiation (DHBI). Patients were grouped using prognostic classification reported by the Medical Research Council. Patients in group I and II showed the best response to therapy with reduction in serum of urinary paraprotein and improvement in symptoms, most notably a marked reduction in bone pain. In these groups five patients have survived over 2 years after therapy. The therapeutic response appeared better in those patients who received DHBI as opposed to those whom treated with single HBI. Patients in group III did not achieve prolonged survival but effective relief of bone pain was a consistent finding in these patients also. Thus HBI represents an alternative to combination chemotherapy as second-line treatment of patients with melphalan-resistant multiple myeloma. A comparative study of HBI versus combination chemotherapy is now indicated to establish which therapeutic approach is most effective

Drug response prediction in high-risk multiple myeloma

DEFF Research Database (Denmark)

Vangsted, A J; Helm-Petersen, S; Cowland, J B

2018-01-01

from high-risk patients by GEP70 at diagnosis from Total Therapy 2 and 3A to predict the response by the DRP score of drugs used in the treatment of myeloma patients. The DRP score stratified patients further. High-risk myeloma with a predicted sensitivity to melphalan by the DRP score had a prolonged...

Detection of Extramedullary Multiple Myeloma in Liver by FDG-PET/CT

Energy Technology Data Exchange (ETDEWEB)

Kim, Daeweung; Kim, Woo Hyoung; Kim, Myoung Hyoun; Choi, Keum Ha; Kim, Chang Guhn [Wonkwang Univ. School of Medicine, Iksan (Korea, Republic of)

2014-06-15

We present the case of a 42-year-old man with a painful mass lesion in the right shoulder that was detected by contrast-enhanced computed tomography (CT) and {sup 18}F-fluoro-2-deoxyglucose ({sup 18}F-FDG) positron emission tomography (PET)/CT. Excisional biopsy revealed infiltration of plasma cells with anaplastic features, consistent with solitary plasmacytoma (PC). Serum analysis showed elevation of serum free lambda light chain levels (27.78 mg/l), with an abnormally high kappa:lambda ratio (2.33) and high total proteins (10.4 g/dl). Serum protein electrophoresis revealed an M spike in the gamma-globulin region (56.1 %=5.8 g/dl). Subsequently, {sup 18}F-FDG PET/CT revealed another hypermetabolic mass in the right lobe of the liver. CT-guided biopsy of the liver lesion revealed plasma cell myeloma, consistent with multiple myeloma. Multiple myeloma presenting as nodular liver masses is very rare in clinical practice. In a retrospective review of more than 2,000 patients, Talamo et al. reported only nine cases where there was nodular involvement of the liver by multiple myeloma. The organ most commonly involved was the liver, followed by pancreas, stomach, peritoneum with malignant ascites, colon, rectum, duodenum and ileum. Therefore, the literature published thus far has been limited to a few reports and case series. Among these reports, some had demonstrated the PET or PET/CT findings of nodular liver involvement of multiple myeloma. About 10 % of the solitary myelomas appeared as extramedullary PC or solitary PC of bone. In spite of the advances in therapy, the treatment of multiple myeloma is still palliative. However, solitary PC could be cured by resection or radiation therapy. Thus, differentiation between PC and multiple myeloma is essential in making a decision for the appropriate therapeutic regimen. {sup 18}F-FDG PET/CT has the unique ability to detect and characterize malignant lesions in one single examination. Schirrmeister et al. reported that

Bortezomib or high-dose dexamethasone for relapsed multiple myeloma

NARCIS (Netherlands)

P.G. Richardson (Paul Gerard); P. Sonneveld (Pieter); M.W. Schuster (Michael); D. Irwin (David); E.A. Stadtmauer (Edward); T. Facon (Thierry); J-L. Harousseau (Jean-Luc); D. Ben-Yehuda (Dina); S. Lonial (Sagar); H. Goldschmidt (Hartmut); D. Reece (Donna); J.F. San Miguel (Jesús Fernando); J. Bladé (Joan); M. Boccadoro (Mario); J. Cavenagh (Jamie); W. Dalton (William); A.L. Boral (Anthony); D.-L. Esseltine (Dixie-Lee); J.B. Porter (Jane); D. Schenkein (David); K.C. Anderson (Kenneth)

2005-01-01

textabstractBACKGROUND: This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies. METHODS: We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3

Myeloma cells suppress osteoblasts through sclerostin secretion

Energy Technology Data Exchange (ETDEWEB)

Colucci, S; Brunetti, G; Oranger, A [Department of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy); Mori, G [Department of Biomedical Science, University of Foggia, Foggia (Italy); Sardone, F [Department of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy); Specchia, G; Rinaldi, E; Curci, P; Liso, V [Department of Emergency and Organ Transplantation, Hematology Section, Bari University Medical School, Bari (Italy); Passeri, G [Department of Internal Medicine and Biomedical Sciences, Center for Metabolic Bone Diseases, University of Parma, Parma (Italy); Zallone, A [Department of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy); Rizzi, R [Department of Emergency and Organ Transplantation, Hematology Section, Bari University Medical School, Bari (Italy); Grano, M [Department of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy)

2011-06-01

Wingless-type (Wnt) signaling through the secretion of Wnt inhibitors Dickkopf1, soluble frizzled-related protein-2 and -3 has a key role in the decreased osteoblast (OB) activity associated with multiple myeloma (MM) bone disease. We provide evidence that another Wnt antagonist, sclerostin, an osteocyte-expressed negative regulator of bone formation, is expressed by myeloma cells, that is, human myeloma cell lines (HMCLs) and plasma cells (CD138+ cells) obtained from the bone marrow (BM) of a large number of MM patients with bone disease. We demonstrated that BM stromal cells (BMSCs), differentiated into OBs and co-cultured with HMCLs showed, compared with BMSCs alone, reduced expression of major osteoblastic-specific proteins, decreased mineralized nodule formation and attenuated the expression of members of the activator protein 1 transcription factor family (Fra-1, Fra-2 and Jun-D). Moreover, in the same co-culture system, the addition of neutralizing anti-sclerostin antibodies restored OB functions by inducing nuclear accumulation of β-catenin. We further demonstrated that the upregulation of receptor activator of nuclear factor κ-B ligand and the downregulation of osteoprotegerin in OBs were also sclerostin mediated. Our data indicated that sclerostin secretion by myeloma cells contribute to the suppression of bone formation in the osteolytic bone disease associated to MM.

Morganella morganii Pericarditis in a Patient with Multiple Myeloma

Directory of Open Access Journals (Sweden)

Takafumi Nakao

2013-01-01

Full Text Available Purulent pericarditis caused by Morganella morganii is extremely rare. We report herein a case of a 61-year-old man who presented with chest pain and dyspnea fourteen days after chemotherapy for multiple myeloma. Echocardiogram and computed tomography revealed a massive pericardial effusion and associated cardiac tamponade. Pericardiocentesis was performed. Pericardial fluid was found to be purulent, and Morganella morganii was isolated from the fluid. The patient was successfully treated with antibiotic therapy and surgical drainage of the fluid. Morganella morganii should be considered a possible pathogen when immunocompromised patients develop purulent pericarditis.

[HSP90 Inhibitor 17-AAG Inhibits Multiple Myeloma Cell Proliferation by Down-regulating Wnt/β-Catenin Signaling Pathway].

Science.gov (United States)

Chen, Kan-Kan; He, Zheng-Mei; Ding, Bang-He; Chen, Yue; Zhang, Li-Juan; Yu, Liang; Gao, Jian

2016-02-01

To investigate the inhibitory effect of HSP90 inhibitory 17-AAG on proliferation of multiple myeloma cells and its main mechanism. The multiple myeloma cells U266 were treated with 17-AAG of different concentrations (200, 400, 600 and 800 nmol/L) for 24, 48, and 72 hours respectively, then the proliferation rate, expression levels of β-catenin and C-MYC protein, as well as cell cycle of U266 cells were treated with 17-AAG and were detected by MTT method, Western blot and flow cytometry, respectively. The 17-AAG showed inhibitory effect on the proliferation of U266 cells in dose- and time-depetent manners (r = -0.518, P AAG displayed no inhibitory effect on proliferation of U266 cells (P > 0.05). The result of culturing U266 cells for 72 hours by 17-AAG of different concentrations showed that the more high of 17-AAG concentration, the more low level of β-catenin and C-MYC proteins (P AAG concentration, the more high of cell ratio in G1 phase (P AAG, the more long time of culture, the more high of cell ratio in G1 phase (P AAG can inhibit the proliferation of multiple myeloma cells, the down-regulation of Wnt/β-catenin signaling pathway and inhibition of HSP90 expression may be the main mechnisms of 17-AAG effect.

Genetic variations in multiple myeloma I

DEFF Research Database (Denmark)

Vangsted, A.; Klausen, T.W.; Vogel, Ulla Birgitte

2012-01-01

Few risk factors have been established for the plasma cell disorder multiple myeloma, but some of these like African American ethnicity and a family history of B-cell lymphoproliferative diseases suggest a genetic component for the disease. Genetic variation represents the genetic basis of variab......Few risk factors have been established for the plasma cell disorder multiple myeloma, but some of these like African American ethnicity and a family history of B-cell lymphoproliferative diseases suggest a genetic component for the disease. Genetic variation represents the genetic basis...

[IgE myeloma. Laboratory typing difficulties].

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Bovone, Nora S; Fuente, María Cristina; Gastiazoro, Ana María; Alfonso, Graciela; Freitas, María Josefina

2014-01-01

The IgE multiple myeloma is a rare neoplasm of plasma cell accounting for 0.01% of all plasma cell dyscrasias. They are generally of more aggressive development and to date there are no more than 50 cases published in current literature. Laboratory studies are, in these cases, essential for the classification of the monoclonal component in serum and urine. The aim of this presentation is to report a patient diagnosed with IgE myeloma and to point out that the laboratory difficulties noted in these rare cases can lead to an erroneous report.

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

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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 (pcancers remains to be determined, and surgical removal remains a challenge for any new experimental treatment of melanoma in mouse models.

Plasma cell morphology in multiple myeloma and related disorders.

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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

Targeting paraprotein biosynthesis for non-invasive characterization of myeloma biology.

Directory of Open Access Journals (Sweden)

Katharina Lückerath

Full Text Available PURPOSE: Multiple myeloma is a hematologic malignancy originating from clonal plasma cells. Despite effective therapies, outcomes are highly variable suggesting marked disease heterogeneity. The role of functional imaging for therapeutic management of myeloma, such as positron emission tomography with 2-deoxy-2-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG-PET, remains to be determined. Although some studies already suggested a prognostic value of ¹⁸F-FDG-PET, more specific tracers addressing hallmarks of myeloma biology, e.g. paraprotein biosynthesis, are needed. This study evaluated the amino acid tracers L-methyl-[¹¹C]-methionine (¹¹C-MET and [¹⁸F]-fluoroethyl-L-tyrosine ((¹⁸F-Fet for their potential to image myeloma and to characterize tumor heterogeneity. EXPERIMENTAL DESIGN: To study the utility of ¹¹C-MET, ¹⁸F-Fet and ¹⁸F-FDG for myeloma imaging, time activity curves were compared in various human myeloma cell lines (INA-6, MM1.S, OPM-2 and correlated to cell-biological characteristics, such as marker gene expression and immunoglobulin levels. Likewise, patient-derived CD138⁺ plasma cells were characterized regarding uptake and biomedical features. RESULTS: Using myeloma cell lines and patient-derived CD138⁺ plasma cells, we found that the relative uptake of ¹¹C-MET exceeds that of ¹⁸F-FDG 1.5- to 5-fold and that of ¹⁸F-Fet 7- to 20-fold. Importantly, ¹¹C-MET uptake significantly differed between cell types associated with worse prognosis (e.g. t(4;14 in OPM-2 cells and indolent ones and correlated with intracellular immunoglobulin light chain and cell surface CD138 and CXCR4 levels. Direct comparison of radiotracer uptake in primary samples further validated the superiority of ¹¹C-MET. CONCLUSION: These data suggest that ¹¹C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with ¹⁸F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor

Multiple myeloma: 45 cases

International Nuclear Information System (INIS)

Yang, Hee Chul; Suh, Jin Suck; Park, Chang Yun

1990-01-01

We evaluated 45 cases of multiple myelomas retrospectively confirmed in Severance Hospital from the period of 1983-1989. In order to assess the radiologic features of the multiple myeloma and to assist in possible early diagnosis and treatment. The result were as follows: 1. IgG(41%) was the most common immunoglobulin type secreted followed by light chain(36%). IgA(19%) and IgD(2%). Two percent of the patients had non-secretory type. 89% of patients were in their stage III of the disease. 2. Among the 45 patients, 96% had abnormal plain radiographic findings with average number of 4.5 lesions. Common sites were the spine, rib, skull, pelvis, and humerus in descending orders. The findings were localized or diffuse osteolytic bone destruction(85%). osteoporosis(49%), pathologic fracture and endosteal scalloping(55%). Osteoporosis was more prominent in stage III than stage II. 3. Both plain X-ray and radioisotope study was available for comparison in 28 patients. Concordance between the two studies were 44%, lesions detected only on plain X-ray film were 51%, and lesions detected only on the radioisotope were 5%. The plain radiography was able to detect only 54% of bone lesions confirmed by bone marrow biopsy. With the above results, accurate evaluation of bone lesions in multiple myeloma may be difficult with radiologic studies only. But familiarity with these radiologic findings of the this disease entity is necessary for early suspicion of the disease, thus for early diagnosis and treatment

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

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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

Smoldering multiple myeloma risk factors for progression

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Sørrig, Rasmus; Klausen, Tobias W; Salomo, Morten

2016-01-01

Several risk scores for disease progression in Smoldering Multiple Myeloma (SMM) patients have been proposed, however, all have been developed using single center registries. To examine risk factors for time to progression (TTP) to Multiple Myeloma (MM) for SMM we analyzed a nationwide population......-based cohort of 321 newly diagnosed SMM patients registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M-protein ≥ 30g/l and immunoparesis significantly influenced......-high risk of transformation to MM. Using only immunoparesis and M-protein ≥ 30g/l, we created a scoring system to identify low, intermediate and high risk SMM. This first population-based study of SMM patients confirms that an M-protein ≥ 30g/l and immunoparesis remain important risk factors for progression...

Fundamentals in the management of multiple myeloma.

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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.

Evaluation of anticancer effects of a novel proteasome inhibitor (Velcade), interferon (alpha-interferon) and anti myeloma antibodies on the growth of myeloma cells

International Nuclear Information System (INIS)

El shershaby, H.M.M.

2013-01-01

Cancer is an abnormal growth of cells caused by multiple changes in gene expression leading to deregulated balance of cell proliferation and cell death and ultimately evolving into a population of cells that can invade tissues and metastasize to distant sites, causing significant morbidity. Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow leading to impaired hematopoiesis and bone diseases, which includes mainly lytic lesions, pathological fractures, hypercalcaemia and osteoporosis. Chemotherapy is the systemic treatment of cancer with anticancer drugs. Chemotherapy uses powerful drugs that work by slowing or stopping the cancer cells from growing, spreading or multiplying to other parts of the body. Extensive studies were run all over the world during the last years to discovery some new drugs which possess anticancer effect with less toxicity and have the ability to increase the survival time. In the current study Bortezomib was employed as chemotherapeutic drug for the treatment of myeloma cells where a variable dose of Bortezomib (5, 10,20,30,50 and 100 nM/ml) were used for treatment of myeloma cells in vitro. The results obtained indicated that the T.C/ml was decreased by increasing the drug conc. compared to that of control group. These results illustrated the effect of Bortezomib on the growth of myeloma cells, where the myeloma cell division was decreased while the older cells were deteriorated so that the T.C/ml were decreased. Also the viability of myeloma cells were significantly decreased after 72 hours of addition at drug concentration 20, 30, 50 and 100 nM/ml).

The case of a multiple myeloma with hyperlipoproteinaemia

International Nuclear Information System (INIS)

Paluszewska, M.; Bobilewicz, D.; Gigier, A.; Zwolinski, J.; Kuratowska, Z.

1994-01-01

The case of a 52-year-old women with hyperlipoproteinaemia, xantomathosis and multiple myeloma was discussed. The lipid disorder was one of the first symptoms and the base for diagnosis. Hyperlipoproteinaemia was probably due to the monoclonal immunoglobulin and lipoprotein interaction or their impaired catabolism. Lipoprotein lipase activity was normal. Cytostatic therapy led to partial remission of multiple myeloma and lipoproteins concentration became normal. (author)

Targeted Therapies for Myeloma and Metastatic Bone Cancers

Science.gov (United States)

2010-09-01

Cancer J Clin 2003; 53:5. Kasugai S, Fujisawa R, Waki Y, Miyamoto K, Ohya K 2000 Selective drug delivery system to bone: small peptide (Asp)6...page. Bone targeted nanoparticles , bone cancer myeloma, mice studies, PLGA , Biodegradable materials. Targeted Therapies for Myeloma and Metastatic Bone...present results from this program at talk at the Particles 2006 –Medical/Biochemical Diagnostic , Pharmaceutical, and Drug Delivery . 3

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

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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

Agricultural Exposures, Multiple Myeloma Etiology: Profile of Jonathan Hofmann

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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.

Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma

DEFF Research Database (Denmark)

Mellqvist, Ulf-Henrik; Gimsing, Peter; Hjertner, Oyvind

2013-01-01

The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370...

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

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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).

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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.

Role of sequential hemi-body irradiation in multiple myeloma: preliminary observations

International Nuclear Information System (INIS)

Kumar, H.S.; Chaudhary, R.K.; Kumar, Vanita

1993-01-01

Ten patients with multiple myeloma presenting in a highly painful condition were included in the study. They were treated by sequential hemi-body irradiation. A dose of 600 cGy was delivered to the upper hemi-body and 800 c Gy to the lower hemi-body. All patients has appreciable relief from pain. The maximum effect was achieved within 24 to 48 hours of treatment. 9 out of the 10 patients has an improvement in the performance status. All these patients were later subjected to combination chemotherapy. (author). 9 refs., 3 tabs

Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells

DEFF Research Database (Denmark)

Standal, Therese; Seidel, Carina; Hjertner, Øyvind

2002-01-01

Multiple myeloma (MM) is a hematologic malignancy characterized by accumulation of plasma cells in the bone marrow (BM). Bone destruction is a complication of the disease and is usually associated with severe morbidity. The balance between receptor activator of nuclear factor-kappaB (NF-kappaB......) ligand and osteoprotegerin (OPG) is of major importance in bone homeostasis. We have recently shown that serum OPG levels are lower in patients with myeloma than in healthy individuals. Here we show that myeloma cells can bind, internalize, and degrade OPG, thereby providing a possible explanation...... for the lower levels of OPG in the BM of patients with MM. This process is dependent on interaction of OPG with heparan sulfates on the myeloma cells. The results suggest a novel biologic mechanism for the bone disease associated with MM and that treatment of the bone disease with OPG lacking the heparin...

Simplified response monitoring criteria for multiple myeloma in patients undergoing therapy with novel agents using computed tomography

Energy Technology Data Exchange (ETDEWEB)

Schabel, Christoph; Horger, Marius; Kum, Sara [Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen (Germany); Weisel, Katja [Department of Internal Medicine II – Hematology & Oncology, Eberhard-Karls-University Tuebingen, Otfried-Müller-Str. 5, 72076 Tuebingen (Germany); Fritz, Jan [Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 600 N Wolfe St., Baltimore, MD 21287 (United States); Ioanoviciu, Sorin D. [Department of Internal Medicine, Clinical Municipal Hospital Timisoara, Gheorghe Dima Str. 5, 300079 Timisoara (Romania); Bier, Georg, E-mail: georg.bier@med.uni-tuebingen.de [Department of Neuroradiology, Eberhard-Karls-University Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen (Germany)

2016-12-15

{sub med}) and response of all myeloma manifestations including osteolyses (Resp{sub total}) was performed using the corrected contingency coefficient (C{sub corr}). Results: The correlation between Resp{sub med} based on length diameter and transverse diameter and Resp{sub total} was perfect (C{sub corr} = 1.0; p < 0.0001) whereas the correlation based on density was moderate (C{sub corr} = 0.54; p < 0.0001). The evaluation of simplified response criteria with a measurement of only 2 medullary lesions yielded the best sensitivity and specificity valued for treatment-induced changes for the length diameter evaluation with 94.4%/95.7% for prediction of progressive disease and 78.6%/93.3% for prediction of therapy response. There were no significant differences between patients treated with bortezomib and lenalidomide (p > 0.05). Conclusion: Measurements of size of a minimum of two medullary lesions is sufficient for response assessment and correlates very well with the course of lytic bone lesions and that of hematologic parameters.

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

Science.gov (United States)

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.

State-of-the-Art Management of Complications of Myeloma and Its Treatment

Directory of Open Access Journals (Sweden)

Monique A. Hartley-Brown

2010-01-01

Full Text Available Multiple myeloma is an incurable disease, although patient survival has increased with the availability of novel agents. Both multiple myeloma and its therapies often affect the renal, immune, skeletal, hematologic, and nervous systems. The resulting organ dysfunctions often impair the quality of life of affected patients, complicate and limit subsequent therapies, and may result in significant mortality. Research on the treatment of complications of multiple myeloma has been limited; hence, preventative and management strategies for patients with these complications are heterogeneous and often based on anecdotal experience. In this paper, we review the effects of myeloma and the novel therapies on organ systems and suggest management strategies.

GWAS of 972 autologous stem cell recipients with multiple myeloma identifies 11 genetic variants associated with chemotherapy-induced oral mucositis

DEFF Research Database (Denmark)

Coleman, Elizabeth Ann; Lee, Jeannette Y; Erickson, Stephen W

2015-01-01

PURPOSE: High-dose chemotherapy and autologous stem cell transplant (ASCT) to treat multiple myeloma (MM) and other cancers carries the risk of oral mucositis (OM) with sequelae including impaired nutritional and fluid intake, pain, and infectious complications. As a result of these problems, can...

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

Science.gov (United States)

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 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.

PET-CT for nuclear medicine diagnostics of multiple myeloma

International Nuclear Information System (INIS)

Dimitrakopoulou-Strauss, A.

2014-01-01

Functional or morphofunctional imaging modalities are used in myeloma patients for the diagnosis and therapy management within research protocols. Despite new staging criteria, which take into account the viability of a myeloma lesion, positron emission tomography (PET) is not used routinely. The impact of PET is therefore open. The role of PET and PET computed tomography (PET-CT) for the diagnosis and therapy management is discussed. The use of PET with 18F-fluorodeoxyglucose (FDG) allows the measurement of viable myeloma lesions and correlates with the stage of disease. A negative FDG examination correlates with a better prognosis. Furthermore, the number of focal lesions as well as the whole functional volume of myeloma lesions in FDG have a prognostic impact. Several studies have demonstrated the impact of FDG for the assessment of therapy monitoring and show that FDG is an earlier indicator for therapy response as compared to magnetic resonance imaging (MRI). The CT component of the new hybrid systems allows the assessment of osteolytic lesions in CT and their viability in FDG. The combination of PET with an MRT scanner allows the simultaneous measurement of bone marrow infiltration, focal lesions and their viability. The use of modern hybrid scanners, such as PET-CT and PET-MRT facilitates the simultaneous measurement of viable myeloma lesions, osteolytic lesions and bone marrow infiltration in the whole body; therefore, it is expected that these imaging modalities will play a greater role both in diagnosis and therapy management. (orig.) [de

Tetraspanin 7 (TSPAN7) expression is upregulated in multiple myeloma patients and inhibits myeloma tumour development in vivo

Energy Technology Data Exchange (ETDEWEB)

Cheong, Chee Man [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); Chow, Annie W.S. [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); Department of Haematology, SA Pathology, Adelaide 5000, SA (Australia); Fitter, Stephen [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); Hewett, Duncan R. [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); School of Medicine, University of Adelaide, Adelaide 5005, SA (Australia); Martin, Sally K. [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); Department of Haematology, SA Pathology, Adelaide 5000, SA (Australia); School of Medicine, University of Adelaide, Adelaide 5005, SA (Australia); Williams, Sharon A. [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); To, L. Bik [Department of Haematology, SA Pathology, Adelaide 5000, SA (Australia); and others

2015-03-01

Background: Increased expression of the tetraspanin TSPAN7 has been observed in a number of cancers; however, it is unclear how TSPAN7 plays a role in cancer progression. Methods: We investigated the expression of TSPAN7 in the haematological malignancy multiple myleoma (MM) and assessed the consequences of TSPAN7 expression in the adhesion, migration and growth of MM plasma cells (PC) in vitro and in bone marrow (BM) homing and tumour growth in vivo. Finally, we characterised the association of TSPAN7 with cell surface partner molecules in vitro. Results: TSPAN7 was found to be highly expressed at the RNA and protein level in CD138{sup +} MM PC from approximately 50% of MM patients. TSPAN7 overexpression in the murine myeloma cell line 5TGM1 significantly reduced tumour burden in 5TGM1/KaLwRij mice 4 weeks after intravenous adminstration of 5TGM1 cells. While TSPAN7 overexpression did not affect cell proliferation in vitro, TSPAN7 increased 5TGM1 cell adhesion to BM stromal cells and transendothelial migration. In addition, TSPAN7 was found to associate with the molecular chaperone calnexin on the cell surface. Conclusion: These results suggest that elevated TSPAN7 may be associated with better outcomes for up to 50% of MM patients. - Highlights: • TSPAN7 expression is upregulated in newly-diagnosed patients with active multiple myeloma. • Overexpression of TSPAN7 inhibits myeloma tumour development in vivo. • TSPAN7 interacts with calnexin at the plasma membrane in a myeloma cell line.

Radiography and bone scintigraphy in multiple myeloma: a comparative analysis

International Nuclear Information System (INIS)

Ludwig, H.; Kumpan, W.; Sinzinger, H.

1982-01-01

The sensitivity of radionuclide imaging for detecting skeletal lesions was compared with that of radiography by evaluating 573 different anatomical sites in 41 patients with multiple myeloma. Radiography revealed a significantly greater number of myeloma-related bone lesions than did radionuclide imaging. Of the 179 myeloma-related bone lesions detected when both techniques were applied, 163 were seen by radiography and 82 by radionuclide imaging. Ninety-seven lesions were detected by radiography alone and 16 lesions seen by scintiscanning only, yielding a sensitivity of 91% for the former and of 46% for the latter technique. Radionuclide imaging proved superior to radiography only occasionally in the rib cage, and rarely in other anatomical sites. These findings suggest that radiography is the method of first choice in obtaining a skeletal survey in patients with multiple myeloma. In cases with continued pain, unexplained by standard radiography, the skeletal survey should be supplemented by tomography and radionuclide imaging. (author)

Dorsal Column Degeneration after Bortezomib Therapy in a Patient with Multiple Myeloma

Directory of Open Access Journals (Sweden)

Tatsuro Joh

2009-10-01

Full Text Available We present here a case of dorsal column degeneration in a female patient with multiple myeloma following exposure to bortezomib. Two days after intravenous administration of a first course of bortezomib 1 mg/m2, the patient developed rapidly-progressive numbness, pain and muscle weakness in the bilateral upper and lower limbs. Following gancyclovir treatment of subsequent cytomegalovirus viremia, the patient went on to receive a course of EPOCH (etoposide 50 mg/m2/day on days 1–4, vincristine 0.4 mg/m2/day on days 1–4, doxorubicin 10 mg/m2/day on days 1–4, cyclophosphamide 750 mg/m2/day on day 6, and prednisolone 60 mg/m2/day on days 1–6. Shortly thereafter, the patient developed bilateral Aspergillus pneumonia. Despite treatment with appropriate antifungal agents, the patient died from respiratory failure due to bilateral diffuse alveolar damage of the lungs and without recovery of severe sensory and motor neuropathy prior to her death. Post mortem examination revealed spongy degeneration of the dorsal column from the medulla oblongata to the cervical spinal cord. Bortezomib-associated peripheral neuropathy in patients with multiple myeloma has been commonly reported but appears to resolve in a majority of these patients after dose reduction or discontinuation. We believe this to be the first report of spinal cord abnormalities in a patient with multiple myeloma treated with bortezomib. Further investigation is required to ascertain the exact mechanism of this central neurotoxic effect and to identify appropriate neuroprotective strategies.

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

Science.gov (United States)

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

Imaging of multiple myeloma and related monoclonal plasma cell diseases. An update

International Nuclear Information System (INIS)

Weber, Marc-Andre; Delorme, Stefan; Hillengass, Jens

2014-01-01

Multiple myeloma is a hematologic disorder characterized by the infiltration and proliferation of monoclonal plasma cells mainly in the bone marrow. The main symptoms are hypercalcemia, renal impairment, cytopenia/anemia and bone disease - summarized as CRAB-criteria. Symptomatic multiple myeloma is consistently preceded by asymptomatic premalignant stages called monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Staging of multiple myeloma is based on the measurement of the monoclonal protein in serum and urine as well as the assessment of impairment of hematopoiesis, renal function and mineralized bone. In the last decade the development of novel therapeutic agents has led to an increase in response rates and survival time of patients with multiple myeloma, which further stresses the value of response assessment by imaging. Cross sectional imaging like MRI and CT is currently replacing conventional radiological surveys in the initial work-up and follow-up of patients with monoclonal plasma cell diseases. The added value of MRI is to improve initial staging by unraveling a diffuse infiltration of bone marrow by plasma cells, a focal pattern or a combination of both. Furthermore, a complete remission of myeloma confirmed by MRI and CT goes along with a better prognosis compared to a complete response based only on serological parameters.

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

Directory of Open Access Journals (Sweden)

Malathi Narayan

2016-06-01

Full Text Available 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 http://www.ebi.ac.uk/pride/archive/projects/PXD003032.

Systemic irradiation in multiple myeloma: a report on nineteen cases

International Nuclear Information System (INIS)

Rostom, A.Y.; O'Cathail, S.M.; Folkes, A.

1984-01-01

Nineteen patients with relapsed or resistant multiple myeloma were treated with sequential half-body irradiation (12) and half-body irradiation only (seven). Haematological toxicity was acceptable and recovery was complete in all but two of the 19 patients following half-body irradiation. However, only six of the 12 patients who subsequently had the remaining half irradiated completely recovered. Blood transfusions were required to correct anaemia in six patients, a platelet transfusion was given to one and one patient required both platelet and blood transfusions. No serious haematological complications were observed. Six of the 13 patients who received upper half-body irradiation of probable chest infection, while one patient of the six who received lower half-body irradiation died of this complication. Some of the seven deaths may have been due to radiation pneumonitis. Two patients developed brain secondaries, possibly indicating a change in the natural history of myeloma produced by this new treatment. Subjective improvement was observed in 17 patients and relief of pain usually occurred within the first 24 h. Objective responses were noted in six patients. The median survival for all patients was 6 months with five patients alive 11-28 months at the time of writing. (author)

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

Science.gov (United States)

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.

Science.gov (United States)

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.

The effect of ranitidine on cellular immunity in patients with multiple myeloma

DEFF Research Database (Denmark)

Nielsen, Hans Jørgen; Nielsen, H; Moesgaard, F

1990-01-01

.19-2.25 nmol/min) (P less than 0.005 between groups). Among ranitidine-treated patients spontaneous NK cell activity was unchanged, while in vitro interleukin-2- and interferon-alpha-stimulated NK cell activity decreased (P less than 0.03, respectively). As production of oxygen radicals constitutes...... after previous cytotoxic therapy were in a stable phase of their disease. All were without clinical signs of infections and at that time had not been treated with other immunomodulating agents. The patients were randomized to oral ranitidine 300 mg twice a day for 21 days or placebo, and several...... immunological parameters related to multiple myeloma were studied. The blood monocyte chemotactic response was improved in patients treated with ranitidine, and superoxide anion production increased from 2.02 nmol/min to 3.86 nmol/min (median values), while it was unchanged in patients given placebo (2...

Late diagnosis of multiple myeloma: a case report

Science.gov (United States)

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.

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

Directory of Open Access Journals (Sweden)

Fabrizio Accardi

2015-01-01

Full Text Available 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.

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

International Nuclear Information System (INIS)

Bam, R; Venkateshaiah, S U; Khan, S; Ling, W; Randal, S S; Li, X; Zhang, Q; Rhee, F van; 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

Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

DEFF Research Database (Denmark)

Fu, Jing; Li, Shirong; Feng, Rentian

2016-01-01

Multiple myeloma (MM) cells secrete osteoclastogenic factors that promote osteolytic lesions; however, the identity of these factors is largely unknown. Here, we performed a screen of human myeloma cells to identify pro-osteoclastogenic agents that could potentially serve as therapeutic targets...

Modern imaging techniques in patients with multiple myeloma

International Nuclear Information System (INIS)

Bannas, Peter; Adam, G.; Derlin, T.; Kroeger, N.

2013-01-01

Imaging studies are essential for both diagnosis and initial staging of multiple myeloma, as well as for differentiation from other monoclonal plasma cell diseases. Apart from conventional radiography, a variety of newer imaging modalities including whole-body low-dose-CT, whole-body MRI and 18F-FDG PET/CT may be used for detection of osseous and extraosseous myeloma manifestations. Despite of known limitations such as limited sensitivity and specificity and the inability to detect extraosseous lesions, conventional radiography still remains the gold standard for staging newly diagnosed myeloma, partly due to its wide availability and low costs. Whole-body low-dose CT is increasingly used due to its higher sensitivity for the detection of osseous lesions and its ability to diagnose extraosseous lesions, and is replacing conventional radiography at selected centres. The highest sensitivity for both detection of bone marrow disease and extraosseous lesions can be achieved with whole-body MRI or 18F-FDG PET/CT. Diffuse bone marrow infiltration may be visualized by whole-body MRI with high sensitivity. Whole-body MRI is at least recommended in all patients with normal conventional radiography and in all patients with an apparently solitary plasmacytoma of bone. To obtain the most precise readings, optimized examination protocols and dedicated radiologists and nuclear medicine physicians familiar with the complex and variable morphologies of myeloma lesions are required. (orig.)

Interleukin-6, a new target for therapy in multiple myeloma?

NARCIS (Netherlands)

van Oers, M. H.; van Zaanen, H. C.; Lokhorst, H. M.

1993-01-01

During the past few years much insight has been gained into the immunobiology of multiple myeloma. It has become evident that the growth of myeloma cells is regulated by cytokines, notably interleukin-6. In this paper a brief review is given of the evidence derived from in vitro as well as in vivo

Global myeloma research clusters, output, and citations: a bibliometric mapping and clustering analysis.

Directory of Open Access Journals (Sweden)

Jens Peter Andersen

Full Text Available International collaborative research is a mechanism for improving the development of disease-specific therapies and for improving health at the population level. However, limited data are available to assess the trends in research output related to orphan diseases.We used bibliometric mapping and clustering methods to illustrate the level of fragmentation in myeloma research and the development of collaborative efforts. Publication data from Thomson Reuters Web of Science were retrieved for 2005-2009 and followed until 2013. We created a database of multiple myeloma publications, and we analysed impact and co-authorship density to identify scientific collaborations, developments, and international key players over time. The global annual publication volume for studies on multiple myeloma increased from 1,144 in 2005 to 1,628 in 2009, which represents a 43% increase. This increase is high compared to the 24% and 14% increases observed for lymphoma and leukaemia. The major proportion (>90% of publications was from the US and EU over the study period. The output and impact in terms of citations, identified several successful groups with a large number of intra-cluster collaborations in the US and EU. The US-based myeloma clusters clearly stand out as the most productive and highly cited, and the European Myeloma Network members exhibited a doubling of collaborative publications from 2005 to 2009, still increasing up to 2013.Multiple myeloma research output has increased substantially in the past decade. The fragmented European myeloma research activities based on national or regional groups are progressing, but they require a broad range of targeted research investments to improve multiple myeloma health care.

Solitary plasmacytoma treated with radiotherapy: Impact of tumor size on outcome

International Nuclear Information System (INIS)

Tsang, Richard W.; Gospodarowicz, Mary K.; Pintilie, Melania; Bezjak, Andrea; Wells, Woodrow; Hodgson, David C.; Stewart, A. Keith

2001-01-01

Purpose: Solitary plasmacytoma (SP) is a rare presentation of plasma cell neoplasms. In contrast to multiple myeloma, long-term disease-free survival and cure is possible following local radiotherapy (RT), particularly for soft tissue presentations. In this study, we attempt to identify factors that predict for local failure, progression to multiple myeloma, and disease-free survival (DFS) in patients mainly managed with local RT. Methods and Materials: We identified 46 patients referred to the Princess Margaret Hospital between 1982 and 1993. The median age was 63 years (range 35-95), with a male:female ratio of 1.9:1. All patients had biopsy-proven SP (osseous: 32, soft tissue: 14). M-protein was abnormal in 19 patients (41%). All patients were treated with local RT (median dose 35 Gy), with 5 patients (11%) also receiving chemotherapy. Maximum tumor size pre-RT ranged from 0 to 18 cm (median 2.5). Results: The 8-year overall survival, DFS, and myeloma-free rates were 65%, 44%, and 50%, respectively. The local control rate was 83%. Factors predictive of progression to myeloma (and poorer DFS) included bone presentation and older age. However, these two factors did not influence local control, which was affected by tumor size. All tumors < 5 cm in bulk (34 patients) were controlled by RT. Anatomic location did not predict outcome; however, 3 of the 5 tumors arising in paranasal sinuses did not achieve local control. Lower RT dose (≤35 Gy) was not associated with a higher risk of local failure. Conclusion: Solitary plasmacytomas are effectively treated with moderate-dose RT, although osseous tumors have a high rate of recurrence as systemic myeloma. Large tumor bulk locally (≥5 cm) predicts for local failure. Combined chemotherapy and RT should be investigated in these high-risk patients to increase the local control rate and the cure rate

CUTANEOUS INVOLVEMENT IN MULTIPLE MYELOMA AT AN UNUSUAL SITE: A RARE CASE REPORT

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Lohit Kumar

2015-05-01

Full Text Available Multiple myeloma is a rare cancer. According to the most recent data from the Surveillance, Epidemiology, and End Results (SEER program, multiple myeloma is the second most common haematological malignancy in the U.S. (after non - Hodgkin lymphoma, constitutes 1% of all cancers and constitutes 2% of all cancer deaths. Cutaneous involvement of multiple myeloma during treatment period is uncommon with fewer described in literature. Moreover, metastatic cutaneous involvement at the sole of the foot during treatment period of a IgA kappa type multiple myeloma patient followed by death has not encountered in literature. We have reported such a case

An exploration of the lived experiences of individuals with relapsed multiple myeloma.

LENUS (Irish Health Repository)

Maher, K

2012-02-01

The experience of living with relapsed Multiple Myeloma (myeloma) for eight patients accessing treatment within a haematology unit in a large London hospital is explored in this study. Myeloma is recognised as incurable and is sometimes described as an \\'incurable chronic disease\\' with a main treatment option of chemotherapy. Hermeneutic phenomenology was the methodology used in conducting the study and data were collected through open-ended, unstructured interviews. Findings suggest that living with relapsed myeloma in the context of a chronic illness causes an ever-shifting perspective between illness and wellness consequently maintaining a state of uncertainty. The patients in this study placed importance on the emotional aspect of their experience. Hope, intuitive knowing and a fighting spirit were expressed as required positive elements that enabled living with relapsed myeloma. These assisted in maintaining normality, coping with bad news and adjusting to the illness. Pervading through the themes was the need to control uncertainty. Having strong support from significant others provided something to live for and the necessary social support required to promote a new orientation to life.

Osteosclerotic Myeloma with Peripheral Neuropathy

African Journals Online (AJOL)

diagnosis of myeloma should, in future, be suspected in these circumstances. ... moved towards the midline, and involved the lower thoracic region of his back for 18 .... further treatment, took his own discharge and has been lost to follow-up.

Recent advances in understanding multiple myeloma [version 1; referees: 4 approved

Directory of Open Access Journals (Sweden)

Binod Dhakal

2016-08-01

Full Text Available There have been major recent advancements in the understanding and management of multiple myeloma. Diagnostic criteria have been revised and former ultra-high-risk smoldering multiple myeloma is now considered multiple myeloma in need of treatment. Understanding clonal progression, evolution, and tides not only has helped elucidate the disease behavior but might help expand therapeutic choices in order to select appropriate treatment for patients. Unprecedented response rates with modern triplet induction therapies containing proteasome inhibitor and immunomodulators have made this approach standard for initial treatment. The US Food and Drug Administration approved four new drugs (two targeted antibodies and two oral agents in 2015 in relapsed/refractory multiple myeloma and these drugs along with the other already-available drugs have now increased the choices of regimens. Even drugs without single-agent activity, such as panobinostat and elotuzumab, have an important role, especially in the proteasome inhibitor refractory setting. Recent studies done in the context of novel agent induction suggest that high-dose therapy followed by autologous transplant continues to improve response rates and progression-free survival, thus underscoring their role in transplant-eligible patients. Evolving paradigms in the treatment of multiple myeloma include newer promising immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations. Though multiple myeloma is still considered incurable, it is clear that with the improved understanding of disease biology and clonal architecture of relapse combined with the availability of multi-targeted approaches, we are ever closer to a lasting cure or transformation into indolent and long-lasting disease courses or both.

Association of IgA multiple myeloma with pre-existing disease

Energy Technology Data Exchange (ETDEWEB)

Schafer, A.I.; Miller, J.B.

1979-01-01

A retrospective analysis of 153 patients with multiple myeloma was performed for evaluation of the possible significance of pre-existing disease. 37% of the group had no significant antecedent disorder. The most common prior illnesses were peptic ulcer disease and gallbladder disease. Of 12 patients in the group who had prior biliary tract disease and for whom immunoelectrophoretic studies were available, eight (66.7%) had IgA paraproteins. This figure is statistically higher than the 14.1% of prevalence of IgA paraproteins in those myeloma patients without biliary disease. We conclude that prior inflammatory gastrointestinal, pulmonary, and, particularly, biliary disease may be implicated in the pathogenesis of the IgA subset of multiple myeloma.

Therapy assessment in multiple myeloma with PET

Energy Technology Data Exchange (ETDEWEB)

Nanni, Cristina [Medicina Nucleare Metropolitana di Bologna, Bologna (Italy); Zamagni, Elena [Bologna University School of Medicine, Seragnoli Institute of Hematology, Bologna (Italy)

2017-08-15

Multiple myeloma is a plasma cell dyscrasia producing bone lytic lesions. In recent years, a wide spectrum of therapeutic approaches are available to treat the disease: an accurate therapy assessment has, therefore, become of utmost importance. In this field, imaging is becoming a cornerstone, especially in association with clinical parameters. Among imaging procedures, FDG PET/CT is recognized to provide reliable information, achieved in a very safe and fast procedure. The literature has produced very concordant results from different groups assessing the value of FDG PET/CT as a prognostic factor in general and in therapy assessment, but some issues remain regarding a standardization of image interpretation especially in borderline cases. So far, no data regarding nor other imaging compounds and the use of hybrid tomographs PET/MR are available to define therapy assessment in PET. (orig.)

Cold atmospheric plasma as a potential tool for multiple myeloma treatment

Science.gov (United States)

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

EARLY APPLICATION OF HIGH CUT-OFF HAEMODYALISIS FOR DE-NOVO MYELOMA NEPHROPATHY IS ASSOCIATED WITH LONG-TERM DIALYSIS-INDEPENDENCY AND RENAL RECOVERY

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Alhossain A. Khalafallah

2013-01-01

Full Text Available 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 reduction of FLC can lead to a higher proportion of patients recovering renal function with a better outcome, especially if extended high cut-off haemodialysis (HCO-HD combined with chemotherapy is used. Patients and Methods In this study, four cases of 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 median 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 on the treatment and become dialysis-independent. One patient with relapsed myeloma remained dialysis dependant. Conclusion Our study suggests that if myeloma nephropathy associated with light-chain disease, 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 trials to confirm our results are warranted. Key Words: Multiple myeloma, renal failure, High cut-off haemodialysis, chemotherapy, outcome.

Monoclonal antibodies in myeloma

DEFF Research Database (Denmark)

Sondergeld, P.; van de Donk, N. W. C. J.; Richardson, P. G.

2015-01-01

The development of monoclonal antibodies (mAbs) for the treatment of disease goes back to the vision of Paul Ehrlich in the late 19th century; however, the first successful treatment with a mAb was not until 1982, in a lymphoma patient. In multiple myeloma, mAbs are a very recent and exciting add...

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

Science.gov (United States)

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.

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

Science.gov (United States)

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 (Pdeficiency.

RECENT ADVANCES IN PATHO-BIOLOGY OF MYELOMA BONE DISEASE: CLINICOPATHOLOGY AND LITERATURE OF REVIEW

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Lohit Kumar

2016-03-01

Full Text Available Bone disease is a hallmark of multiple myeloma, presenting as lytic lesions associated with bone pain, pathological fractures requiring surgery and/or radiation to bone, spinal cord compression and hypercalcaemia. Increased osteoclastic activity unaccompanied by a compensatory increase in osteoblast function, leading to enhanced bone resorption results in bone disease. The interaction of plasma cells with the bone marrow microenvironment has been shown to play a vital role. Also, interactions of myeloma cells with osteoclasts enhance myeloma growth and survival, and thereby create a vicious cycle leading to extensive bone destruction and myeloma cell expansion.

Effects of radiotherapy in the treatment of multiple myeloma; Stellenwert der Strahlentherapie und deren Nebenwirkungen bei der Behandlung von Patienten mit Multiplem Myelom

Energy Technology Data Exchange (ETDEWEB)

Ochtrop, Thomas Alexander

2015-07-01

Palliative irradiation of osteolytic lesions is a considerable component in the treatment for patients with multiple myeloma. In this study, we analyzed the efficacy of irradiation in these patients. Patients and methods: We retrospectively analyzed 153 patients with multiple myeloma who were admitted to our department between 1989 and 2013. According to the staging system of Durie and Salmon 116 patients were classified as stage III. 107/153 patients were treated with radiotherapy of at least one and up to 6 bony lesions at different times. In order to evaluate the effect of local radiotherapy on pain relief and bone recalcification a uni- and multivariate analysis was performed using a binary logistic regression model to correct for multiple measurements. Complete information on dose, fractionation and volume of radiotherapy was available from 81 patients treated in 136 target volumes for pain relief, and from 69 patients treated in 108 target volumes for recalcification. Total radiation doses varied between 8 Gy to 50 Gy (median dose 25 Gy in 2.5 Gy fractions, 5 times a week). Results: Radiotherapy resulted in complete local pain relief in 31% and partial local pain relief in 54% of the patients. In the univariate analysis, higher total radiation doses (p = 0.023) and higher age (p = 0.014) at the time of radiotherapy were significantly associated with a higher likelihood of pain relief, whereas no significant association was detected for concurrent systemic treatment, type and stage of myeloma and location of bone lesions. The same variables were independent predictors for pain relief in the multivariate analysis. Recalcification was observed in 48% of irradiated bone lesions. In the uni- and multivariate analysis higher radiation doses were significantly associated (p = 0.048) with an increased likelihood of recalcification. Side effects of radiotherapy were generally mild. Conclusions: Higher total biological radiation doses were associated with better pain

Pulmonary Embolism as the First Manifestation of Multiple Myeloma

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N. Vallianou

2013-01-01

Full Text Available Multiple myeloma is considered a hypercoagulable state due to several mechanisms such as the increased IL-6 and immunoglobulins production, the defective fibrinolytic mechanism, and the acquired resistance to activated protein C that are involved in the pathogenesis and clinical futures of the disease. We describe a case of a female patient who presented to the hospital with pulmonary embolism as the first manifestation of the hypercoagulability of multiple myeloma.

Primary laryngeal localization of multiple myeloma: A case report

OpenAIRE

Allegra, Eugenia; Marino, Nicol?; Modica, Domenico; Emmanuele, Carmela; Saita, Vincenzo

2017-01-01

Multiple myeloma is a lymphoproliferative disease that may involve the bone marrow as well as extramedullary soft tissues. However, laryngeal localization of multiple myeloma is extremely rare. We herein present the case of a 68-year-old male patient with a history of dyspnea, dysphonia and dysphagia. Laryngoscopic examination revealed a lesion involving the right glottis and right vestibular (false) vocal fold, with absence of ipsilateral laryngeal motility and constriction of the airway. Co...

Thymidine secretion by hybridoma and myeloma cells

International Nuclear Information System (INIS)

Spilsberg, Bjorn; Rise, Frode; Petersen, Dirk; Nissen-Meyer, Jon

2006-01-01

Secretion of thymidine appeared to be a common property of hybridoma and myeloma cells, but not of other cell types, which were tested. Of three hybridoma cell lines tested, all secreted thymidine in amounts resulting in the accumulation of thymidine to concentrations of 10-20 μM in the culture medium. Also three of five myeloma cell lines that were analyzed secrete thymidine, but none of the other cell types that were studied. Thymidine was purified to homogeneity (4 mg purified from 3 l of culture medium) and identified as such by nuclear magnetic resonance spectroscopy. The cells that secreted thymidine showed high resistance to the growth inhibitory effect of thymidine

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

Science.gov (United States)

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.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Free light chains of immunoglobulins in the diagnosis and prognosis of multiple myeloma

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N. V. Lyubimova

2017-01-01

Full Text Available Background: Analysis of free light chains of immunoglobulins (FLC in the serum is an effective method in the diagnosis of multiple myeloma. Plasma cells produce two types of FLC: κand λ-FLC. FLC, which are not incorporated into monoclonal intact immunoglobulins, are released into circulation, and then are filtered and reabsorbed in kidneys depending on their molecular weight. Circulating FLC commonly form homodimers, known as Bence-Jones protein, which is a biomarker of Bence-Jones multiple myeloma. According to the international guidelines, the ratio κ/λ FLC is an important diagnostic criterion of multiple myeloma. Aim: To evaluate the diagnostic and prognostic value of serum FLC in multiple myeloma patients. Materials and methods: We examined 118 patients with multiple myeloma, admitted to the Department of Hemoblastosis Chemotherapy of N.N. Blokhin Russian Cancer Research Center from 2010 to 2016, and 68 healthy men and women. Serum concentrations of FLC were measured with an immunoturbidimetric method using the test-system Freelite Human Lambda and Freelite Human Kappa (Binding Site Inc.. Results: The levels of monoclonal κor λ-FLC in patients with G-, A-myeloma and Bence-Jones multiple myeloma were significantly higher than those in the control group (p < 0.005. The diagnostic sensitivity of quantification of FLC and their ratio was 87.3% and 89.8%, and in combination with the use of immune electrophoresis it was close to 100%. Analysis of progression free survival and overall survival showed significant differences (p < 0.04 between the groups of patients according their κ/λ FLC ratio. The basal value of κ/λ FLC ratio of less than 0.04 and more than 140 was a  predictor of unfavorable outcome. Conclusion: The inclusion of the determination of serum FLC into the assessment plan of patients with suspected monoclonal gammapathy makes it possible to increase diagnostic sensitivity of the available methods for paraprotein

Acquired amylase production induced by radiotherapy in a myeloma patient

Energy Technology Data Exchange (ETDEWEB)

Yamakawa, Tamami; Nagoshi, Haruhisa; Takahashi, Atushi [Saint Marianna Univ., Kawasaki, Kanagawa (Japan). School of Medicine] [and others

1995-10-01

A 55-year-old patient with multiple myeloma (IgG-{lambda}) diagnosed in November 1988 was admitted because of bone pain throughout the body. After plasmapheresis and several courses of chemotherapy, a massive tumor of the left thoracic wall involving the rib appeared. Radiotherapy was performed to ameliorate the severe chest pain, after which myelomatous pleural effusion appeared on the left side. The serum, urine and pleural effusion revealed increased activity of amylase of the salivary type. Amylase activity was also detected in the supernatant of myeloma cells cultured from pleural effusion. We reviewed 12 cases of ectopic amylase-producing multiple myeloma. All the cases except one have been reported from Japan, and hyperamylasemia in these cases was detected at diagnosis or during course of the illness. Moreover, cytogenetic analysis of myeloma cells of previous reports revealed structural abnormalities including chromosome 1, near the amylase gene locus. This case also showed t (1; 10) (q21?; q26) by examination of 8 metaphase derived from bone marrow. These observations suggested that ectopic amylase production was induced by irradiation to the plasmacytoma of thoracic wall. (author).

Acquired amylase production induced by radiotherapy in a myeloma patient

International Nuclear Information System (INIS)

Yamakawa, Tamami; Nagoshi, Haruhisa; Takahashi, Atushi

1995-01-01

A 55-year-old patient with multiple myeloma (IgG-λ) diagnosed in November 1988 was admitted because of bone pain throughout the body. After plasmapheresis and several courses of chemotherapy, a massive tumor of the left thoracic wall involving the rib appeared. Radiotherapy was performed to ameliorate the severe chest pain, after which myelomatous pleural effusion appeared on the left side. The serum, urine and pleural effusion revealed increased activity of amylase of the salivary type. Amylase activity was also detected in the supernatant of myeloma cells cultured from pleural effusion. We reviewed 12 cases of ectopic amylase-producing multiple myeloma. All the cases except one have been reported from Japan, and hyperamylasemia in these cases was detected at diagnosis or during course of the illness. Moreover, cytogenetic analysis of myeloma cells of previous reports revealed structural abnormalities including chromosome 1, near the amylase gene locus. This case also showed t (1; 10) (q21?; q26) by examination of 8 metaphase derived from bone marrow. These observations suggested that ectopic amylase production was induced by irradiation to the plasmacytoma of thoracic wall. (author)

Development of a "Myeloma Risk Score" using a population-based registry on paraproteinemia and myeloma

NARCIS (Netherlands)

Ong, F; Hermans, J; Noordijk, E M; De Kieviet, W; Seelen, P J; Wijermans, P W; Kluin-Nelemans, J C

1997-01-01

Diagnostic systems for monoclonal gammopathies use bone marrow and X-ray examinations to exclude multiple myeloma (MM). Data from a population-based registry of unselected patients with paraproteinemia indicate that these tests are often done only when MM is suspected. We used 441 randomly selected

Magnetic resonance imaging of the spine in multiple myeloma

International Nuclear Information System (INIS)

Tanaka, Masato; Nakahara, Shinnosuke; Koura, Hiroshi; Kai, Nobuo; Asaumi, Koji; Tanaka, Shunsuke; Sezaki, Tatsuo; Fukuda, Shunichi; Sunami, Kazutaka

2000-01-01

The characteristics of diagnostic imaging of the spine in multiple myeloma were examined. Twenty-one patients with stage II-III multiple myeloma (male=12, female=9, mean age=64) underwent MRI of the spine. Other diagnostic imaging modalities used in these patients included, CT bone scintigraphy, and radiography. All images of the spine were assessed and compared with the MRI images. The type of progression was evaluated based on the tumor distribution classification established by Sezaki. T1-weighted images of all 21 patients showed low signals in vertebral bodies, including 14 cases with a focal low signal intensity and 7 cases with diffuse low signal intensity. On the T2-weighted images, 15 of the 21 cases (71%) showed equivalent signals, while T2*-weighted images obtained by the field-echo method yielded high signals in 10 out of 11 cases. It was difficult to differentiate between senile osteoporosis and multiple myeloma by MRI, but CT images clearly distinguished between them. The results suggested that fat-suppressive T1-contrast images and T2*-weighted images are useful in detecting lesions, especially focal low signal intensity lesions. Patients with the multiple-lesion-tumor type of disease were more likely to develop paralysis more than those with the diffuse myeloproliferative type. Thus, the tumor distribution classification established by Sezaki was useful in considering radiotherapy for the treatment of patients at risk of paralysis. Bone scintigraphy revealed accumulation only in spinal lesions caused by compression fractures, while CT appeared to be useful in localizing the diffuse myeloproliferative type of lesions. The problems associated with diagnosis by MRI are differentiation of multiple myeloma from senile osteoporosis and metastatic bone tumors of the spine. There are few specific findings in multiple myeloma. (K.H.)

Advancements in Nanomedicine for Multiple Myeloma.

Science.gov (United States)

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.

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

Science.gov (United States)

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

An autopsy case of multiple myeloma with veno-occlusive disease of the liver induced by ionizing radiation

International Nuclear Information System (INIS)

Ueno, Hironori; Inagaki, Yasutaka; Yonei, Yoshikazu; Ozawa, Yukako; Atsukawa, Kazuhiro; Tsukada, Nobuhiro; Miyamoto, Kei; Suzuki, Osamu; Kiryu, Yasuyoshi

1995-01-01

An autopsy case of multiple myeloma which accompanied radiation-induced veno-occlusion of the liver is presented. A 62-year-old woman with a chief complaint of low back pain was diagnosed as having multiple myeloma. Approximately one year later, the patient was treated with chemotherapy, consisting of VCR, MCNU, ADR, PSL, and CPA, and X-irradiation of 30 Gy to the bilateral trunk for medically intractable rib pain. The irradiation field included the entire liver. Six months later, she was admitted to the hospital due to abdominal distention and massive amounts of ascites. Various examinations failed to make a qualitative diagnosis. Postmortem examination revealed fibrotic occlusion of the central vein which is typical for veno-occlusion disease of the liver. This finding was restricted to the area that was not shielded, irrespective of anatomical structure, strongly suggesting radiation-induced veno-occlusion of the liver. (N.K.)

Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders

DEFF Research Database (Denmark)

Rawstron, Andy C; Orfao, Alberto; Beksac, Meral

2008-01-01

The European Myeloma Network (EMN) organized two flow cytometry workshops. The first aimed to identify specific indications for flow cytometry in patients with monoclonal gammopathies, and consensus technical approaches through a questionnaire-based review of current practice in participating...

The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma

OpenAIRE

Hernández-García, Susana; San-Segundo, Laura; González-Méndez, Lorena; Corchete, Luis A; Misiewicz-Krzeminska, Irena; Martín-Sánchez, Montserrat; López-Iglesias, Ana-Alicia; Algarín, Esperanza Macarena; Mogollón, Pedro; Díaz-Tejedor, Andrea; Paíno, Teresa; Tunquist, Brian; Mateos, María-Victoria; Gutiérrez, Norma C; Díaz-Rodriguez, Elena

2017-01-01

[EN]Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor of this protein, has demonstrated activity in heavily pre-treated multiple myeloma patients. The aim of the work herein was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. The ability of filanesib to enhance the activity of pomali...

Multiple myeloma and central nervous system involvement: experience of a Brazilian center

Directory of Open Access Journals (Sweden)

Ana Luiza Miranda Silva Dias

2018-01-01

Full Text Available Introduction: The estimated involvement of the central nervous system in patients with multiple myeloma is rare at about 1%. The infiltration can be identified at the time multiple myeloma is diagnosed or during its progression. However, it is more common in refractory disease or during relapse. Methods: This retrospective cohort study reviewed data from medical records of patients followed up at the Gammopathy Outpatient Clinic of Santa Casa de Misericórdia de São Paulo from January 2008 to December 2016. Results: Twenty patients were included, with a median follow-up of 33.5 months after central nervous system infiltration. The prevalence was 7%. The median age at diagnosis of multiple myeloma was 56.1 years, with 70% of participants being female. Sixteen patients had central nervous system infiltration at diagnosis of multiple myeloma. Seventeen patients had exclusive osteodural lesions and three had infiltrations of the leptomeninge, of which one had exclusive involvement and two had associated osteodural lesions. The median overall survival was 40.3 months after central nervous system involvement. The median overall survival in the group with central nervous system infiltration at relapse was 7.4 months. The patients with leptomeningeal involvement had a median overall survival of 5.8 months. Conclusion: Central nervous system infiltration is a rare condition, but it should be considered as a possibility in patients with multiple myeloma and neurological symptoms. The best treatment regimen for this condition remains unknown and, in most cases, the prognosis is unfavorable. Keywords: Central nervous system, Multiple myeloma, Radiotherapy, Chemotherapy, Prognosis

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

Science.gov (United States)

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

Science.gov (United States)

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.

Multiple myeloma among atomic bomb survivors, Hiroshima and Nagasaki, 1950 - 76

International Nuclear Information System (INIS)

Ichimaru, Michito; Ishimaru, Toranosuke; Mikami, Motoko; Matsunaga, Masako.

1979-10-01

The relationship between atomic bomb exposure and the occurrence of multiple myeloma has been evaluated in a fixed cohort of approximately 100,000 A-bomb survivors and nonexposed controls during the period from October 1950 to December 1976. Analysis of these data revealed the standardized relative risk adjusted for city, sex, and age at the time of the bombs (ATB) to be significantly greater in the group of individuals who received 100 rad or more of radiation than in their controls. An excess risk became apparent in the high dose group about 20 years after exposure. The excess risk of multiple myeloma in those persons aged 20 - 59 ATB is estimated to be approximately 0.24 per million person-years per rad (PYR) in kerma dose and approximately 0.48 per million PYR in bone marrow dose. The interval between radiation exposure and the occurrence of an excess risk for multiple myeloma in the high dose population is considerably longer than that for leukemia. The cases of multiple myeloma observed in the high dose group showed no unusual clinical features. (author)

The first report of myeloma with IgD κ and free κ in Indonesia

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Riadi Wirawan

2011-08-01

Full Text Available IgD κ myeloma is a rare plasma cell neoplasm case and has never been reported before in Indonesia. In normal condition, IgD level in blood is very low, therefore increase of IgD level in myeloma could be missed by serum protein electrophoresis. A case of a 59 years old female with severe bone pain is reported. In radiology evaluation, there were thoracal compression fracture and thoracal foramen narrowing. For this patient, the myeloma diagnosis was based on WHO criteria, the stage IIIb was based on Durie and Salmon criteria, and bad prognosis with prognostic index stage III diagnosis was based on International Prognostic Index from International Myeloma Working Group, respectively. In serum protein electrophoresis we found a very small monoclonal spike and in immunofi xation there were monoclonal IgD κ and free light chain κ. (Med J Indones 2011; 20:217-21Keywords: immunofixation, myeloma IgD κ, protein electrophoresis

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

Science.gov (United States)

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

Science.gov (United States)

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.

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.

Science.gov (United States)

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.

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

Science.gov (United States)

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.

Sarcoidosis and multiple myeloma: Concurrent presentation of an unusual association

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Vidya Nair

2016-01-01

Full Text Available 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.

European perspective on multiple myeloma treatment stratgies in 2014

DEFF Research Database (Denmark)

Ludwig, Heinz; Sonneveld, Pieter; Davies, Faith

2014-01-01

The treatment of multiple myeloma has undergone significant changes and has resulted in the achievement of molecular remissions, the prolongation of remission duration, and extended survival becoming realistic goals, with a cure being possible in a small but growing number of patients. In addition...... recommendations for the management of patients with myeloma. Treatment approaches depend on "fitness," with chronological age still being an important discriminator for selecting therapy. In younger, fit patients, a short three drug-based induction treatment followed by autologous stem cell transplantation (ASCT...

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

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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.

The structural modification of cassava starch using a saline water pretreatment

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Hanny Frans SANGIAN

2018-04-01

Full Text Available Abstract The cassava has been modified successfully by using the saline water, which was abundantly available on the planet. The biomass was submerged in saline waters that salt concentrations were altered at 0, 3.5 percent (seawater and 10 percent (w/w and were kept 5 days. After recovery by washing steps, the treated solids were characterized by using XRD (X-ray diffraction , FTIR (Fourier transform infra-red, and SEM (Scanning electron microscopic. The results showed that the XRD pattern of saline water pretreatment decreased significantly. The biggest decrease of X-ray intensity occurred at around 18o. Meanwhile, the fingerprint of FTIR revealed the transmittance intensity of infra-red ray of saline water treated solid inclined for all wave constant numbers, suggesting that many hydrogen bonds were disconnected. Those findings also were enhanced by SEM pictures that showed the change of surface morphology of treated biomass. It was indicative that cassava structure was modified becoming more textured after employing saline water pretreatment. This work is an innovative finding to gradually substitute commercial ionic liquids that are very expensive with saline water for biomass pretreatment.

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

Science.gov (United States)

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.

Recent Advances in the Pathogenesis and Management of Cast Nephropathy (Myeloma Kidney

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Stephanie Stringer

2011-01-01

Full Text Available Multiple myeloma is an incurable plasma cell malignancy that is often accompanied by renal failure; there are a number of potential causes of this, of which cast nephropathy is the most important. Renal failure is highly significant in myeloma, as patient survival can be stratified by the severity of the renal impairment. Consequently, there is an ongoing focus on the pathological basis of cast nephropathy and the optimal treatment regimens in this setting, including effective chemotherapy regimens to reduce light chain production and emerging extracorporeal techniques to remove circulating light chains. This paper bridges recent advances in the pathogenesis and management of cast nephropathy in multiple myeloma.

radiochemical studies on the growth of myeloma cells

International Nuclear Information System (INIS)

Elshershaby, H.M.M.

2008-01-01

cancer is a disease of unregulated cell growth. humans of all ages develop cancer, and a wide variety of organs are affected. multiple myeloma is a cancer in which antibody-producing plasma cells grow in an uncontrolled and invasive (malignant) manner. melphalan (DNA cross-linker), is one of the most widely used and effective drugs in the treatment of multiple myeloma. thalidomide as an immunomodulatory agent is clinically useful in a number of cancers. antitumor activity may be related to a number of known properties, including antitumor necrosis factor (TNF)-α and T-cell costimulatory and antiangiogenic effect. however, it may also involve direct antitumor effects. radiotherapy is an important modality in the treatment of cancer. the aim of radiotherapy is to deliver radiation doses and schedules that kill cancer cells, while preserving normal tissue function. the aim of these studies was to evaluate the therapeutic effects of some chemical substances (chemotherapy)such as melphalan and thalidomide and γ-radiation (radiotherapy)on the growth of myeloma cells. also some confirmatory tests such as β2-microglobulin, caspases enzymes 8 and 9 and flow cytometric analyses were performed for the obtained optimum doses.

Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients

NARCIS (Netherlands)

Broyl, Annemiek; Hose, Dirk; Lokhorst, Henk; de Knegt, Yvonne; Peeters, Justine; Jauch, Anna; Bertsch, Uta; Buijs, Arjan; Stevens-Kroef, Marian; Beverloo, H. Berna; Vellenga, Edo; Zweegman, Sonja; Kersten, Marie-Josée; van der Holt, Bronno; el Jarari, Laila; Mulligan, George; Goldschmidt, Hartmut; van Duin, Mark; Sonneveld, Pieter

2010-01-01

To identify molecularly defined subgroups in multiple myeloma, gene expression profiling was performed on purified CD138(+) plasma cells of 320 newly diagnosed myeloma patients included in the Dutch-Belgian/German HOVON-65/GMMG-HD4 trial. Hierarchical clustering identified 10 subgroups; 6

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

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Desai, Varsha G., E-mail: varsha.desai@fda.hhs.gov [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Herman, Eugene H. [Division of Drug Safety Research, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993 (United States); Moland, Carrie L.; Branham, William S. [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Lewis, Sherry M. [Office of Scientific Coordination, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Davis, Kelly J. [Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR 72079 (United States); George, Nysia I. [Division Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States); Lee, Taewon [Department of Information and Mathematics, Korea University, Jochiwon, Chungnam 339-700 (Korea, Republic of); Kerr, Susan [Arkansas Heart Hospital, Little Rock, AR 72211 (United States); Fuscoe, James C. [Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 (United States)

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. 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.

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

Science.gov (United States)

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.

Science.gov (United States)

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

2014-11-11

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.

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

Science.gov (United States)

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?

Science.gov (United States)

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

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

Directory of Open Access Journals (Sweden)

Michele Mussap

2014-01-01

Full Text Available 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.

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

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McSweeney, E.N.; Tobias, J.S.; Goldstone, A.H.; Richards, J.D.M. (University Coll. Hospital, London (United Kingdom)); Blackman, G. (Middlesex Hospital, London (United Kingdom))

1993-01-01

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 chemo-resistant to initial therapy. Fifteen patients received [alpha]IFN-2b maintenance therapy post-DHBI, at a dose of 3 Mu three times per week. 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. We conclude that DHBI is an effective treatment in patients with relapsed multiple myeloma and in those who are chemoresistant to initial therapy. Cytopenia was a significant problem post-DHBI, such that the role of maintenance [alpha]IFN therapy could not be fully evaluated. (author).

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

International Nuclear Information System (INIS)

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

1993-01-01

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 chemo-resistant to initial therapy. Fifteen patients received αIFN-2b maintenance therapy post-DHBI, at a dose of 3 Mu three times per week. 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. αIFN did not appear to prolong survival (OS or PFS) post-DHBI. We conclude that DHBI is an effective treatment in patients with relapsed multiple myeloma and in those who are chemoresistant to initial therapy. Cytopenia was a significant problem post-DHBI, such that the role of maintenance αIFN therapy could not be fully evaluated. (author)

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

Science.gov (United States)

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.

IgM myeloma: A multicenter retrospective study of 134 patients.

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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.

Multiple myeloma associated with acquired cutis laxa.

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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.

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

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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].

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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.

The pituitary tumor transforming gene 1 (PTTG-1: An immunological target for multiple myeloma

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Gagliano Nicoletta

2008-04-01

Full Text Available Abstract Background Multiple Myeloma is a cancer of B plasma cells, which produce non-specific antibodies and proliferate uncontrolled. Due to the potential relapse and non-specificity of current treatments, immunotherapy promises to be more specific and may induce long-term immunity in patients. The pituitary tumor transforming gene 1 (PTTG-1 has been shown to be a novel oncogene, expressed in the testis, thymus, colon, lung and placenta (undetectable in most other tissues. Furthermore, it is over expressed in many tumors such as the pituitary adenoma, breast, gastrointestinal cancers, leukemia, lymphoma, and lung cancer and it seems to be associated with tumorigenesis, angiogenesis and cancer progression. The purpose was to investigate the presence/rate of expression of PTTG-1 in multiple myeloma patients. Methods We analyzed the PTTG-1 expression at the transcriptional and the protein level, by PCR, immunocytochemical methods, Dot-blot and ELISA performed on patient's sera in 19 multiple myeloma patients, 6 different multiple myeloma cell lines and in normal human tissue. Results We did not find PTTG-1 presence in the normal human tissue panel, but PTTG-1 mRNA was detectable in 12 of the 19 patients, giving evidence of a 63% rate of expression (data confirmed by ELISA. Four of the 6 investigated cell lines (66.6% were positive for PTTG-1. Investigations of protein expression gave evidence of 26.3% cytoplasmic expression and 16% surface expression in the plasma cells of multiple myeloma patients. Protein presence was also confirmed by Dot-blot in both cell lines and patients. Conclusion We established PTTG-1's presence at both the transcriptional and protein levels. These data suggest that PTTG-1 is aberrantly expressed in multiple myeloma plasma cells, is highly immunogenic and is a suitable target for immunotherapy of multiple myeloma.

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

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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.

Destabilization of Akt Promotes the Death of Myeloma Cell Lines

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Yanan Zhang

2014-01-01

Full Text Available Constitutive activation of Akt is believed to be an oncogenic signal in multiple myeloma and is associated with poor patient prognosis and resistance to available treatment. The stability of Akt proteins is regulated by phosphorylating the highly conserved turn motif (TM of these proteins and the chaperone protein HSP90. In this study we investigate the antitumor effects of inhibiting mTORC2 plus HSP90 in myeloma cell lines. We show that chronic exposure of cells to rapamycin can inhibit mTORC2 pathway, and AKT will be destabilized by administration of the HSP90 inhibitor 17-allylamino-geldanamycin (17-AAG. Finally, we show that the rapamycin synergizes with 17-AAG and inhibits myeloma cells growth and promotes cell death to a greater extent than either drug alone. Our studies provide a clinical rationale of use mTOR inhibitors and chaperone protein inhibitors in combination regimens for the treatment of human blood cancers.

Radiological diagnostics of multiple myeloma; Radiologische Diagnostik des multiplen Myeloms

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D' Anastasi, M.; Grandl, S.; Reiser, M.F.; Baur-Melnyk, A. [Klinikum der Ludwig-Maximilians-Universitaet Muenchen, Campus Grosshadern, Institut fuer Klinische Radiologie, Muenchen (Germany)

2014-06-15

Robust and reliable imaging methods are required to estimate the skeletal tumor load in multiple myeloma, as well as for the diagnosis of extraskeletal manifestations. Imaging also plays an essential role in the assessment of fracture risk and of vertebral fractures. The conventional skeletal survey has been the gold standard in the imaging of multiple myeloma for many years. Other modalities which have been investigated and are in use are whole-body computed tomography (WBCT), 18F-fluorodeoxyglucose positron emission tomography computed tomography (FDG PET-CT) and whole-body magnetic resonance imaging (WBMRI). These techniques are able to depict both mineralized bone and the bone marrow with a high sensitivity for myeloma lesions. Several studies have shown that cross-sectional imaging is superior to the skeletal survey in the detection of myeloma lesions and WBMRI has been shown to be significantly more sensitive than WBCT for the detection of focal myeloma lesions as well as for diffuse infiltration. The FDG PET-CT technique has a sensitivity comparable to WBMRI. Due to the higher sensitivity in the detection of myeloma lesions WBCT and WBMRI should replace the skeletal survey. A WBCT should be performed if there is suspicion of multiple myeloma. If no focal lesions are found WBMRI or at least MRI of the spine and pelvis should be additionally performed if available. If WBMRI has been initially performed and focal lesions are present, an additional WBCT may be performed to assess the extent of bone destruction and fracture risk. In cases of monoclonal gammopathy of undetermined significance (MGUS), solitary and smoldering myeloma, a WBMRI, if available, should be performed in addition to WBCT. (orig.) [German] Die Aufgabe der bildgebenden Diagnostik beim multiplen Myelom (MM) ist die zuverlaessige Erfassung der Tumorlast im Skelett sowie auch der extraskelettalen Manifestationen und der assoziierten Komplikationen (z. B. Wirbelkoerperfrakturen, Frakturgefahr

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

Science.gov (United States)

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

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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

COMPARATIVE EFFICACY OF HYPERTONIC SALINE AND NORMAL SALINE SOLUTIONS IN EXPERIMENTALLY INDUCED ENDOTOXIC SHOCK IN DOGS

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M. A. ZAFAR, G. MUHAMMAD, M. H. HUSSAIN, T. AHMAD, A. YOUSAF AND I. SARFARAZ

2009-07-01

Full Text Available This study was contemplated to determine the comparative beneficial effects of hypertonic saline solution and sterile saline solution in induced endotoxic shock in dogs. For this purpose, 12 healthy Mongrel dogs were randomly divided into two equal groups (A and B. All the animals were induced endotoxaemia by slow intravenous administration of Escherichia coli endotoxins 0111:B4. Group A was treated with normal saline solution @ 90 ml/kg BW, while group B was given hypertonic saline solution @ 4 ml/kg BW, followed by normal saline solution @ 10 ml/kg BW. Different parameters were observed for evaluation of these fluids including clinical and haematological parameters, serum electrolytes, mean arterial pressure, and blood gases at different time intervals up to 24 hours post treatments. After infusion of respective fluids, all parameters returned to baseline values in both the groups but group B showed better results than group A except bicarbonates, which better recovered in group A. Thus, it was concluded that a small-volume of hypertonic saline solution could be effectively used in reversing the endotoxaemia. Moreover, it provides a rapid and inexpensive resuscitation from endotoxic shock.

Heterogeneity in the multiple myeloma tumor clone

NARCIS (Netherlands)

Guikema, JEJ; Hovenga, S; Vellenga, E; Bos, NA

Multiple Myeloma ( MM) is a plasma cell malignancy which is characterized by a very heterogeneous disease outcome. Heterogeneity in plasma cell characteristics, including morphology, maturation status, immunophenotype and genetic abnormalities partly account for the variable disease outcome.

Assessment and monitoring of patients receiving chemotherapy for multiple myeloma: strategies to improve outcomes

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Faiman B

2016-05-01

Full Text Available Beth Faiman, Jason Valent Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA Abstract: Improved understanding as to the biology of multiple myeloma (MM and the bone marrow microenvironment has led to the development of new drugs to treat MM. This explosion of new and highly effective drugs has led to dramatic advances in the management of MM and underscores the need for supportive care. Impressive and deep response rates to chemotherapy, monoclonal antibodies, and small molecule drugs provide hope of a cure or prolonged remission for the majority of individuals. For most patients, long-term, continuous therapy is often required to suppress the malignant plasma cell clone, thus requiring clinicians to become more astute in assessment, monitoring, and intervention of side effects as well as monitoring response to therapy. Appropriate diagnosis and monitoring strategies are essential to ensure that patients receive the appropriate chemotherapy and supportive therapy at relapse, and that side effects are appropriately managed to allow for continued therapy and adherence to the regimen. Multiple drugs with complex regimens are currently available with varying side effect profiles. Knowledge of the drugs used to treat MM and the common adverse events will allow for preventative strategies to mitigate adverse events and prompt intervention. The purpose of this paper is to review updates in the diagnosis and management of MM, and to provide strategies for assessment and monitoring of patients receiving chemotherapy for MM. Keywords: multiple myeloma, treatment, symptoms, assessment, monitoring, symptom management, targeted therapies

Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance

International Nuclear Information System (INIS)

Kraus, M; Bader, J; Overkleeft, H; Driessen, C

2013-01-01

HIV protease inhibitors (HIV-PI) are oral drugs for HIV treatment. HIV-PI have antitumor activity via induction of ER-stress, inhibition of phospho-AKT (p-AKT) and the proteasome, suggesting antimyeloma activity. We characterize the effects of all approved HIV-PI on myeloma cells. HIV-PI were compared regarding cytotoxicity, proteasome activity, ER-stress induction and AKT phosphorylation using myeloma cells in vitro. Nelfinavir is the HIV-PI with highest cytotoxic activity against primary myeloma cells and with an IC 50 near therapeutic drug blood levels (8–14 μM), irrespective of bortezomib sensitivity. Only nelfinavir inhibited intracellular proteasome activity in situ at drug concentrations <40 μℳ. Ritonavir, saquinavir and lopinavir inhibited p-AKT comparable to nelfinavir, and showed similar synergistic cytotoxicity with bortezomib against bortezomib-sensitive cells. Nelfinavir had superior synergistic activity with bortezomib/carfilzomib in particular against bortezomib/carfilzomib-resistant myeloma cells. It inhibited not only the proteasomal β1/β5 active sites, similar to bortezomib/carfilzomib, but in addition the β2 proteasome activity not targeted by bortezomib/carfilzomib. Additional inhibition of β2 proteasome activity is known to sensitize cells for bortezomib and carfilzomib. Nelfinavir has unique proteasome inhibiting activity in particular on the bortezomib/carfilzomib-insensitive tryptic (β2) proteasome activity in intact myeloma cells, and is active against bortezomib/carfilzomib-resistant myeloma cells in vitro

NCI collaborates with Multiple Myeloma Research Foundation

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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

Heterogeneity in the multiple myeloma tumor clone

NARCIS (Netherlands)

Guikema, Jeroen E. J.; Hovenga, Sjoerd; Vellenga, Edo; Bos, Nicolaas A.

2004-01-01

Multiple Myeloma (MM) is a plasma cell malignancy which is characterized by a very heterogeneous disease outcome. Heterogeneity in plasma cell characteristics, including morphology, maturation status, immunophenotype and genetic abnormalities partly account for the variable disease outcome. Although

Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin

International Nuclear Information System (INIS)

Olsen, O E; Wader, K F; Misund, K; Våtsveen, T K; Rø, T B; Mylin, A K; Turesson, I; Størdal, B F; Moen, S H; Standal, T; Waage, A; Sundan, A; Holien, T

2014-01-01

Multiple myeloma is a malignancy of plasma cells predominantly located in the bone marrow. A number of bone morphogenetic proteins (BMPs) induce apoptosis in myeloma cells in vitro, and with this study we add BMP-9 to the list. BMP-9 has been found in human serum at concentrations that inhibit cancer cell growth in vitro. We here show that the level of BMP-9 in serum was elevated in myeloma patients (median 176 pg/ml, range 8–809) compared with healthy controls (median 110 pg/ml, range 8–359). BMP-9 was also present in the bone marrow and was able to induce apoptosis in 4 out of 11 primary myeloma cell samples by signaling through ALK2. BMP-9-induced apoptosis in myeloma cells was associated with c-MYC downregulation. The effects of BMP-9 were counteracted by membrane-bound (CD105) or soluble endoglin present in the bone marrow microenvironment, suggesting a mechanism for how myeloma cells can evade the tumor suppressing activity of BMP-9 in multiple myeloma

Biochemical markers of bone metabolism reflect osteoclastic and osteoblastic activity in multiple myeloma

DEFF Research Database (Denmark)

Abildgaard, N; Glerup, H; Rungby, Jørgen

2000-01-01

In order to evaluate the use of recently developed assays of bone metabolism in multiple myeloma we performed a histomorphometric study of bone biopsies in 16 myeloma patients. Furthermore, we measured the levels of interleukin-6 (IL-6), soluble IL-6 receptor (IL-6sR), IL-1beta, tumour necrosis f...

Computed Tomography diagnosis of skeletal involvement in multiple myeloma

International Nuclear Information System (INIS)

Scutellari, Pier Nuccio; Galeotti, Roberto; Leprotti, Stefano; Piva, Nadia; Spanedda, Romedio

1997-01-01

The authors assess the role of Computed Topography in the diagnosis and management of multiple myeloma (MM) and investigate if Computed Tomography findings can influence the clinical approach, prognosis and treatment. 273 multiple myeloma patients submitted to Computed Tomography June 1994, to December, 1996. The patients were 143 men and 130 women (mean age: 65 years): 143 were stage I, 38 stage II and 92 stage III according to Durie and Salomon's clinical classification. All patients were submitted to blood tests, spinal radiography and Computed Tomography, the latter with serial 5-mm scans on several vertebral bodies. Computed Tomography despicted vertebral arch and process involvement in 3 cases with the vertebral pedicle sign. Moreover, Computed Tomography proved superior to radiography in showing the spread of myelomatous masses into the soft tissues in a case with solitary permeative lesion in the left public bone, which facilitated subsequent biopsy. As for extraosseous localizations, Computed Tomography demonstrated thoracic soft tissue (1 woman) and pelvic (1 man) involvement by myelomtous masses penetrating into surrounding tissues. In our series, only a case of osteosclerotic bone myeloma was observed in the pelvis, associated with lytic abnormalities. Computed Tomography findings do not seem to improve the clinical approach and therapeutic management of the disease. Nevertheless, the authors reccommend Computed Tomography for some myelomatous conditions, namely: a) in the patients with focal bone pain but normal skeletal radiographs; b) in the patients with M protein, bone marrow plasmocytosis and back pain, but with an incoclusive multiple myeloma diagnosis; c) to asses bone spread in the regions which are anatomically complex or difficult to study with radiography and to depict soft tissue involvement; d) for bone biopsy

Plasmacytoma Infiltrating Leiomyoma in Multiple Myeloma

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2018-01-19

REPORT TYPE 3. DATES COVERED (From - To) 01/19/2018 Poster 01/19/2018-01/21/2018 4. TITLE AND SUBTITLE Sa. CONTRACT NUMBER Plasmacytoma...Infiltrating Leiomyoma in Multiple Myeloma Sb. GRANT NUMBER Sc. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Sd. PROJECT NUMBER Capt Eden, Rina Se. TASK NUMBER Sf

A Case of Mediastinal Extramedullary Plasmacytoma Associated with Multiple Myeloma

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Min, Ji Hye; Kim, Tae Sung; Ko, Young Hyeh; Kim, Ki Hyun [Samsung Medical Center, Sungkyunkwan University, Seoul (Korea, Republic of)

2010-08-15

Extramedullary plasmacytoma is a rare manifestation of multiple myeloma, and involvement of the mediastinum by extramedullary plasmacytoma is very rare. We report here on a rare case of a large mediastinal extramedullary plasmacytoma and several pleural nodules with pleural effusions in a 45-year-old male patient with multiple myeloma that involved the thoracic spine and the calvarium. The mediastinal extramedullary plasmacytoma manifested on CT as an 11 x 4.5 cm-sized, relatively homogeneous, mildly enhancing, anterior mediastinal mass with several pleural nodules, and this simulated malignant lymphoma or malignant thymic epithelial tumor.

The expression of p53 protein in patients with multiple myeloma

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Marković Olivera

2007-01-01

Full Text Available Introduction: Although mutations of p53 are one of the most often acquired genetic changes in malignant tumors, these mutations are rare events in patients with newly diagnosed multiple myeloma (MM. Moreover, there are a few literature data about clinical significance of p53 overexpression in multiple myeloma. Objective The aim of our study was to evaluate the clinical significance of p53 immunoexpression in multiple myeloma. Method A total of 58 patients with newly diagnosed MM (26 females and 32 males, mean age 62 years were enrolled in the study. The diagnosis of MM was made according to criteria of Chronic Leukemia-Myeloma Task Force. Clinical staging was done according to Durie and Salmon classification (4 patients had disease stage I, 15 patients stage II and 39 patients stage III. The histological grade and histological stage were determined according to predominant plasma cell morphology and volume of myeloma infiltration, respectively. Standard immunohistochemical analysis with p53 antibody in B5-fixed and paraffin- embedded bone marrow specimens was used to evaluate the expression of p53 in myeloma cells. The specimens were considered positive when ≥5% of plasma cells exhibited clear nuclear positivity. Results Out of 58 patients, p53 expression was detected in 9 (15.52%. No significant correlation was found between p53 expression and clinical stage (I+II vs. III, Я2-microglobulin level (≤6 mg/L vs. >6mg/L, histological grade (I vs. II+III, histological stage (<20% vs. 21-50% vs. >50% and the extent of osteolytic lesions (≤3 vs. >3 lesions. Median survival of patients with p53 immunoreactivity in =>5% of plasma cells was 10 months, whilst median survival of patients with p53 immunoreactivity in <5% of plasma cells was 36 months. However, such difference was not significant (p=0.2. Conclusion The frequency of p53 immunoexpression in our group of newly diagnosed MM was relatively low. Although p53 immunoexpression was not

Multiple myeloma and central nervous system involvement: experience of a Brazilian center.

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Dias, Ana Luiza Miranda Silva; Higashi, Fabiana; Peres, Ana Lúcia M; Cury, Pricilla; Crusoé, Edvan de Queiroz; Hungria, Vânia Tietsche de Moraes

The estimated involvement of the central nervous system in patients with multiple myeloma is rare at about 1%. The infiltration can be identified at the time multiple myeloma is diagnosed or during its progression. However, it is more common in refractory disease or during relapse. This retrospective cohort study reviewed data from medical records of patients followed up at the Gammopathy Outpatient Clinic of Santa Casa de Misericórdia de São Paulo from January 2008 to December 2016. Twenty patients were included, with a median follow-up of 33.5 months after central nervous system infiltration. The prevalence was 7%. The median age at diagnosis of multiple myeloma was 56.1 years, with 70% of participants being female. Sixteen patients had central nervous system infiltration at diagnosis of multiple myeloma. Seventeen patients had exclusive osteodural lesions and three had infiltrations of the leptomeninge, of which one had exclusive involvement and two had associated osteodural lesions. The median overall survival was 40.3 months after central nervous system involvement. The median overall survival in the group with central nervous system infiltration at relapse was 7.4 months. The patients with leptomeningeal involvement had a median overall survival of 5.8 months. Central nervous system infiltration is a rare condition, but it should be considered as a possibility in patients with multiple myeloma and neurological symptoms. The best treatment regimen for this condition remains unknown and, in most cases, the prognosis is unfavorable. Copyright © 2017. Published by Elsevier Editora Ltda.

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

Science.gov (United States)

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.

New treatment strategies for multiple myeloma by targeting Bcl-2 and the mevalonate pathway

NARCIS (Netherlands)

Donk, N.W.C.J. van de

2003-01-01

Multiple myeloma is a B-lineage neoplasia. Enhanced proliferation and defects in the regulation of programmed cell death account for the expansion of the malignant clone. Emergence of drug resistance is the primary cause of treatment failure in myeloma. Various studies have indicated that inhibition

Long-term survival of patients with multiple myeloma and acute renal failure at presentation.

Science.gov (United States)

Lazarus, H M; Adelstein, D J; Herzig, R H; Smith, M C

1983-03-01

Eight patients presented with simultaneous multiple myeloma and acute renal failure requiring hemodialysis. Patients had no known pre-existing renal disease nor exposure to nephrotoxic agents or x-ray contrast dye. Renal failure was attributed to light chain nephropathy in all cases. In 4 of these patients the diagnosis of myeloma was initially unsuspected. Renal biopsies in 3 of these patients, and post-mortem material in a fourth revealed the changes of "myeloma kidney." No patient regained renal function and all required chronic hemodialysis. Among these eight patients, three survived for periods greater than 21 months.

MicroRNA Transfer Between Bone Marrow Adipose and Multiple Myeloma Cells.

Science.gov (United States)

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.

"ROLE OF ALLOGENEIC TRANSPLANTATION IN MULTIPLE MYELOMA IN THE ERA OF NEW DRUGS"

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Benedetto Bruno

2010-06-01

            Allografting is a potentially curative treatment for a subset of multiple myeloma patients for its well documented graft-vs-myeloma effects. However, its role has been hotly debated. Even though molecular remissions have been reported up to 50% after high-dose myeloablative conditionings, their applications, given the high toxicity, have been for long limited to younger relapsed/refractory patients. These limitations have greatly been reduced through the introduction of non-myeloablative/reduced-intensity conditionings.             The introduction of new drugs, characterised by low risks of early mortality, indeed requires to define role and timing of an allograft to capture the subset of patients who may most benefit from graft-vs-myeloma effects.   Ultimately, new drugs should not be viewed as mutually exclusive with an allograft. They may be employed to achieve profound cytoreduction before and enhance graft-versus-myeloma effects as consolidation/maintenance therapy after an allograft. However, this combination should be explored only in well-designed clinical trials.

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

Science.gov (United States)

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.

Pleural Effusion in Multiple Myeloma.

Science.gov (United States)

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

Whole-body MRI, dynamic contrast-enhanced MRI, and diffusion-weighted imaging for the staging of multiple myeloma

Energy Technology Data Exchange (ETDEWEB)

Dutoit, Julie C.; Verstraete, Koenraad L. [Ghent University Hospital, Department of Radiology, Ghent (Belgium)

2017-06-15

Magnetic resonance imaging (MRI) is the most sensitive imaging technique for the detection of bone marrow infiltration, and has therefore recently been included in the new diagnostic myeloma criteria, as proposed by the International Myeloma Working Group. Nevertheless, conventional MRI only provides anatomical information and is therefore only of limited use in the response assessment of patients with multiple myeloma. The additional information from functional MRI techniques, such as diffusion-weighted imaging and dynamic contrast-enhanced MRI, can improve the detection rate of bone marrow infiltration and the assessment of response. This can further enhance the sensitivity and specificity of MRI in the staging of multiple myeloma patients. This article provides an overview of the technical aspects of conventional and functional MRI techniques with practical recommendations. It reviews the diagnostic performance, prognostic value, and role in therapy assessment in multiple myeloma and its precursor stages. (orig.)

Light chain deposition disease in multiple myeloma: MR imaging features correlated with histopathological findings

International Nuclear Information System (INIS)

Baur, A.; Staebler, A.; Reiser, M.; Lamerz, R.; Bartl, R.

1998-01-01

The clinical, histopathological, and imaging findings on MRI of a 56-year-old woman with light chain deposition disease occurring in multiple myeloma are presented. Light chain deposition disease is a variant of multiple myeloma with distinct clinical and histological characteristics. MRI of this patient also revealed an infiltration pattern in the bone marrow distinct from that of typical multiple myeloma. Multiple small foci of low signal intensity were present on T1- and T2-weighted spin echo and STIR images, corresponding to conglomerates of light chains in bone marrow biopsy. Contrast-enhanced T1-weighted spin echo images show diffuse enhancement of 51% over all vertebral bodies, with a minor enhancement of the focal conglomerates of light chains. Light chain deposition disease in multiple myeloma should be added to the list of those few entities with normal radiographs and discrete low-signal marrow lesions on T1- and T2-weighted spin echo pulse sequences. (orig.)

Iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) imaging of multiple myeloma: initial clinical efficiency results

International Nuclear Information System (INIS)

Takasu, Miyuki; Tani, Chihiro; Sakoda, Yasuko; Ishikawa, Miho; Tanitame, Keizo; Date, Shuji; Akiyama, Yuji; Awai, Kazuo; Sakai, Akira; Asaoku, Hideki; Kajima, Toshio

2012-01-01

To evaluate the effectiveness of the iterative decomposition of water and fat with echo asymmetric and least-squares estimation (IDEAL) MRI to quantify tumour infiltration into the lumbar vertebrae in myeloma patients without visible focal lesions. The lumbar spine was examined with 3 T MRI in 24 patients with multiple myeloma and in 26 controls. The fat-signal fraction was calculated as the mean value from three vertebral bodies. A post hoc test was used to compare the fat-signal fraction in controls and patients with monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma or symptomatic myeloma. Differences were considered significant at P 2 -microglobulin-to-albumin ratio were entered into the discriminant analysis. Fat-signal fractions were significantly lower in patients with symptomatic myelomas (43.9 ±19.7%, P 2 -microglobulin-to-albumin ratio facilitated discrimination of symptomatic myeloma from non-symptomatic myeloma in patients without focal bone lesions. circle A new magnetic resonance technique (IDEAL) offers new insights in multiple myeloma. (orig.)

Smoldering multiple myeloma: prevalence and current evidence guiding treatment decisions

Directory of Open Access Journals (Sweden)

Blum A

2018-04-01

Full Text Available Agnieszka Blum, Despina Bazou, Peter O’Gorman Department of Hematology, Mater Misericordiae University Hospital, Dublin, UK Abstract: Smoldering multiple myeloma (SMM is an asymptomatic plasma cell proliferative disorder associated with risk of progression to symptomatic multiple myeloma (MM or amyloidosis. In comparison to monoclonal gammopathy of undetermined significance (MGUS, SMM has a much higher risk of progression to MM. Thanks to advances in our understanding of the risk factors, the subset of patients with ultra-high risk of progression to MM (80%–90% at 2 years has been identified. The revision of the diagnostic criteria resulted in changes in the management of this cohort of patients. In contrast to the management guidelines for MGUS patients, SMM patients need to be studied more intensively in order to identify biomarkers necessary for accurate risk stratification. In this review, we focus on the risk of progression from SMM to MM, as well as the influence of early treatment on overall survival, time to progression and quality of life. Keywords: smoldering multiple myeloma, risk factor, biomarker, genomic aberrations, glycan analysis

G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma

NARCIS (Netherlands)

van de Donk, N. W. C. J.; de Weerdt, O.; Veth, G.; Eurelings, M.; van Stralen, E.; Frankel, S. R.; Hagenbeek, A.; Bloem, A. C.; Lokhorst, H. M.

2004-01-01

Expression of Bcl-2 in multiple myeloma is associated with resistance to chemotherapeutic drugs. Conversely, suppression of Bcl-2 enhanced the chemosensitivity of myeloma cells in vitro. G3139 is an antisense oligodeoxynucleotide targeted to the first six codons of the Bcl-2 mRNA open reading frame.

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.

Science.gov (United States)

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.

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

Directory of Open Access Journals (Sweden)

Kumar A

2011-06-01

Full Text Available Amit Kumar, Xinran Li, Michael A Sandoval, B Leticia Rodriguez, Brian R Sloat, Zhengrong CuiUniversity of Texas at Austin, College of Pharmacy, Pharmaceutics Division, Austin, TX, USABackground: 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.Keywords: antibody responses, safety of microneedles, transepidermal water loss

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

Science.gov (United States)

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.

Single nucleotide polymorphisms in the promoter region of the IL1B gene influence outcome in multiple myeloma patients treated with high-dose chemotherapy independently of relapse treatment with thalidomide and bortezomib

DEFF Research Database (Denmark)

Vangsted, Annette J.; Klausen, Tobias W.; Abildgaard, Niels

2011-01-01

the impact on outcome of HDT, INF-α maintenance treatment, and treatment with thalidomide and bortezomib at relapse, in relation to the major identified functional polymorphisms in the promoter region of IL1B. The wild-type C-allele of IL1B C-3737T and non-carriage of the IL1B promoter haplotype TGT (−3737T...... carrying the wild-type C-allele of IL1B C-3737T (HR, 1.6 (1.1–2.4)). Furthermore, among INF-α treated patients, gene–gene interaction studies on IL1B C-3737T and NFКB1-94ins/del ATTG revealed a fourfold increase in TTF for homozygous carriers of wild-type alleles at both loci as compared to variant allele...... carriers at both loci. No relation to genotype and outcome was found for relapse patients treated with thalidomide or bortezomib. Our results indicate that a subpopulation of myeloma patients carrying the wild-type C-allele of IL1B C-3737T and non-carriers of the promoter haplotype TGT (−3737T, −1464G...

Continuous lenalidomide treatment for newly diagnosed multiple myeloma

DEFF Research Database (Denmark)

Palumbo, Antonio; Hajek, Roman; Delforge, Michel

2012-01-01

Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednis...

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

Science.gov (United States)

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).

MR imaging studies of multiple myeloma in the vertebral column

International Nuclear Information System (INIS)

Albert, S.; Leeds, N.E.

1990-01-01

This paper studies the sensitivity and characteristics of MR imaging in the diagnosis of myeloma in the vertebral column. The cervical, thoracic, and lumbar spines of 12 patients with known multiple myeloma were imaged with small flip angle, fast gradient-echo, proton-density (FPD) as well as spin-echo T1-weighted, T2-weighted, and intermediate (SE 2,000/20-30) imaging. The FPD images were acquired with pulse sequence gradient recalled acquisition in a steady state at a magnetic field strength of 1.5T with use of a license-plate and a circular surface coil

Therapeutic effects of compound hypertonic saline on rats with sepsis

Directory of Open Access Journals (Sweden)

Fang Dong

2014-09-01

Full Text Available Sepsis is one of the major causes of death and is the biggest obstacle preventing improvement of the success rate in curing critical illnesses. Currently, isotonic solutions are used in fluid resuscitation technique. Several studies have shown that hypertonic saline applied in hemorrhagic shock can rapidly increase the plasma osmotic pressure, facilitate the rapid return of interstitial fluid into the blood vessels, and restore the effective circulating blood volume. Here, we established a rat model of sepsis by using the cecal ligation and puncture approach. We found that intravenous injection of hypertonic saline dextran (7.5% NaCl/6% dextran after cecal ligation and puncture can improve circulatory failure at the onset of sepsis. We found that the levels of tumor necrosis factor-α, interleukin-1β, interleukin-6 and intracellular adhesion molecule 1 levels in the lung tissue of cecal ligation and puncture rats treated with hypertonic saline dextran were significantly lower than the corresponding levels in the control group. We inferred that hypertonic saline dextran has a positive immunoregulatory effect and inhibits the overexpression of the inflammatory response in the treatment of sepsis. The percentage of neutrophils, lung myeloperoxidase activity, wet to dry weight ratio of lung tissues, histopathological changes in lung tissues, and indicators of arterial blood gas analysis was significantly better in the hypertonic saline dextran-treated group than in the other groups in this study. Hypertonic saline dextran-treated rats had significantly improved survival rates at 9 and 18 h compared to the control group. Our results suggest that hypertonic saline dextran plays a protective role in acute lung injury caused after cecal ligation and puncture. In conclusion, hypertonic/hyperoncotic solutions have beneficial therapeutic effects in the treatment of an animal model of sepsis.

Concomitant HIV infection in newly diagnosed multiple myeloma ...

African Journals Online (AJOL)

RESEARCH ... To compare the presenting features of HIV-positive patients diagnosed with MM ..... Especially since recent publications are showing trends of .... 18. Agrawal S, Deshpande A. A unique presentation of multiple myeloma in an ...

New experimental model of multiple myeloma.

Science.gov (United States)

Telegin, G B; Kalinina, A R; Ponomarenko, N A; Ovsepyan, A A; Smirnov, S V; Tsybenko, V V; Homeriki, S G

2001-06-01

NSO/1 (P3x63Ay 8Ut) and SP20 myeloma cells were inoculated to BALB/c OlaHsd mice. NSO/1 cells allowed adequate stage-by-stage monitoring of tumor development. The adequacy of this model was confirmed in experiments with conventional cytostatics: prospidium and cytarabine caused necrosis of tumor cells and reduced animal mortality.

Microbial Fuel Cells under Extreme Salinity

Science.gov (United States)

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

Tracking human multiple myeloma xenografts in NOD-Rag-1/IL-2 receptor gamma chain-null mice with the novel biomarker AKAP-4

International Nuclear Information System (INIS)

Mirandola, Leonardo; Yu, Yuefei; Jenkins, Marjorie R; Chiaramonte, Raffaella; Cobos, Everardo; John, Constance M; Chiriva-Internati, Maurizio

2011-01-01

Multiple myeloma (MM) is a fatal malignancy ranking second in prevalence among hematological tumors. Continuous efforts are being made to develop innovative and more effective treatments. The preclinical evaluation of new therapies relies on the use of murine models of the disease. Here we describe a new MM animal model in NOD-Rag1null IL2rgnull (NRG) mice that supports the engraftment of cell lines and primary MM cells that can be tracked with the tumor antigen, AKAP-4. Human MM cell lines, U266 and H929, and primary MM cells were successfully engrafted in NRG mice after intravenous administration, and were found in the bone marrow, blood and spleen of tumor-challenged animals. The AKAP-4 expression pattern was similar to that of known MM markers, such as paraproteins, CD38 and CD45. We developed for the first time a murine model allowing for the growth of both MM cell lines and primary cells in multifocal sites, thus mimicking the disease seen in patients. Additionally, we validated the use of AKAP-4 antigen to track tumor growth in vivo and to specifically identify MM cells in mouse tissues. We expect that our model will significantly improve the pre-clinical evaluation of new anti-myeloma therapies

Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy

NARCIS (Netherlands)

G. Mulligan (George); D.I. Lichter (David); A.D. Bacco (Alessandra Di); S.J. Blakemore (Stephen); A. Berger (Allison); E. Koenig (Erik); H. Bernard (Hugues); W.L. Trepicchio (William); B. Li (Bin); R. Neuwirth (Rachel); N. Chattopadhyay (Nibedita); J.B. Bolen (Joseph); A.J. Dorner (Andrew); H. van de Velde (Helgi); D. Ricci (Deborah); S. Jagannath (Sundar); J.R. Berenson (James); P.G. Richardson (Paul Gerard); E.A. Stadtmauer (Edward); R.Z. Orlowski (Robert); S. Lonial (Sagar); K.C. Anderson (Kenneth); P. Sonneveld (Pieter); J.F. San Miguel (Jesús Fernando); D.-L. Esseltine (Dixie-Lee); M. Schu (Matthew)

2014-01-01

textabstractVarious translocations and mutations have been identified in myeloma, and certain aberrations, such as t(4;14) and del17, are linked with disease prognosis. To investigate mutational prevalence in myeloma and associations between mutations and patient outcomes, we tested a panel of 41

Insights on Genomic and Molecular Alterations in Multiple Myeloma and Their Incorporation towards Risk-Adapted Treatment Strategy: Concise Clinical Review

Directory of Open Access Journals (Sweden)

Taiga Nishihori

2017-01-01

Full Text Available Although recent advances in novel treatment approaches and therapeutics have shifted the treatment landscape of multiple myeloma, it remains an incurable plasma cell malignancy. Growing knowledge of the genome and expressed genomic information characterizing the biologic behavior of multiple myeloma continues to accumulate. However, translation and incorporation of vast molecular understanding of complex tumor biology to deliver personalized and precision treatment to cure multiple myeloma have not been successful to date. Our review focuses on current evidence and understanding of myeloma biology with characterization in the context of genomic and molecular alterations. We also discuss future clinical application of the genomic and molecular knowledge, and more translational research is needed to benefit our myeloma patients.

Spontaneous tumour lysis syndrome in a case of multiple myeloma – A rare occurrence

Directory of Open Access Journals (Sweden)

Kavitha Saravu

2013-03-01

Full Text Available We describe a case of a 40-year-old male patient who was found to have multiple myeloma with spontaneous tumour lysis syndrome (TLS, following a compression fracture of the L–2 vertebrae. Multiple myeloma was confirmed by bone marrow analysis and the M–band on serum protein electrophoresis. Hyperuricaemia (26.2 mg/dL, hyperkalaemia (> 7.0 mEq/L, hyperphosphatemia (16.2 mg of phosphorus/dL, normocalcemia and acute kidney injury, prior to anticancer treatment suggested spontaneous TLS. Inciting events for tumour lysis, such as chemotherapy, dehydration and exposure to steroids were absent. Patient received hydration, hypourecemic drugs and haemodialysis. This case report highlights the rare presentation of multiple myeloma with spontaneous TLS.

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

Science.gov (United States)

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

Platelet factor-4 and its p17-70 peptide inhibit myeloma proliferation and angiogenesis in vivo

International Nuclear Information System (INIS)

Yang, Longjiang; Du, Juan; Hou, Jian; Jiang, Hua; Zou, Jianfeng

2011-01-01

Angiogenesis plays an important role in the development of multiple myeloma (MM). The interaction between MM cells and the bone marrow microenvironment stimulates the proliferation and migration of endothelial progenitor cells (EPCs). Vascular endothelial growth factor (VEGF) contributes to the formation of new blood vessels by actively recruiting circulating EPCs. The production of proangiogenic and antiangiogenic factors is also dysregulated in MM. Platelet factor 4 (PF4) is a potent angiostatic cytokine that inhibits angiogenesis and tumor growth in several animal models. In this study, we stably transfected human myeloma cell lines with the PF4 gene or the sequence encoding its more potent p17-70 peptide and investigated the effects of PF4 and p17-70 on angiogenesis and tumor growth in vitro and in a SCID-rab myeloma model. PF4 and p17-70 significantly attenuated VEGF production, both in vitro and in vivo. In a migration study using a Transwell system, PF4 or p17-70 markedly suppressed the migration of co-cultured human endothelial progenitor cells. PF4 or p17-70 also caused a significant reduction in microvessel densities in myeloma xenografts and markedly reduced the tumor volume in the SCID mice. Kaplan-Meier analysis demonstrated that PF4 and p17-70 significantly extended the overall survival of SCID mice bearing human myeloma xenografts. Our findings indicate that PF4 or p17-70 could be valuable in combating multiple myeloma by disrupting tumor angiogenesis

Monocyte/macrophage-derived soluble CD163: A novel biomarker in multiple myeloma

DEFF Research Database (Denmark)

Andersen, Morten Nørgaard; Abildgaard, Niels; Maniecki, Maciej B

2014-01-01

fluids (soluble CD163, sCD163). In this study, we examined serum sCD163 as a biomarker in patients with newly diagnosed multiple myeloma. METHODS: Peripheral blood (n = 104) and bone marrow (n = 17) levels of sCD163 were measured using an enzyme-linked immunosorbent assay. RESULTS: At diagnosis, high s......CD163 was associated with higher stage according to the International Staging System (ISS) and with other known prognostic factors in multiple myeloma (creatinine, C-reactive protein, and beta-2 microglobulin). Soluble CD163 decreased upon high-dose treatment, and in a multivariate survival analysis...... in bone marrow samples than in the matched blood samples, which indicate a localized production of sCD163 within the bone marrow microenvironment. CONCLUSIONS: Soluble CD163 was found to be a prognostic marker in patients with multiple myeloma. This may indicate that macrophages and/or monocytes have...

S-phase induction by interleukin-6 followed by chemotherapy in patients with refractory multiple myeloma

DEFF Research Database (Denmark)

de Nully Brown, P; Jensen, P O; Diamant, M

1998-01-01

.0 microg/kg (n = 6) by subcutaneous injection once daily for 5 days and chemotherapy was administered on the last day of rhIL-6 injection. The effect of rhIL-6 treatment on labeling index (LI) was heterogeneous, but no statistically significant change was noted for this particular group as a whole. In two......The plasma cell labeling index (PCLI) in patients with multiple myeloma (MM) is relatively low and this has been associated with the low rate of remission following chemotherapy. Interleukin-6 (IL-6) has been demonstrated to be a major growth factor of myeloma cells. In order to increase the S......-phase proportion of myeloma cells, which might increase the sensitivity to chemotherapy, we gave rhIL-6 followed by chemotherapy to 15 myeloma patients with refractory disease. A total of 25 treatment cycles were administered since ten patients had two cycles. The rhIL-6 dose was 2.5 (n = 3), 5.0 (n = 6) and 10...

Localized extramedullary relapse after autologous hematopoietic stem cell transplantation in multiple myeloma

International Nuclear Information System (INIS)

Erkus, Muhan; Meteoglu, Ibrahim; Bolaman, Zahit; Kadikoylu, Gurhan

2005-01-01

Extramedullary plasmacytomas are rare manifestation of plasma cell malignancies. After hematopoietic stem cell transplantation HSCT, presentation of localized plasmacytoma with extramedullary growth is very unusual. We report a case of a 56-year-old woman with Dune-Salmon stage IIIA immunoglobulin A-kappa multiple myeloma, which presented 120 days after autologous HSCT with extramedullary plasmacytoma arising from a lymph node in supraclavicular region. The patient had no pretransplant-history related with extramedullary disease. There was no increase of plasma cells in bone marrow or monoclonal protein in urine or serum. Aspiration smears of lymph node revealed a population of plasmacytoid cells at various stages of maturation. The patient was successfully treated with local radiotherapy and has remained progression-free for more than 20 months. (author)

Aberrant microRNA expression in multiple myeloma

DEFF Research Database (Denmark)

Dimopoulos, Konstantinos; Gimsing, Peter; Grønbæk, Kirsten

2013-01-01

Multiple myeloma (MM) is a devastating disease with a complex biology, and in spite of improved survivability by novel treatment strategies over the last decade, MM is still incurable by current therapy. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at a post...

Salinity and pH effects on floating and emergent macrophytes in a constructed wetland.

Science.gov (United States)

Hadad, H R; Mufarrege, M M; Di Luca, G A; Maine, M A

2017-04-01

Salvinia herzogii, Pistia stratiotes and Eichhornia crassipes (floating species) were the dominant macrophytes in a constructed wetland (CW) over the first years of operation. Later, the emergent Typha domingensis displaced the floating species, becoming dominant. The industrial effluent treated at this CW showed high pH and salinity. The aim of this work was to study the tolerance of floating species and T. domingensis exposed to different pH and salinity treatments. Treatments at pH 8, 9, 10 and 11 and salinities of 2,000; 3,000; 4,000; 6,000; and 8,000 mg L -1 were performed. Floating macrophytes were unable to tolerate the studied pH and salinity ranges, while T. domingensis tolerated higher pH and salinity values. Many industrial effluents commonly show high pH and salinity. T. domingensis demonstrated to be a suitable macrophyte to treat this type of effluents.

Association between diffuse idiopathic skeletal hyperostosis and multiple myeloma

International Nuclear Information System (INIS)

Scutellari, P.N.; Orzincolo, C.D.; Castaldi, G.

1995-01-01

Radiologic studies were performed over a 26-month period in a series of 97 consecutive patients with multiple myeloma (56 male and 41 female, aged 42-91 years). Both myelomatous bone lesions and hyperostosis similar to DISH were found in these patients. The prevalence of DISH in association with multiple myeloma (21 male and 8 females patients) was higher (29.8%) than in our control group (973 patients, 449 male and 524 female) or in the general population (15-20%). The involved segments of the column were thoracic in 11 males and 7 females, cervical in 8 males and 2 females, and lumbar in 5 males and 4 females. Ossifying enthesopathy in the pelvis (''whiskering'') was observed in 7 males and 1 female. (orig./MG)

Association between diffuse idiopathic skeletal hyperostosis and multiple myeloma

Energy Technology Data Exchange (ETDEWEB)

Scutellari, P.N. [Inst. of Radiology, Ferrara Univ. School of Medicine (Italy); Orzincolo, C.D. [Dept. of Radiology, St. Anna Hospital, Ferrara (Italy); Castaldi, G. [Dept. of Medicine, St. Maria delle Croci Hospital, Ravenna (Italy)

1995-10-01

Radiologic studies were performed over a 26-month period in a series of 97 consecutive patients with multiple myeloma (56 male and 41 female, aged 42-91 years). Both myelomatous bone lesions and hyperostosis similar to DISH were found in these patients. The prevalence of DISH in association with multiple myeloma (21 male and 8 females patients) was higher (29.8%) than in our control group (973 patients, 449 male and 524 female) or in the general population (15-20%). The involved segments of the column were thoracic in 11 males and 7 females, cervical in 8 males and 2 females, and lumbar in 5 males and 4 females. Ossifying enthesopathy in the pelvis (``whiskering``) was observed in 7 males and 1 female. (orig./MG)

The use of biochemical markers of bone remodeling in multiple myeloma: a report of the International Myeloma Working Group

DEFF Research Database (Denmark)

Terpos, E; Dimopoulos, M A; Sezer, O

2010-01-01

progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti...

Molecular purging of multiple myeloma cells by ex-vivo culture and retroviral transduction of mobilized-blood CD34+ cells

Directory of Open Access Journals (Sweden)

Corneo Gianmarco

2007-07-01

Full Text Available Abstract Background Tumor cell contamination of the apheresis in multiple myeloma is likely to affect disease-free and overall survival after autografting. Objective To purge myeloma aphereses from tumor contaminants with a novel culture-based purging method. Methods We cultured myeloma-positive CD34+ PB samples in conditions that retained multipotency of hematopoietic stem cells, but were unfavourable to survival of plasma cells. Moreover, we exploited the resistance of myeloma plasma cells to retroviral transduction by targeting the hematopoietic CD34+ cell population with a retroviral vector carrying a selectable marker (the truncated form of the human receptor for nerve growth factor, ΔNGFR. We performed therefore a further myeloma purging step by selecting the transduced cells at the end of the culture. Results Overall recovery of CD34+ cells after culture was 128.5%; ΔNGFR transduction rate was 28.8% for CD34+ cells and 0% for CD138-selected primary myeloma cells, respectively. Recovery of CD34+ cells after ΔNGFR selection was 22.3%. By patient-specific Ig-gene rearrangements, we assessed a decrease of 0.7–1.4 logs in tumor load after the CD34+ cell selection, and up to 2.3 logs after culture and ΔNGFR selection. Conclusion We conclude that ex-vivo culture and retroviral-mediated transduction of myeloma leukaphereses provide an efficient tumor cell purging.

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

DEFF Research Database (Denmark)

Overdijk, M. B.; Verploegen, S.; Bogels, M.

2015-01-01

Daratumumab (DARA) is a human CD38-specific IgG1 antibody that is in clinical development for the treatment of multiple myeloma (MM). The potential for IgG1 antibodies to induce macrophage-mediated phagocytosis, in combination with the known presence of macrophages in the tumor microenvironment...... in MM and other hematological tumors, led us to investigate the contribution of antibody-dependent, macrophage-mediated phagocytosis to DARA's mechanism of action. Live cell imaging revealed that DARA efficiently induced macrophage-mediated phagocytosis, in which individual macrophages rapidly...... and sequentially engulfed multiple tumor cells. DARA-dependent phagocytosis by mouse and human macrophages was also observed in an in vitro flow cytometry assay, using a range of MM and Burkitt's lymphoma cell lines. Phagocytosis contributed to DARA's anti-tumor activity in vivo, in both a subcutaneous...

Multiple myeloma presenting as CEA-producing rectal cancer.

Science.gov (United States)

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.

Identify multiple myeloma stem cells: Utopia?

Science.gov (United States)

Saltarella, Ilaria; Lamanuzzi, Aurelia; Reale, Antonia; Vacca, Angelo; Ria, Roberto

2015-01-26

Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.

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

Directory of Open Access Journals (Sweden)

Aurelio Lopez

2015-01-01

Full Text Available 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.

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

Science.gov (United States)

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

MULTIPLE MYELOMA PRESENTED AS AN ANTERIOR CHEST WALL MASS DIAGNOSED BY CYTOLOGICAL EXAMINATION : A CASE REPORT

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Parvathi

2015-02-01

Full Text Available Myeloma is a malignancy of terminally differentiated B cells (plasma cells that produce a complete and / or partial monoclonal immunoglobulin protein. Myeloma accounts for approximately 1% of all malignancies and 10% of haematological tumors. It becomes difficult to arrive at early diagnosis because myeloma manifests itself in different forms. The disease usually presents as bone pains, pathological fractures and anemia but can also present as swelling in jaw, orbit, rib, sternoclavicular area, scalp, paraspinal region and tonsil. We present a case of multiple myeloma in 63 year old male which presented as a soft tissue mass on anterior chest wall and diagnosed by FNAC . This case is presented because diagnosis was made on cytology and not many cases have been reported in literature where FNAC helped in making the diagnosis. This increases the hope of early diagnosis so that treatment can be advocated

EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

International Nuclear Information System (INIS)

Huang, Er-Wen; Xue, Sheng-Jiang; Li, Xiao-Yan; Xu, Suo-Wen; Cheng, Jian-Ding; Zheng, Jin-Xiang; Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong; Li, Jie; Liu, Chao

2014-01-01

Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma

EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

Energy Technology Data Exchange (ETDEWEB)

Huang, Er-Wen [Guangzhou Institute of Forensic Science, Guangzhou (China); Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Xue, Sheng-Jiang [Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Li, Xiao-Yan [Department of Pharmacy, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Xu, Suo-Wen [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Cheng, Jian-Ding; Zheng, Jin-Xiang [Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong [Guangzhou Institute of Forensic Science, Guangzhou (China); Li, Jie, E-mail: mdlijie@sina.com [Department of Anaesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Liu, Chao, E-mail: liuchaogaj@21cn.com [Guangzhou Institute of Forensic Science, Guangzhou (China)

2014-05-02

Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma.

The impact of recent chemotherapy innovation on the longevity of myeloma patients

DEFF Research Database (Denmark)

Hostenkamp, Gisela; Lichtenberg, Frank R.

2015-01-01

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...... 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...

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

Science.gov (United States)

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

Science.gov (United States)

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.

Science.gov (United States)

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.

Science.gov (United States)

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.

A novel selective small-molecule PI3K inhibitor is effective against human multiple myeloma in vitro and in vivo

International Nuclear Information System (INIS)

Glauer, J; Pletz, N; Schön, M; Schneider, P; Liu, N; Ziegelbauer, K; Emmert, S; Wulf, G G; Schön, M P

2013-01-01

Developing effective therapies against multiple myeloma (MM) is an unresolved challenge. Phosphatidylinositol-3-kinase (PI3K) activation may be associated with tumor progression and drug resistance, and inhibiting PI3K can induce apoptosis in MM cells. Thus, targeting of PI3K is predicted to increase the susceptibility of MM to anticancer therapy. The lead compound of a novel class of PI3K inhibitors, BAY80-6946 (IC 50 =0.5 nM against PI3K-α), was highly efficacious in four different MM cell lines, where it induced significant antitumoral effects in a dose-dependent manner. The compound inhibited cell cycle progression and increased apoptosis (P<0.001 compared with controls). Moreover, it abrogated the stimulation conferred by insulin-like growth-factor-1, a mechanism relevant for MM progression. These cellular effects were paralleled by decreased Akt phosphorylation, the main downstream target of PI3K. Likewise, profound antitumoral activity was observed ex vivo, as BAY80-6946 significantly inhibited proliferation of freshly isolated myeloma cells from three patients (P<0.001 compared with vehicle). In addition, BAY80-6946 showed convincing in vivo activity against the human AMO-1 and MOLP-8 myeloma cell lines in a preclinical murine xenograft model, where treatment with 6 mg/kg every other day for 2 weeks reduced the cell numbers by 87.0% and 69.3%, respectively (P<0.001 compared with vehicle), without overt toxicity in treated animals

musculoskeletal presentation of multiple myeloma at general

African Journals Online (AJOL)

2014-09-01

Sep 1, 2014 ... Results: A total of 62 patients were diagnosed with multiple myeloma, 63% were female. ... Conclusion: Presence of bone pain and anaemia should alert the clinician to investigate along the ... not found to fall among the ten most common cancers ..... Dugan LO, Dugan DA, Dugan WM Jr. Back pain: the.

Recombinant alpha-interferon as salvage therapy in multiple myeloma

African Journals Online (AJOL)

1989-08-05

Aug 5, 1989 ... Ten patients with end-stage multiple myeloma refractory to conventional chemotherapy and ... malities and relief of pain using local radiotherapy. However, .... therapy programmes. However, the role of this agent remains.

Curcumin Enhances Bortezomib Treatment of Myeloma by Inhibiting ...

African Journals Online (AJOL)

Keywords: Curcumin, Bortezomib, Myeloma cells, Cell growth, Apoptosis, Heat shock protein 90. Tropical Journal of ... strategies have been employed, including traditional chemotherapy, ... particularly on account of bortezomib's adverse effects such as nausea, diarrhea, ... (MM.1R), which were kindly provided by Dr.

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

Science.gov (United States)

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.

Science.gov (United States)

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.

Multivertebral and epidural involvement of the multiple myeloma, as confirmed by magnetic resonance imaging

Energy Technology Data Exchange (ETDEWEB)

Okuda, Yasuhiro; Tamaki, Norihiko; Hosoda, Koukichi; Ehara, Kazumasa; Matsumoto, Satoshi

1987-08-01

A case is reported of a multiple myeloma exhibiting symptoms of paraparesis as an initial manifestation following tetraparesis, but with no particular common symptoms of multiple myeloma. Laboratory findings, however, strongly suggested multiple myeloma, and this was confirmed by a biopsy. Radiological investigations could not show all the features of this tumor invasion, but revealed only the osteosclerotic and destructive changes in the cervical and thoracic spine, plus a complete block at the C2 level. Magnetic resonance imaging, however, disclosed entire lesions. There existed multiple vertebral involvements and an epidural invasion of the tumor, continuing to an extraspinal mass. Multiple myeloma is a disorder with varied manifestations; it is rarely present as a primary neuropathological entity. Among these manifestations, initial neurological manifestations in the form of peripheral neuropathy have been reported most commonly. Unusual clinical presentations such as in our case may result in an erroneous and delayed diagnosis unless an early and correct identification of the lesion is made. Magnetic resonance imaging is thought to be the most useful technique to detect such a multiple lesion in the spinal canal with no invasive manipulation.

Lack of survival improvement with novel anti-myeloma agents for patients with multiple myeloma and central nervous system involvement: the Greek Myeloma Study Group experience.

Science.gov (United States)

Katodritou, Eirini; Terpos, Evangelos; Kastritis, Efstathios; Delimpasis, Sossana; Symeonidis, Argiris S; Repousis, Panagiotis; Kyrtsonis, Marie-Christine; Vadikolia, Chrysa; Michalis, Eurydiki; Polychronidou, Genovefa; Michael, Michael; Papadaki, Sofia; Papathanasiou, Maria; Kokoviadou, Kyriaki; Kioumi, Anna; Vlachaki, Eythimia; Hadjiaggelidou, Christina; Kouraklis, Alexandra; Patsias, Ioannis; Gavriatopoulou, Maria; Kotsopoulou, Maria; Verrou, Evgenia; Gastari, Vasiliki; Christoulas, Dimitrios; Giannopoulou, Evlambia; Pouli, Anastasia; Konstantinidou, Pavlina; Anagnostopoulos, Achilles; Dimopoulos, Meletios-Athanasios

2015-12-01

Involvement of the central nervous system (CNS) is a rare complication of multiple myeloma (MM). Herein, we have described the incidence, characteristics, prognostic factors for post CNS-MM survival, and outcome of CNS-MM and explored the efficacy of novel agents (NA) (thalidomide, bortezomib, lenalidomide) in this setting. Between 2000 and 2013, 31 (0.9 %) out of 3408 newly diagnosed symptomatic MM patients, consecutively diagnosed and treated during the same period in 12 Greek centers, developed CNS-MM (M/F 15/16, median age 59 years, range 20-96 years; newly diagnosed/relapsed-refractory 2/29; median time to CNS-MM diagnosis 29 months). Clinical and laboratory characteristics were retrospectively recorded. Twenty-six percent of patients had circulating plasma cells (PCs) or plasma cell leukemia (PCL) at CNS-MM and 39 % had skull-derived plasmacytomas, suggesting hematological and contiguous spread. Treatment for CNS-MM was offered in 29/31 patients and 11/29 responded (NA 18/29, additional radiotherapy 9/28, intrathecal chemotherapy 13/29). The median post CNS-MM survival was 3 months (95 % CI 1.9-4.1) and did not differ between patients treated with NA and/or radiotherapy vs. others. In the multivariate analysis, prior treatment of MM with NA, extramedullary disease (EMD) during MM course (i.e., plasmacytomas, circulating PCs, or documented PCL) and abnormally high LDH at MM diagnosis were independent prognostic factors, whereas treatment of CNS-MM with NA did not predict for post CNS-MM survival. Despite the relatively limited number of patients due to the rarity of CNS-MM, our results suggest that NA do not seem to improve post CNS-MM survival. Patients with EMD display shortened post CNS-MM survival and should be followed thoroughly.

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

Science.gov (United States)

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-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment

Energy Technology Data Exchange (ETDEWEB)

Borsi, Enrica, E-mail: enrica.borsi2@unibo.it [Department of Experimental Diagnostic and Specialty Medicine (DIMES), “L. and A. Seràgnoli”, Bologna University School of Medicine, S. Orsola' s University Hospital (Italy); Perrone, Giulia [Fondazione IRCCS Istituto Nazionale dei Tumori, Hematology Department, Via Venezian 1, 20133 Milano (Italy); Terragna, Carolina; Martello, Marina; Zamagni, Elena; Tacchetti, Paola; Pantani, Lucia; Brioli, Annamaria; Dico, Angela Flores; Zannetti, Beatrice Anna; Rocchi, Serena; Cavo, Michele [Department of Experimental Diagnostic and Specialty Medicine (DIMES), “L. and A. Seràgnoli”, Bologna University School of Medicine, S. Orsola' s University Hospital (Italy)

2014-11-01

Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma. - Highlights: • HIF-1α inhibition induces a mild apoptotic cell death. • Down-modulation of cytokine-induced signaling cascades upon HIF-1α inhibition. • Reduced interaction between MM cells and BMSCs upon HIF-1α down-modulation. • Reduced PCs adhesion to the extracellular matrix protein induced by EZN-2968. • HIF-1α inhibition may be an attractive therapeutic strategy for Multiple Myeloma.

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

Science.gov (United States)

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.

NF-kappa B modulation is involved in celastrol induced human multiple myeloma cell apoptosis.

Directory of Open Access Journals (Sweden)

Haiwen Ni

Full Text Available Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. To investigate the effect of celastrol on human multiple myeloma cell cycle arrest and apoptosis and explore its molecular mechanism of action. The activity of celastrol on LP-1 cell proliferation was detected by WST-8 assay. The celastrol-induced cell cycle arrest was analyzed by flow cytometry after propidium iodide staining. Nuclear translocation of the nuclear factor kappa B (NF-κB was observed by fluorescence microscope. Celastrol inhibited cell proliferation of LP-1 myeloma cell in a dose-dependent manner with IC50 values of 0.8817 µM, which was mediated through G1 cell cycle arrest and p27 induction. Celastrol induced apoptosis in LP-1 and RPMI 8226 myeloma cells in a time and dose dependent manner, and it involved Caspase-3 activation and NF-κB pathway. Celastrol down-modulated antiapoptotic proteins including Bcl-2 and survivin expression. The expression of NF-κB and IKKa were decreased after celastrol treatment. Celastrol effectively blocked the nuclear translocation of the p65 subunit and induced human multiple myeloma cell cycle arrest and apoptosis by p27 upregulation and NF-kB modulation. It has been demonstrated that the effect of celastrol on NF-kB was HO-1-independent by using zinc protoporphyrin-9 (ZnPPIX, a selective heme oxygenase inhibitor. From the results, it could be inferred that celastrol may be used as a NF-kB inhibitor to inhibit myeloma cell proliferation.

Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures

NARCIS (Netherlands)

Lokhorst, H. M.; Lamme, T.; de Smet, M.; Klein, S.; de Weger, R. A.; van Oers, R.; Bloem, A. C.

1994-01-01

Long-term bone marrow cultures (LTBMC) from patients with multiple myeloma (MM) and normal donors were analyzed for immunophenotype and cytokine production. Both LTBMC adherent cells from myeloma and normal donor origin expressed CD10, CD13, the adhesion molecules CD44, CD54, vascular cell adhesion

Extraosseous Multiple Myeloma with Retroperitoneal Manifestation: A Case Report

International Nuclear Information System (INIS)

Berdugo, Juan Oswaldo; Nieto, Sonia Janeth; Garzon, Julian Gonzalo

2008-01-01

This paper presents a case of a 57 years old man (patient of Hospital Militar Central of Bogota, Colombia) with weight loss and a mass in the right clavicle. Plain film radiography shows a lytic lesion in the sternum side of the clavicle. biopsy reports a plasmacytomas, radiotherapy was performed. Three years later lesions of similar characteristics within ribs and a focal lesion in left testicle were detected. The diagnosis was multiple myeloma, Chemotherapy and orquidectomy were performed. One year after, patient complained of diffuse abdominal pain and loss weight, contrast abdominal CT was performed. Computed tomography showed a left heterogeneous mass with irregular contours that involved the retroperitoneal space occupying its three compartments. Biopsy was performed and reported pleomorphicplasmocytic proliferation with nuclear enlargement and hyperchromic nuclei consistent with multiple myeloma with abdominal involvement.

Multiple myeloma presenting as CEA-producing rectal cancer

Directory of Open Access Journals (Sweden)

Giampaolo Talamo

2010-03-01

Full Text Available 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.

Bortezomib in the management of multiple myeloma

Directory of Open Access Journals (Sweden)

Jacob P Laubach

2009-09-01

Full Text Available Jacob P Laubach, Constantine S Mitsiades, Teru Hideshima, Robert Schlossman, Dharminder Chauhan, Nikhil Munshi, Irene Ghobrial, Nicole Carreau, Kenneth C Anderson, Paul G RichardsonDepartment of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USAAbstract: Multiple myeloma (MM is a B-cell malignancy characterized by clonal expansion of plasma cells within the bone marrow, the presence of a serum and/or urine monoclonal protein, lytic bone lesions, and anemia. On a cellular level, the disease is characterized by complex interactions between tumor cells and the surrounding bone marrow microenvironment. Understanding of the relationship between malignant plasma cells and the microenvironment has sparked ongoing efforts to develop targeted therapeutic agents for treatment of this disease. The successful development of the first-in-class small-molecule proteasome inhibitor bortezomib occurred as a result of these efforts. This review focuses on the rationale for bortezomib therapy in the treatment of patients with newly diagnosed and relapsed MM, important treatment-related side effects, and future directions for use of bortezomib and other, emerging proteasome inhibitors.Keywords: multiple myeloma, bortezomib, stem cell transplantation, peripheral neuropathy

Plasmablastic myeloma presenting as rapidly progressive renal failure in a young adult

Directory of Open Access Journals (Sweden)

M Srija

2014-01-01

Full Text Available Multiple myeloma (MM is a condition where there is malignant proliferation of plasma cells. There is a strong correlation with age, peaking at 60-70 years. The clinical course in adolescents and young individuals is generally indolent and the survival is longer. We report a case of a 28-year-old male, who was diagnosed to have plasmablastic myeloma, an atypical variant of MM with a poor prognosis, presenting as rapidly progressive renal failure. He was given induction chemotherapy and then underwent autologous peripheral blood stem cell transplantation.

MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin.

Science.gov (United States)

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.

Healthcare resource use and costs associated with chronic kidney disease in US private insurance patients with multiple myeloma.

Science.gov (United States)

Bhowmik, Debajyoti; Song, Xue; Intorcia, Michele; Kent, Shia T; Shi, Nianwen

2018-01-01

Objectives Within a median 1.2 years after patients have an initial diagnosis with multiple myeloma, up to 61% were diagnosed with renal impairment and 50% were diagnosed with chronic kidney disease. This study estimated economic burden associated with chronic kidney disease in multiple myeloma patients in the US. Methods In this retrospective cohort study, patients ≥18 years old with ≥1 inpatient or ≥ 2 outpatient multiple myeloma diagnoses between 1 January 2008 and 31 March 2015 were identified from MarketScan® Commercial and Medicare Supplemental Databases. Chronic kidney disease patients had ≥1 diagnosis of chronic kidney disease Stages 1-5 (first chronic kidney disease diagnosis date = index date) on or after the first multiple myeloma diagnosis, and were propensity score matched 1:1 to multiple myeloma patients without chronic kidney disease, end-stage renal disease, dialysis, or other type of chronically impaired renal function. All patients had ≥six-month continuous enrollment prior to index date and were followed for ≥one month from index date until the earliest of inpatient death, end of continuous enrollment, or end of the study period (30 September 2015). The per-patient per-year healthcare resource utilization and costs were measured during follow-up. Costs were total reimbursed amount in 2016 US dollars. Results A total of 2541 multiple myeloma patients with chronic kidney disease stages 1-5 and 2541 matched controls met the study criteria and were respectively 69.3 and 69.6 years, 54.5% and 55.3% men, and had 572.2 and 533.4 mean days of follow up. Compared to controls, chronic kidney disease patients had significantly (all P chronic kidney disease, end-stage renal disease, or dialysis had $78,455 ( P chronic kidney disease in patients with multiple myeloma was estimated to be between $34,754 and $78,455 per-patient per-year. Given its substantial clinical and economic impact, preservation of renal function is important in

Dexamethasone, all trans retinoic acid and interferon alpha 2a in patients with refractory multiple myeloma.

Science.gov (United States)

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.

Multiple myeloma presenting as mandibular pain

LENUS (Irish Health Repository)

Crowley, Miriam

2016-10-01

Introduction: Multiple myeloma (MM) is a systemic malignancy of plasma cells defined by monoclonal production of circulating immunoglobulins. Bone pain is a presenting feature in the majority of cases. Treatment may involve intravenous use of bisphosphonates, chemotherapy or haematopoietic stem cell transplantation. Here, we illustrate a first presentation of MM in a patient with mandibular pain and discuss radiographic, diagnostic and treatment challenges of orofacial issues in patients with MM.\\r\

Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells

International Nuclear Information System (INIS)

Born, E J; Hartman, S V; Holstein, S A

2013-01-01

Multiple myeloma is characterized by the production of substantial quantities of monoclonal protein. We have previously demonstrated that select inhibitors of the isoprenoid biosynthetic pathway (IBP) induce apoptosis of myeloma cells via inhibition of Rab geranylgeranylation, leading to disruption of monoclonal protein trafficking and induction of the unfolded protein response (UPR) pathway. Heat-shock protein 90 (HSP90) inhibitors disrupt protein folding and are currently under clinical investigation in myeloma. The effects of combining IBP and HSP90 inhibitors on cell death, monoclonal protein trafficking, the UPR and chaperone regulation were investigated in monoclonal protein-producing cells. An enhanced induction of cell death was observed following treatment with IBP and HSP90 inhibitors, which occurred through both ER stress and non-ER stress pathways. The HSP90 inhibitor 17-AAG abrogated the effects of the IBP inhibitors on intracellular monoclonal protein levels and localization as well as induction of the UPR in myeloma cells. Disparate effects on chaperone expression were observed in myeloma vs amyloid light chain cells. Here we demonstrate that the novel strategy of targeting MP trafficking in concert with HSP90 enhances myeloma cell death via a complex modulation of ER stress, UPR, and cell death pathways

Zingiber officinale, Piper retrofractum and Combination Induced Apoptosis and p53 Expression in Myeloma and WiDr Cell Lines

Directory of Open Access Journals (Sweden)

HENY EKOWATI

2012-09-01

Full Text Available In previous studies, Zingiber officinale, Piper retrofractum, and the combination showed cytotoxic activity, induced apoptosis, and p53 expression of HeLa, T47D, and MCF-7 cell lines. This study was conducted to investigate the cytotoxic and apoptotic activity of Zingiber officinale (ZO, Piper retrofractum (PR, and the combination as well as their effect to p53 expression on Myeloma and WiDr cells. The powder of ZO, PR, and ZO + PR combination (1:1 were macerated with 96% ethanol for 3 x 24 hours. MTT cytotoxic assay was performed on Myeloma and WiDr cell lines. Apoptotic cells were stained with ethidium bromide and acridine orange. Imunohistochemical expression of p53 was examined on Myeloma and WiDr cell lines. Doxorubicin was used as positive control in all assays. Results showed that ZO, PR, and ZO + PR combination had cytotoxic activity on Myeloma cells with IC50 of 28, 36, and 55 mg/ml respectively and WiDr cell lines with IC50 of 74, 158, and 64 mg/ml respectively, induced apoptotic activity, and increased p53 expression on Myeloma and WiDr cells. These results suggest that ZO, PR, and their combination induced Myeloma and WiDr cells in apoptosis through p53 expression.

Modern imaging techniques in patients with multiple myeloma; Moderne Bildgebungsverfahren beim Multiplen Myelom

Energy Technology Data Exchange (ETDEWEB)

Bannas, Peter; Adam, G.; Derlin, T. [Universitaetsklinikum Hamburg-Eppendorf, Hamburg (Germany). Klinik und Poliklinik fuer Diagnostische und Interventionelle Radiologie; Kroeger, N. [Universitaetsklinikum Hamburg-Eppendorf, Hamburg (Germany). Klinik und Poliklinik fuer Stammzelltransplantation

2013-01-15

Imaging studies are essential for both diagnosis and initial staging of multiple myeloma, as well as for differentiation from other monoclonal plasma cell diseases. Apart from conventional radiography, a variety of newer imaging modalities including whole-body low-dose-CT, whole-body MRI and 18F-FDG PET/CT may be used for detection of osseous and extraosseous myeloma manifestations. Despite of known limitations such as limited sensitivity and specificity and the inability to detect extraosseous lesions, conventional radiography still remains the gold standard for staging newly diagnosed myeloma, partly due to its wide availability and low costs. Whole-body low-dose CT is increasingly used due to its higher sensitivity for the detection of osseous lesions and its ability to diagnose extraosseous lesions, and is replacing conventional radiography at selected centres. The highest sensitivity for both detection of bone marrow disease and extraosseous lesions can be achieved with whole-body MRI or 18F-FDG PET/CT. Diffuse bone marrow infiltration may be visualized by whole-body MRI with high sensitivity. Whole-body MRI is at least recommended in all patients with normal conventional radiography and in all patients with an apparently solitary plasmacytoma of bone. To obtain the most precise readings, optimized examination protocols and dedicated radiologists and nuclear medicine physicians familiar with the complex and variable morphologies of myeloma lesions are required. (orig.)

Raman spectroscopy differentiates between sensitive and resistant multiple myeloma cell lines

Science.gov (United States)

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.

Cardioverter-defibrillator implantation in myeloma-associated cardiac amyloidosis.

Science.gov (United States)

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.

Sacroplasty for Local or Massive Localization of Multiple Myeloma

International Nuclear Information System (INIS)

Basile, Antonio; Tsetis, Dimitrios; Cavalli, Maide; Fiumara, Paolo; Raimondo, Francesco Di; Coppolino, Francesco; Coppolino, Carmelo; Mundo, Elena; Desiderio, Carla; Granata, Antonio; Patti, Maria Teresa

2010-01-01

The purpose of this study was to assess the efficacy of cementoplasty in the treatment of sacral multiple myelomas. We retrospectively reviewed the records of eight patients (four women and four men; age range 47-68 years; mean age 57.8) who underwent cementoplasty for painful osteolytic localization of multiple myeloma between April 2007 and May 2009. The patients had difficulty walking because of increasing pain. Six patients had persistent pain despite other cementoplasties for vertebral and femoral localization, whereas two patients referred at the time of diagnosis had only sacral lesions. The clinical indication for treatment was (1) a pain intensity score ≥5 on visual analogue scale (VAS) and (2) pain totally or partially refractory to analgesic treatment in patients with a life expectancy >3 months. Technical planning was based on computed tomography and/or magnetic resonance imaging. Six patients had previously undergone radiotherapy or chemotherapy and were receiving varying doses of analgesics, whereas sacroplasty represented the first treatment for two patients. Five patients had monolateral local involvement, and the other patients had massive involvement of the sacrum; Technical success was achieved in all cases. We had only one small and asymptomatic foraminal leak. All patients experienced improvement in symptoms after the procedure, as demonstrated by improved VAS scores and performance status (PS) and decreased analgesic dose constant during follow-up. In our experience, percutaneous stabilization can be used effectively and safely in patients with focal or extensive involvement of the sacrum by multiple myeloma.

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.

Science.gov (United States)

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.

THERAPY-RELATED MYELOID MALIGNANCIES IN MYELOMA

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Xenofon Papanikolaou

2011-10-01

Full Text Available Therapy related myeloid malignancies are an increasingly recognized treatment complication in patients undergoing therapy for multiple myeloma. The main predisposing factors are the alkylating agents, topoisomerase II inhibitors and radiotherapy, but recently questions have been raised regarding the immunomodulatory agent lenalidomide. Little is known about the new antimyeloma agents in the context of therapy related myeloid malignanices. The duration of treatment and the time from diagnosis are the main contributing factors in alkylating induced myeloid malignancies which occur 5-10 years after treatment, chromosome 5 and 7 abnormalities being the characteristic finding. High dose therapy (HDT does not seem to be a major contributing factor per se in multiple myeloma. In a number of large published series, all the factors related with therapy-induced myelodysplasia were defined prior to HDT. Topoisomerase II inhibitors induce mainly acute leukemias which invariably correlate with dysregulation of the MLL gene. Radiotherapy causes therapy related myelodysplasia if applied in bone marrow producing areas, especially if combined with chemotherapy. Therapy related myeloid malignancies generally herald a poor prognosis. Karyotypic abnormalities seem to be the main prognostic factor. In all cases the risk for therapy related myeloid malignancies drops sharply by 10 years after the treatment.

THERAPY-RELATED MYELOID MALIGNANCIES IN MYELOMA

Directory of Open Access Journals (Sweden)

Bart Barlogie

2011-01-01

Full Text Available

Therapy related myeloid malignancies are an increasingly recognized treatment complication in patients undergoing therapy for multiple myeloma. The main predisposing factors are the alkylating agents, topoisomerase II inhibitors and radiotherapy, but recently questions have been raised regarding the immunomodulatory agent lenalidomide. Little is known about the new antimyeloma agents in the context of therapy related myeloid malignanices. The duration of treatment and the time from diagnosis are the main contributing factors in alkylating induced myeloid malignancies which occur 5-10 years after treatment, chromosome 5 and 7 abnormalities being the characteristic finding. High dose therapy (HDT does not seem to be a major contributing factor per se in multiple myeloma. In a number of large published series, all the factors related with therapy-induced myelodysplasia were defined prior to HDT. Topoisomerase II inhibitors induce mainly acute leukemias which invariably correlate with dysregulation of the MLL gene. Radiotherapy causes therapy related myelodysplasia if applied in bone marrow producing areas, especially if combined with chemotherapy. Therapy related myeloid malignancies generally herald a poor prognosis. Karyotypic abnormalities seem to be the main prognostic factor. In all cases the risk for therapy related myeloid malignancies drops sharply by 10 years after the treatment.

From the bench to the bedside: emerging new treatments in multiple myeloma

Science.gov (United States)

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

Antithyroid drugs induced agranulocytosis and multiple myeloma: case report and general considerations.

Science.gov (United States)

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.

An Application for Measuring Frailty of Myeloma Cancer Patients

DEFF Research Database (Denmark)

Corradini, Andrea; Bøgelund Hansen, Martin; Savic, Toma

2016-01-01

In this paper, we report on a responsive web-based application that we have been developing for the cancer hospital in the city of Vejle, Denmark. The application administers and handles systematic frailty scoring of patients with multiple myeloma (bone marrow cancer) and thereby helps the doctor...... make a more efficient and more effective treatment choice. The application is currently being tested with a small number of patients and is to replace the frailty measurement system used until now, which is usually done by the doctor on a per patient basis.......In this paper, we report on a responsive web-based application that we have been developing for the cancer hospital in the city of Vejle, Denmark. The application administers and handles systematic frailty scoring of patients with multiple myeloma (bone marrow cancer) and thereby helps the doctor...

Hypophosphatemic osteomalacia: an unusual clinical presentation of multiple myeloma.

Science.gov (United States)

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.

Metastatic Breast Cancer or Multiple Myeloma? Camouflage by Lytic Lesions

Directory of Open Access Journals (Sweden)

Bruce Hough

2010-01-01

Full Text Available We report a case of a female with stage I infiltrating ductal carcinoma who received adjuvant therapy including trastuzumab. One year later she developed lytic lesions and was retreated with trastuzumab that was held after she developed symptomatic heart failure. Lytic lesions were attributed to relapse of breast cancer, and cardiac failure attributed to prior trastuzumab therapy. After complications necessitated multiple hospitalizations, a further workup revealed that the lytic lesions were not metastatic breast cancer but multiple myeloma. Her advanced multiple myeloma was associated with systemic amyloidosis involving gut and heart, which ultimately led to her demise. This report addresses the pitfalls of overlapping symptoms and the question of which patients with suspected metastatic disease should undergo a biopsy.

Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma

DEFF Research Database (Denmark)

Zweegman, Sonja; van der Holt, Bronno; Mellqvist, Ulf-Henrik

2016-01-01

The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalid......The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone......, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen...... with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-Belgium Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/NMSG18 trial). The primary end point was progression-free survival (PFS...

CDK2 phosphorylation of Smad2 disrupts TGF-beta transcriptional regulation in resistant primary bone marrow myeloma cells.

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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.

Molecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing

Directory of Open Access Journals (Sweden)

Ikeda H

2015-10-01

Full Text Available Hiroshi Ikeda,1 Kazuya Ishiguro,1 Tetsuyuki Igarashi,1 Yuka Aoki,1 Toshiaki Hayashi,1 Tadao Ishida,1 Yasushi Sasaki,1,2 Takashi Tokino,2 Yasuhisa Shinomura1 1Department of Gastroenterology, Rheumatology and Clinical Immunology, 2Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan Abstract: A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM, Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients. Keywords: multiple myeloma, drug resistance, genome-wide sequencing, semiconductor sequencer, target therapy

Immunological Dysregulation in Multiple Myeloma Microenvironment

OpenAIRE

Romano, Alessandra; Conticello, Concetta; Cavalli, Maide; Vetro, Calogero; La Fauci, Alessia; Parrinello, Nunziatina Laura; Di Raimondo, Francesco

2014-01-01

Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extr...

Clinicopathological features of plasmablastic multiple myeloma

DEFF Research Database (Denmark)

Møller, Hanne E H; Preiss, Birgitte S; Pedersen, Per

2015-01-01

Multiple myeloma (MM) is a common malignant hematological disease displaying considerable heterogeneity. Historical data indicate a prognostic significance of plasmablastic morphology, proliferation, and adverse cytogenetics, but there is little knowledge on the degree of interdependency......, which indicates that plasmablastic morphology reflects advanced and highly proliferative disease. However, plasmablastic morphology did not correlate with established adverse prognostic cytogenetics identified by FISH, for example, t(4;14), t(14;16) and del(17p)....

Iodine-based contrast media, multiple myeloma and monoclonal gammopathies

DEFF Research Database (Denmark)

Stacul, Fulvio; Bertolotto, Michele; Thomsen, Henrik S

2018-01-01

OBJECTIVES: Many radiologists and clinicians still consider multiple myeloma (MM) and monoclonal gammopathies (MG) a contraindication for using iodine-based contrast media. The ESUR Contrast Media Safety Committee performed a systematic review of the incidence of post-contrast acute kidney injury...

A Next-Generation Sequencing Strategy for Evaluating the Most Common Genetic Abnormalities in Multiple Myeloma.

Science.gov (United States)

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.

Curcumin Enhances Bortezomib Treatment of Myeloma by Inhibiting ...

African Journals Online (AJOL)

Purpose: To investigate whether curcumin augments bortezomib-induced apoptosis in myeloma cells (MM1.R line), and to explore the molecular mechanism with regard to heat shock protein 90 (HSP90) expression. Methods: MTT cell viability assay was used to assess growth inhibition of MM1.R cells at different ...

Decorin is down-regulated in multiple myeloma and MGUS bone marrow plasma and inhibits HGF-induced myeloma plasma cell viability and migration

DEFF Research Database (Denmark)

Kristensen, Ida Bruun; Pedersen, Lise Mariager; Rø, Torstein Baade

2013-01-01

pathway in multiple myeloma (MM). METHODS: Decorin levels in paired peripheral blood and bone marrow plasma samples from healthy volunteers (HV) (n=23), and patients with monoclonal gammopathy of undetermined significance (MGUS) (n=41) and MM (n=19) were determined by ELISA. Further, the ability...

Human mesenchymal stromal cell transplantation modulates neuroinflammatory milieu in a mouse model of amyotrophic lateral sclerosis.

Science.gov (United States)

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.

A novel option for reducing free light chains in myeloma kidney: supra-hemodiafiltration with endogenous reinfusion (HFR).

Science.gov (United States)

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 .

Study on the effect of treating soil salinity stress in some economic plants with gamma radiation

International Nuclear Information System (INIS)

Mohamed, H.A.K.

1998-01-01

Based upon on the results of a preliminary experiment, experimental plants (two varieties of barley, two varieties of wheat in addition to faba bean and pea plant) were cultivated in the field under the effect of all levels of salinity and /or gamma doses which improved the inhibitory effect of salinity on germination percent, seedling length and fresh and dry weights of 10 days old seedlings. The results showed that gamma doses used had an antagonistic effect to the effect of salinity on shoot length, fresh and dry weights, pigment, polysaccharides, free proline, protein and nucleic acids while, had synergistic effect on soluble sugars content

Safety of thalidomide in newly diagnosed elderly myeloma patients

DEFF Research Database (Denmark)

Palumbo, Antonio; Waage, Anders; Hulin, Cyrille

2013-01-01

Background. Melphalan-prednisone-thalidomide (MPT) improves outcome in multiple myeloma (MM) patients, and it is now considered a standard of care for patients not eligible for transplantation. However, this treatment is a major source of morbidity. Design and Methods. An individual patient data...

[Diagnostic and evolutionary profile of multiple myeloma in Senegal: monocentric study conducted from 2005 to 2016].

Science.gov (United States)

Fall, Seynabou; Dieng, Fatma; Diouf, Coumba; Djiba, Boundia; Ndao, Awa Cheikh; Ndiaye, Fatou Samba Diago

2017-01-01

Accessibility to innovative multiple myeloma therapies is limited in sub-Saharan Africa. This study aimed to describe the diagnostic and evolutionary features observed during treatment of our patients with myeloma. We conducted a retrospective, descriptive, analytical study (2005 - 2016) of patients with myeloma included in the study based on International Myeloma Working Group (IMWG) Criteria (2003,2014) at the Hopital Aristide Le Dantec (Senegal). We collected data from 136 medical records (69 men, 67 women) of patients with an average age of 59 years ± 10.1 years, who were less than 65 years of age in 69.1% of cases. Tell-tale signs included bone pain (96.3%), renal failure (36.8%), infection (23.5%), pathological fracture (17.6%), spinal cord compression (16.9%) and malignant hypercalcaemia (16.2%). Isotopic antiglobulin test showed that anti-IgG could be detected in 61.3% of cases and Kappa in 65% of cases. Patients were classified stage III (59.4%) and I-II (40.6%)of the index staging system. The median survival of patients under conventional traitement (Méphalan-Prédnisone: 67.6%, innovative: 5.9%) was 20 months (1-78 months). Survival rates are better in the absence of neurological and infectious complications and for patients with score I-II of the index Staging System. In our study, multiple myeloma was frequently diagnosed before age 65, at advanced stage of tumor mass. Early detection and access to adequate therapies could improve overall survival.

Influence of Disease and Patient Characteristics on Daratumumab Exposure and Clinical Outcomes in Relapsed or Refractory Multiple Myeloma

DEFF Research Database (Denmark)

Yan, Xiaoyu; Clemens, Pamela L; Puchalski, Thomas

2018-01-01

OBJECTIVE: The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM). PATIENTS AND METHODS: Baseline myeloma type, ...

Evolutionary Dynamics of Tumor-Stroma Interactions in Multiple Myeloma.

Directory of Open Access Journals (Sweden)

Javad Salimi Sartakhti

Full Text Available Cancer cells and stromal cells cooperate by exchanging diffusible factors that sustain tumor growth, a form of frequency-dependent selection that can be studied in the framework of evolutionary game theory. In the case of multiple myeloma, three types of cells (malignant plasma cells, osteoblasts and osteoclasts exchange growth factors with different effects, and tumor-stroma interactions have been analysed using a model of cooperation with pairwise interactions. Here we show that a model in which growth factors have autocrine and paracrine effects on multiple cells, a more realistic assumption for tumor-stroma interactions, leads to different results, with implications for disease progression and treatment. In particular, the model reveals that reducing the number of malignant plasma cells below a critical threshold can lead to their extinction and thus to restore a healthy balance between osteoclast and osteoblast, a result in line with current therapies against multiple myeloma.

Multiple myeloma: radiology or bone scanning

International Nuclear Information System (INIS)

Leonard, R.C.F.; Owen, J.P.; Proctor, S.J.; Hamilton, P.J.

1981-01-01

A comparative study of radionuclide bone scanning and skeletal radiology in patients with multiple myeloma revealed four principal findings: (i) There were no cases of negative bone scans with positive skeletal radiographs. (ii) Lytic bone lesions were seriously underestimated by bone scans. (iii) Bone scans tended to pick up lesions in ribs missed on the skeletal surveys. (iv) Patients with bone pain were more likely to have positive bone scans and skeletal radiographs than asymptomatic patients. (author)

Radiography and bone scintigraphy in bone marrow transplant multiple myeloma patients

International Nuclear Information System (INIS)

Aagren, B.; Aspelin, P.

1997-01-01

Purpose: To compare conventional radiography and bone scintigraphy in relation to clinical outcome in bone marrow transplant multiple myeloma patients. Material and Methods: A total of 70 radiographies and 70 bone scintigraphies were compared in 35 patients. Results: The skull, the extremities, the iliac and public bones were better assessed with radiography. For new vertebral lesions and for lesions in the ribs and sternum, bone scintigraphy proved superior. For the sacrum, the methods were equal. When bone scintigraphy was used as a complement to radiography, 4% more pathological sites were found. No patient had both a normal radiography and a pathological bone scintigraphy, but 5 patients had both a normal bone scintigraphy and a pathological radiography. The results of the radiological examinations did not always correlate with the clinician's grading of the patient's disease. The radiological examinations had no prognostic value for the 7 patients examined on several occasions. Conclusion: The ability of conventional radiography and bone scintigraphy to disclose myeloma lesions varies, depending on location and size of the lesions. Radiography should remain the primary examination modality also for bone marrow transplant multiple myeloma patients. Bone scintigraphy can severe as a complement for investigating unexplained pain, e.g. caused by lesions in vertebrae or ribs. (orig.)

Predicting the impact of combined therapies on myeloma cell growth using a hybrid multi-scale agent-based model.

Science.gov (United States)

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.

The shaping and functional consequences of the dosage effect landscape in multiple myeloma.

Science.gov (United States)

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

Measuring the frailty index of multiple myeloma cancer patients

DEFF Research Database (Denmark)

Corradini, Andrea; Bøgelund Hansen, Martin; Savic, Toma

2016-01-01

We report on a responsive web-based application that we have been developing for the cancer hospital in Vejle, Denmark. The application administers and handles systematic frailty scoring of patients with multiple myeloma and helps doctors make a more efficient and effective treatment choice. The ...

Abnormal neural activation patterns underlying working memory impairment in chronic phencyclidine-treated mice.

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Yosefu Arime

Full Text Available 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.

Diagnostic x-ray procedures and risk of leukemia, lymphoma, and multiple myeloma

International Nuclear Information System (INIS)

Boice, J.D. Jr.; Morin, M.M.; Glass, A.G.; Friedman, G.D.; Stovall, M.; Hoover, R.N.; Fraumeni, J.F. Jr.

1991-01-01

Exposure to diagnostic x-rays and the risk of leukemia, non-Hodgkin's lymphoma (NHL), and multiple myeloma were studied within two prepaid health plans. Adult patients with leukemia (n = 565), NHL (n = 318), and multiple myeloma (n = 208) were matched to controls (n = 1390), and over 25,000 x-ray procedures were abstracted from medical records. Dose response was evaluated by assigning each x-ray procedure a score based on estimated bone marrow dose. X-ray exposure was not associated with chronic lymphocytic leukemia, one of the few malignant conditions never linked to radiation (relative risk [RR], 0.66). For all other forms of leukemia combined (n = 358), there was a slight elevation in risk (RR, 1.17) but no evidence of a dose-response relationship when x-ray procedures near the time of diagnosis were excluded. Similarly, patients with NHL were exposed to diagnostic x-ray procedures more often than controls (RR, 1.32), but the RR fell to 0.99 when the exposure to diagnostic x-ray procedures within 2 years of diagnosis was ignored. For multiple myeloma, overall risk was not significantly high (RR, 1.14), but there was consistent evidence of increasing risk with increasing numbers of diagnostic x-ray procedures. These data suggest that persons with leukemia and NHL undergo x-ray procedures frequently just prior to diagnosis for conditions related to the development or natural history of their disease. There was little evidence that diagnostic x-ray procedures were causally associated with leukemia or NHL. The risk for multiple myeloma, however, was increased among those patients who were frequently exposed to x-rays

Serum galectin-1 in patients with multiple myeloma

DEFF Research Database (Denmark)

Andersen, Morten Nørgaard; Ludvigsen, Maja; Abildgaard, Niels

2017-01-01

with worse disease state or poor outcome. Gal-1 can be secreted from cells by an unknown mechanism, and levels in blood samples were associated with high tumor burden and worse disease state in cHL and CLL patients. However, serum levels of Gal-1 have never been investigated in patients with multiple myeloma...

Old but Still Relevant: High Resolution Electrophoresis and Immunofixation in Multiple Myeloma.

Science.gov (United States)

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.

Cytogenetic effects of sildenafil citrate (Viagra) on SWR/J mouse bone marrow cells.

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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.

Double filtration plasmapheresis in a dog with multiple myeloma and hyperviscosity syndrome

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I. Lippi

2015-08-01

Full Text Available A 12 year old, 38 kg, mix-breed, intact male dog presented with a 20 day history of clinical signs consistent with hyperviscosity syndrome secondary to multiple myeloma. The dog received three double filtration plasmapheresis treatments on day 0, 7 and 22 after presentation. A significant (p<0.05 reduction in serum total protein, alpha-2 and gamma globulins was found following each treatment. These reductions were accompanied by a complete resolution, although temporary, of the clinical signs of hyperviscosity syndrome. The present study reported for the first time the use of double filtration plasmapheresis to reduce clinical signs of hyperviscosity syndrome in a dog with multiple myeloma.

IgG4 plasma cell myeloma: new insights into the pathogenesis of IgG4-related disease.

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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

Science.gov (United States)

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.

The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP

DEFF Research Database (Denmark)

Vangsted, Annette Juul; Klausen, Tobias Wirenfeldt; Gimsing, Peter

2011-01-01

The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor ¿B (NF-¿B). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with inte......The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor ¿B (NF-¿B). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated...... with interferon-a (INF-a) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NF¿B1. By linkage disequilibrium mapping, we found that variant...... alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3-6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p¿=¿0.003) and overall survival (OS; p¿=¿0.02). Haplotype analyses revealed that none...

The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in RAI and CD3EAP

DEFF Research Database (Denmark)

Vangsted, Annette J.; Klausen, Tobias Wirenfeldt; Gimsing, Peter

2011-01-01

The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF–κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with inte......The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF–κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated...... with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant...... alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3–6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p = 0.003) and overall survival (OS; p = 0.02). Haplotype analyses revealed that none...

Effective bioremediation of a petroleum-polluted saline soil by a surfactant-producing Pseudomonas aeruginosa consortium

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Ali Ebadi

2017-11-01

Full Text Available Bacteria able to produce biosurfactants can use petroleum-based hydrocarbons as a carbon source. Herein, four biosurfactant-producing Pseudomonas aeruginosa strains, isolated from oil-contaminated saline soil, were combined to form a bacterial consortium. The inoculation of the consortium to contaminated soil alleviated the adverse effects of salinity on biodegradation and increased the rate of degradation of petroleum hydrocarbon approximately 30% compared to the rate achieved in non-treated soil. In saline condition, treatment of polluted soil with the consortium led to a significant boost in the activity of dehydrogenase (approximately 2-fold. A lettuce seedling bioassay showed that, following the treatment, the soil's level of phytotoxicity was reduced up to 30% compared to non-treated soil. Treatment with an appropriate bacterial consortium can represent an effective means of reducing the adverse effects of salinity on the microbial degradation of petroleum and thus provides enhancement in the efficiency of microbial remediation of oil-contaminated saline soils.

B cell lymphoma and myeloma in murine Gaucher's disease

NARCIS (Netherlands)

Pavlova, E. V.; Wang, S. Z.; Archer, J.; Dekker, N. [=Nick; Aerts, J. M. F. G.; Karlsson, S.; Cox, T. M.

2013-01-01

Multiple myeloma and B cell lymphoma are leading causes of death in Gaucher's disease but the nature of the stimulus driving the often noted clonal expansion of immunoglobulin-secreting B cells and cognate lymphoid malignancy is unknown. We investigated the long-term development of B cell

Plasma Cell Neoplasms (Including Multiple Myeloma)—Patient Version

Science.gov (United States)

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.

Science.gov (United States)

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,…

Immunoparesis and polyclonal immunoglobulin recovery after auto-SCT for patients with multiple myeloma treated at a single institution.

Science.gov (United States)

Jimenez-Zepeda, Victor H; Duggan, Peter; Neri, Paola; Chaudhry, Ahsan; Tay, Jason; Bahlis, Nizar

2017-11-21

Immunoparesis and polyclonal immunoglobulin recovery have been recently described as common indicators of immune dysfunction in patients with multiple myeloma. In the present study, we aimed to assess the impact of immunoparesis and polyclonal immunoglobulin recovery at day-100 post autologous stem cell transplant (auto-SCT) on clinical outcomes. A total of 302 patients were included for the analysis of immunoparesis, and 197 were evaluable for polyclonal immunoglobulin recovery evaluation. Immunoparesis was observed in 93.5% of cases, with 47% of cases having polyclonal immunoglobulin recovery at 12 months post auto-SCT. Median overall and progression-free survival were longer in the group of patients with complete or partial normalization of polyclonal immunoglobulins. Patients receiving consolidation had a lower level of polyclonal reconstitution. In conclusion, polyclonal immunoglobulin recovery by 12 months post-auto-SCT is associated with superior overall and progression free survival in patients with MM. Efforts to better enhance polyclonal recovery deserve further investigation.

Stokes shift spectroscopy for the early diagnosis of epithelial precancers in DMBA treated mouse skin carcinogenesis

Science.gov (United States)

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.

Treatment of aggressive multiple myeloma by high-dose chemotherapy and total body irradiation followed by blood stem cells autologous graft

International Nuclear Information System (INIS)

Fermand, J.P.; Levy, Y.; Gerota, J.; Benbunan, M.; Cosset, J.M.; Castaigne, S.; Seligmann, M.; Brouet, J.C.

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 15 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

A temporal study on #betta#2-microglobulin as marker for diagnosis and monitoring of multiple myeloma

International Nuclear Information System (INIS)

Neri, B.

1982-01-01

The most important objective carried on, in the field of oncology has been the finding of new means to improve diagnosis and monitoring of neoplastic diseases. So we have chronobiologically studied the behaviour of #betta# 2 -microglobulin, in three groups of patients: Group A: 11 healthy subjects; Group B: 11 untreated patients with multiple myeloma and Group C: 11 multiple myeloma patients, after treatment with polychemoterapy. #betta# 2 -microglobulin, was assayed in serum obtained at six consecutive 4-hourly intervals, by radioimmunoassay, the levels and the various rhythm parameters were analyzed by ''Group mean cosinor'' test. The data suggest, that a circadian rhythm for #betta# 2 -microglobulin in the three groups is not detectable; but ''mesor test'' establishes significant differences (p 2 -microglobulin, in diagnosis and monitoring of multiple myeloma, is suggested

The impact of recent chemotherapy innovation on the longevity of myeloma patients in the U.S. and international evidence

DEFF Research Database (Denmark)

Lichtenberg, Frank R.; Hostenkamp, Gisela

There were no innovations in chemotherapy for myeloma patients during the period 1977-1997, but there have been several important innovations since 1997. We investigate the impact of recent chemotherapy innovation on the longevity of myeloma patients using both time-series U.S. data...... and longitudinal data on 26 countries. In the US, the average annual rate of increase of life expectancy of myeloma patients at time of diagnosis was over five times as large during 1997-2005 as it had been during 1975-1997. We estimate that almost two-thirds (0.99 years) of the 1997-2005 increase in life...... expectancy was due to the increase in the number of chemotherapy regimens now preferred by specialists, and that the cost per U.S. life-year gained from post-1997 chemotherapy innovation did not exceed $45,551. We also investigate the impact of chemotherapy innovation on the myeloma mortality rate using...

Hemin inhibits cyclooxygenase-2 expression through nuclear factor-kappa B activation and ornithine decarboxylase expression in 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin

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Park, Jae Hee; Lee, Chang Ki [Department of Oral Biology, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Oral Cancer Research Institute, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Hwang, Young Sun [Department of Applied Life Science and Brain Korea 21 Project, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Park, Kwang-Kyun [Department of Oral Biology, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Department of Applied Life Science and Brain Korea 21 Project, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Chung, Won-Yoon [Department of Oral Biology, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Department of Applied Life Science and Brain Korea 21 Project, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of)], E-mail: wychung@yuhs.ac

2008-07-03

Inflammation induced by various stimuli has been found to be associated with increased risk for most types of human cancer. Inflammation facilitates the initiation of normal cells, as well as the growth of initiated cells and their progression to malignancy through production of proinflammatory cytokines and diverse reactive oxygen/nitrogen species. These also activate the signaling molecules that are involved in inflammation and carcinogenesis. Our previous studies have demonstrated that hemin inhibited 7,12-dimethylbenz[a]anthracene (DMBA)-induced bacterial mutagenesis and oxidative DNA damage, reduced the level of DNA-DMBA adduct and 12-O-tetradecanoylphorobl-13-acetate (TPA)-induced tumor formation in DMBA-initiated ICR mouse skin, and inhibited myeloperoxidase and ornithine decarboxylase (ODC) activity and H{sub 2}O{sub 2} formation in TPA-treated mouse skin. In the present study, to further elucidate the molecular mechanisms underlying the chemopreventive activity of hemin, its effect on the expression of ODC and cyclooxygenase (COX)-2, and the activation of nuclear factor-kappa B (NF-{kappa}B) and mitogen-activated protein kinases (MAPKs) regulating these proteins were explored in mouse skin with TPA-induced inflammation. Topically applied hemin inhibited ear edema and epidermal thickness in mice treated with TPA. Pretreatment with hemin reduced the expression of ODC and COX-2, and also reduced NF-{kappa}B activation in TPA-stimulated mouse skin. In addition, hemin suppressed the TPA-induced activation of extracellular signal-regulated protein kinase (ERK) and p38 MAPK in a dose-dependent manner. Taken together, hemin inhibited TPA-induced COX-2 expression by altering NF-{kappa}B signaling pathway via ERK and p38 MAPK, as well as TPA-induced ODC expression in mouse skin. Thereby, hemin may be an attractive candidate for a chemopreventive agent.

Hemin inhibits cyclooxygenase-2 expression through nuclear factor-kappa B activation and ornithine decarboxylase expression in 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin

International Nuclear Information System (INIS)

Park, Jae Hee; Lee, Chang Ki; Hwang, Young Sun; Park, Kwang-Kyun; Chung, Won-Yoon

2008-01-01

Inflammation induced by various stimuli has been found to be associated with increased risk for most types of human cancer. Inflammation facilitates the initiation of normal cells, as well as the growth of initiated cells and their progression to malignancy through production of proinflammatory cytokines and diverse reactive oxygen/nitrogen species. These also activate the signaling molecules that are involved in inflammation and carcinogenesis. Our previous studies have demonstrated that hemin inhibited 7,12-dimethylbenz[a]anthracene (DMBA)-induced bacterial mutagenesis and oxidative DNA damage, reduced the level of DNA-DMBA adduct and 12-O-tetradecanoylphorobl-13-acetate (TPA)-induced tumor formation in DMBA-initiated ICR mouse skin, and inhibited myeloperoxidase and ornithine decarboxylase (ODC) activity and H 2 O 2 formation in TPA-treated mouse skin. In the present study, to further elucidate the molecular mechanisms underlying the chemopreventive activity of hemin, its effect on the expression of ODC and cyclooxygenase (COX)-2, and the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) regulating these proteins were explored in mouse skin with TPA-induced inflammation. Topically applied hemin inhibited ear edema and epidermal thickness in mice treated with TPA. Pretreatment with hemin reduced the expression of ODC and COX-2, and also reduced NF-κB activation in TPA-stimulated mouse skin. In addition, hemin suppressed the TPA-induced activation of extracellular signal-regulated protein kinase (ERK) and p38 MAPK in a dose-dependent manner. Taken together, hemin inhibited TPA-induced COX-2 expression by altering NF-κB signaling pathway via ERK and p38 MAPK, as well as TPA-induced ODC expression in mouse skin. Thereby, hemin may be an attractive candidate for a chemopreventive agent

Economic evaluation of therapies for patients suffering from relapsed-refractory multiple myeloma in Greece

Directory of Open Access Journals (Sweden)

Fragoulakis V

2013-04-01

��€78,900 and €48,928 (95% UI €48,300–€49,556 for lenalidomide–dexamethasone and bortezomib, respectively. The incremental cost per life year gained with lenalidomide–dexamethasone was estimated at €29,415 (95% UI €23,484–€37,583 and the incremental cost per QALY gained at €38,268 (95% UI €27,001–€58,065. The probability of lenalidomide–dexamethasone being a cost-effective therapy option at a threshold three times the per capita income (€60,000 per QALY was higher than 95%. The results remained constant, without altering the conclusions, under several hypothetical scenarios. Conclusion: The combination of lenalidomide and dexamethasone may represent a cost-effective choice relative to bortezomib monotherapy for patients in Greece with previously treated multiple myeloma. Keywords: multiple myeloma, economic evaluation, lenalidomide, dexamethasone, bortezomib

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

DEFF Research Database (Denmark)

Nijhof, I. S.; Groen, R. W. J.; Noort, W. A.

2015-01-01

lenalidomide- and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumab-mediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide......Purpose: Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new...... therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination...

Polymorphisms in the genes ERCC2, XRCC3 and CD3EAP influence treatment outcome in multiple myeloma patients undergoing autologous bone marrow transplantation

DEFF Research Database (Denmark)

Vangsted, Annette; Gimsing, Peter; Klausen, Tobias W

2007-01-01

) of polymorphism in the DNA repair genes ERCC1, ERCC2 and XRCC3, and in the apoptotic genes PPP1R13L and CD3EAP in 348 patients with multiple myeloma undergoing autologous bone marrow transplantation. Carriers of the variant C-allele of ERCC2 K751Q, the variant T-allele of XRCC3 T241M and the variant A...... the outcome for patients treated with autologous stem cell transplantation. Udgivelsesdato: 2007-Mar-1...

Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model

International Nuclear Information System (INIS)

Buck, Nicole E.; Pennell, Samuel D.; Wood, Leonie R.; Pitt, James J.; Allen, Katrina J.; Peters, Heidi L.

2012-01-01

Highlights: ► Fetal cells were transplanted into a methylmalonic acid mouse model. ► Cell engraftment was detected in liver, spleen and bone marrow. ► Biochemical disease correction was measured in blood samples. ► A double dose of 5 million cells (1 week apart) proved more effective. ► 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 disorder 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 μmol/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 μmol/L (double dose of 5 million cells). In conclusion, higher levels of engraftment may be required for greater disease correction; however these studies show promising results for cell transplantation biochemical

Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model

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Buck, Nicole E., E-mail: nicole.buck@mcri.edu.au [Metabolic Research, Murdoch Childrens Research Institute, The University of Melbourne, Department of Paediatrics, Royal Children' s Hospital, Flemington Road, Parkville, VIC 3052 (Australia); Pennell, Samuel D.; Wood, Leonie R. [Metabolic Research, Murdoch Childrens Research Institute, The University of Melbourne, Department of Paediatrics, Royal Children' s Hospital, Flemington Road, Parkville, VIC 3052 (Australia); Pitt, James J. [Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children' s Hospital, Parkville (Australia); Allen, Katrina J. [Gastro and Food Allergy, Murdoch Childrens Research Institute, Parkville (Australia); Peters, Heidi L. [Metabolic Research, Murdoch Childrens Research Institute, The University of Melbourne, Department of Paediatrics, Royal Children' s Hospital, Flemington Road, Parkville, VIC 3052 (Australia)

2012-10-12

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 disorder 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 engraftment may

Paraneoplastic addisonian pigmentation and acquired ichthyosis as presenting features of multiple myeloma

International Nuclear Information System (INIS)

Dar, N.R.; Raza, N.

2010-01-01

Black brown hyperpigmentation of the mucosae, sun exposed skin, palmar creases and frictional sites (Addisonian pigmentation) is characteristic of Addison disease. However, it can also occur as a para neoplastic manifestation of tumours like bronchogenic carcinoma. Acquired ichthyosis starts later in life and can also be a para neoplastic presentation.We report a unique combination of para neoplastic Addisonian pigmentation and acquired ichthyosis as presenting features in a patient with undiagnosed multiple myeloma. To the best of our knowledge this combination of para neoplastic dermatosis has not been documented before in multiple myeloma. It is concluded that the presence of more than one suspicious dermatosis may be an indicator of being para neoplastic requiring necessary work-up. (author)

Gamabufotalin triggers c-Myc degradation via induction of WWP2 in multiple myeloma cells.

Science.gov (United States)

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.

Imaging of multiple myeloma and related monoclonal plasma cell diseases. An update; Bildgebung des multiplen Myeloms und verwandter monoklonaler Plasmazellerkrankungen. Ein Update

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Weber, Marc-Andre [Universitaetsklinikum, Heidelberg (Germany). Abt. Diagnostische und Interventionelle Radiologie; Delorme, Stefan [Deutsches Krebsforschungszentrum, Heidelberg (Germany). Abt. Radiologie; Hillengass, Jens [Universitaetsklinikum, Heidelberg (Germany). Sektion Multiples Myelom

2014-09-15

Multiple myeloma is a hematologic disorder characterized by the infiltration and proliferation of monoclonal plasma cells mainly in the bone marrow. The main symptoms are hypercalcemia, renal impairment, cytopenia/anemia and bone disease - summarized as CRAB-criteria. Symptomatic multiple myeloma is consistently preceded by asymptomatic premalignant stages called monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Staging of multiple myeloma is based on the measurement of the monoclonal protein in serum and urine as well as the assessment of impairment of hematopoiesis, renal function and mineralized bone. In the last decade the development of novel therapeutic agents has led to an increase in response rates and survival time of patients with multiple myeloma, which further stresses the value of response assessment by imaging. Cross sectional imaging like MRI and CT is currently replacing conventional radiological surveys in the initial work-up and follow-up of patients with monoclonal plasma cell diseases. The added value of MRI is to improve initial staging by unraveling a diffuse infiltration of bone marrow by plasma cells, a focal pattern or a combination of both. Furthermore, a complete remission of myeloma confirmed by MRI and CT goes along with a better prognosis compared to a complete response based only on serological parameters.

Delineation of a novel pre-B cell component in plasma cell myeloma: immunochemical, immunophenotypic, genotypic, cytologic, cell culture, and kinetic features.

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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.

IL-6-induced Bcl6 variant 2 supports IL-6-dependent myeloma cell proliferation and survival through STAT3

International Nuclear Information System (INIS)

Tsuyama, Naohiro; Danjoh, Inaho; Otsuyama, Ken-ichiro; Obata, Masanori; Tahara, Hidetoshi; Ohta, Tsutomu; Ishikawa, Hideaki

2005-01-01

IL-6 is a growth and survival factor for myeloma cells, although the mechanism by which it induces myeloma cell proliferation through gene expression is largely unknown. Microarray analysis showed that some B-cell lymphoma-associated oncogenes such as Bcl6, which is absent in normal plasma cells, were upregulated by IL-6 in IL-6-dependent myeloma cell lines. We found that Bcl6 variant 2 was upregulated by STAT3. ChIP assay and EMSA showed that STAT3 bound to the upstream region of variant 2 DNA. Expression of p53, a direct target gene of Bcl6, was downregulated in the IL-6-stimulated cells, and this process was impaired by an HDAC inhibitor. Bcl6 was knocked down by introducing small hairpin RNA, resulting in decreased proliferation and increased sensitivity to a DNA damaging agent. Thus, STAT3-inducible Bcl6 variant 2 appears to generate an important IL-6 signal that supports proliferation and survival of IL-6-dependent myeloma cells

MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells

Science.gov (United States)

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.

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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.

Science.gov (United States)

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.

Infusion of hypertonic saline (7.5% NaCl) causes minor immunological changes in normovolaemic women

DEFF Research Database (Denmark)

Petersen, Jens Aage Kølsen; Nielsen, J O D; Bendtzen, K

2004-01-01

Haemorrhagic shock is treated effectively by infusion of hypertonic saline/colloid solutions. Furthermore, previous studies found hypertonicity to affect immune responses in animals and in human blood cell cultures. It is unknown, however, whether hypertonic saline infusion affects immune responses...

Efficacy and safety of bortezomib-based retreatment at the first relapse in multiple myeloma patients: A retrospective study.

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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.

Science.gov (United States)

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.

Effects of environmental conditions on soil salinity and arid region in Tunisia

International Nuclear Information System (INIS)

Ben Ahmed, C.; Ben Rouina, B.; Boukhris, M.

2009-01-01

The shortage of water resources of good water quality is becoming an issue in the arid and semi arid regions. for this reason, the use of water resources of marginal quality such as treated wastewater and saline groundwater has become and important consideration, particularly in arid region in Tunisia, where large quantities of saline water are used for irrigation. (Author)

Intracranial involvement in plasmacytomas and multiple myeloma: a pictorial essay

Energy Technology Data Exchange (ETDEWEB)

Cerase, Alfonso; Gennari, Paola; Monti, Lucia; Venturi, Carlo [Azienda Ospedaliera Universitaria Senese, Unit of Diagnostic and Therapeutic Neuroradiology, and InterDepartmental Center of Nuclear Magnetic Resonance, Policlinico ' Santa Maria alle Scotte' , Siena (Italy); Tarantino, Annachiara; Muccio, Carmine Franco [Azienda Ospedaliera ' G. Rummo' , Unit of Neuroradiology, Department of Neurosciences, Benevento (Italy); Gozzetti, Alessandro [University of Siena, Unit of Hematology and Transplants, Policlinico ' Santa Maria alle Scotte' , Siena (Italy); Di Blasi, Arturo [Azienda Ospedaliera ' G. Rummo' , Unit of Pathology, Department of Oncology, Benevento (Italy)

2008-08-15

The purpose of this pictorial essay is to increase awareness of the clinical presentation, neuroradiological findings, treatment options, and neuroradiological follow-up of plasmacytomas and multiple myeloma with intracranial growth. This pictorial essay reviews the clinical features and neuroradiological findings in seven patients (four women, three men; age range at diagnosis 62-82 years) followed in two institutions. Six patients, one with IgG-{kappa} plasmacytoma, and five with IgG-{kappa}(n=3), IgG-{lambda}(n=1), and nonsecretory (n=1) multiple myeloma, had been seen over a period of 9 years in one institution, and the other patient with IgG-{kappa} plasmacytoma had been seen over a period of 3.5 years in the other. Intracranial involvement is rare, most frequently resulting from osseous lesions in the cranial vault, skull base, nose, or paranasal sinuses. Primary dural or leptomeningeal involvement is rarer. Some typical findings of a dural and/or osseous plasmacytoma include iso- to hyperdensity on CT scan, T1 equal to high signal intensity and T2 markedly hypointense signal on MRI, and high vascularity possibly documented on intraarterial digital subtraction angiography. However, the neuroradiological findings generally lack specificity, since they are generally no different from those of meningioma, metastasis, lymphoma, dural sarcoma, plasma cell granuloma, infectious meningitis, and leptomeningeal carcinomatosis. The spectrum of clinical and neuroradiological evaluation shows that intracranial involvement from plasmacytoma and multiple myeloma must be taken into account in the differential diagnosis of cranial osseous and meningeal disease. (orig.)

[Multiple myeloma : What has been confirmed in therapy?

Science.gov (United States)

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.

Deleterious Effects of Intra-arterial Administration of Particulate Steroids on Microvascular Perfusion in a Mouse Model.

Science.gov (United States)

Laemmel, Elisabeth; Segal, Nicolas; Mirshahi, Massoud; Azzazene, Dalel; Le Marchand, Sylvie; Wybier, Marc; Vicaut, Eric; Laredo, Jean-Denis

2016-06-01

Purpose To determine the in vivo effects of several particulate steroids on microvascular perfusion by using intravital microscopy in a mice model and to investigate the in vitro interactions between these particulate steroids and red blood cells (RBCs). Materials and Methods The study was conducted in agreement with the guidelines of the National Committee of Ethic Reflection on Animal Experimentation. By using intravital microscopy of mouse cremaster muscle, the in vivo effects of several particulate steroids on microvascular perfusion were assessed. Four to five mice were allocated to each of the following treatment groups: saline solution, dexamethasone sodium phosphate, a nonparticulate steroid, and the particulate steroids cortivazol, methylprednisolone, triamcinolone, and prednisolone. By using in vitro blood microcinematography and electron microscopy, the interactions between these steroids and human RBCs were studied. All results were analyzed by using nonparametric tests. Results With prednisolone, methylprednisolone, or triamcinolone, blood flow was rapidly and completely stopped in all the arterioles and venules (median RBC velocity in first-order arterioles, 5 minutes after administration was zero for these three groups) compared with a limited effect in mice treated with saline, dexamethasone, and cortivazol (20.3, 21.3, and 27.5 mm/sec, respectively; P effect was associated with a large decrease in the functional capillary density (4.21, 0, and 0 capillaries per millimeter for methylprednisolone, triamcinolone, or prednisolone, respectively, vs 21.0, 21.4, and 19.1 capillaries per millimeter in mice treated with saline, dexamethasone, and cortivazol, respectively; P steroids. Conclusion Several particulate steroids have an immediate and massive effect on microvascular perfusion because of formation of RBC aggregates associated with the transformation of RBCs into spiculated RBCs. (©) RSNA, 2016 Online supplemental material is available for this

Comparison of Neuroprotective Effect of Bevacizumab and Sildenafil following Induction of Stroke in a Mouse Model

Directory of Open Access Journals (Sweden)

Ivan Novitzky

2016-01-01

Full Text Available To evaluate the effect of bevacizumab and sildenafil on stroke parameters in a mouse model, middle cerebral artery occlusion was induced in male C57Bl/6 mice using an intra-arterial filament method. The filament was removed after 60 minutes, and the mice were immediately given a single intraperitoneal injection of saline, bevacizumab, or sildenafil. An additional group of mice (n=7 received bevacizumab 6 h after MCAO induction. The mice were euthanized 24 hours later and evaluated for infarct area and brain edema using triphenyltetrazolium chloride staining and ImageJ. In the saline-treated mice (n=16, total stroke volume was 19.20±6.38 mm3, mean penumbra area was 4.5±2.03 mm3, and hemispheric asymmetry was 106.5%. Corresponding values in the bevacizumab group (n=19 were 17.79±5.80 mm3, 7.3±3.5 mm3, and 108.6%; in the delayed (6 h bevacizumab injected mice (n=7 they were 9.80±8.00 mm3, 2.4±2.0 mm3, and 98.2%; and in the sildenafil group (n=16 they were 18.42±5.41 mm3, 5.7±2.02 mm3, and 109.9%. The bevacizumab group had a significantly larger mean penumbra area when given immediately and smaller total stroke area in both groups than the saline- (p=0.03 and sildenafil-treated (p=0.003 groups. Only delayed bevacizumab group had reduced edema. Bevacizumab, injected immediately or delayed after injury, exerts a neuroprotective/salvage effect, whereas immediate treatment with sildenafil does not. Inflammation may play a role in the neuroprotective effect.

The Effects of In-Hospital Intravenous Cold Saline in Postcardiac Arrest Patients Treated with Targeted Temperature Management.

Science.gov (United States)

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.

Science.gov (United States)

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.

Growth and nutrient concentrations of maize in pressmud treated saline-sodic soils

Directory of Open Access Journals (Sweden)

D. Muhammad

2009-05-01

Full Text Available n open-air pot experiment was conducted to investigate effects of pressmud (PM on saline-sodic soil reclamation, mitigating the adverse effects of saline irrigation and increase of maize (Zea mays L. growth. Pressmud was added at the rate of 0, 5, 10 and 20 Mg ha-1 to pots containing 6.8 kg air dried surface (0-20 cm soil collected from two sites. The increasing levels of PM enhanced maize plant height, shoots and roots biomass in both soils. However, the Soil 2, with initial EC and SAR of 5.43 dS m-1 and 18.67(m mol L-11/2, respectively, produced comparatively more biomass at all PM levels than Soil 1 [silty-clay loam, EC = 6.22 dS m-1, SAR = 20.72 (m mol L- 1 1/2]. The [P] in shoots was maximum at the highest PM in both the soils but the [K] increased with PM levels in Soil 1 and decreased in Soil 2 due to the dilution effect. The Soil 1 maintained several folds more [Na] in shoots and consequently lower K:Na ratio than Soil 2. The post harvest soil pH, Na, Ca+Mg and SAR in saturation extracts decreased with increasing levels of PM as compared to control. Soil 2 released more volume of leachate as compared to Soil 1 but the leachate EC and [Na] were comparable while [Ca+Mg] were relatively higher in Soil 2. The higher removal of total salts from Soil 2 resulted in lower soil pH, EC and SAR in this soil as compared to Soil 1. The increases in crop growth with each increment of PM up to 20 Mg ha-1 in the present study proved the benefits of PM in increasing crop yields and suggested that doses higher than 20 Mg PM ha-1 could be applied to the saline-sodic soils ofthe area to get maximum possible crop yields depending on soil and water quality

Water and salinity stress in grapevines: early and late changes in transcript and metabolite profiles.

Science.gov (United States)

Cramer, Grant R; Ergül, Ali; Grimplet, Jerome; Tillett, Richard L; Tattersall, Elizabeth A R; Bohlman, Marlene C; Vincent, Delphine; Sonderegger, Justin; Evans, Jason; Osborne, Craig; Quilici, David; Schlauch, Karen A; Schooley, David A; Cushman, John C

2007-04-01

Grapes are grown in semiarid environments, where drought and salinity are common problems. Microarray transcript profiling, quantitative reverse transcription-PCR, and metabolite profiling were used to define genes and metabolic pathways in Vitis vinifera cv. Cabernet Sauvignon with shared and divergent responses to a gradually applied and long-term (16 days) water-deficit stress and equivalent salinity stress. In this first-of-a-kind study, distinct differences between water deficit and salinity were revealed. Water deficit caused more rapid and greater inhibition of shoot growth than did salinity at equivalent stem water potentials. One of the earliest responses to water deficit was an increase in the transcript abundance of RuBisCo activase (day 4), but this increase occurred much later in salt-stressed plants (day 12). As water deficit progressed, a greater number of affected transcripts were involved in metabolism, transport, and the biogenesis of cellular components than did salinity. Salinity affected a higher percentage of transcripts involved in transcription, protein synthesis, and protein fate than did water deficit. Metabolite profiling revealed that there were higher concentrations of glucose, malate, and proline in water-deficit-treated plants as compared to salinized plants. The metabolite differences were linked to differences in transcript abundance of many genes involved in energy metabolism and nitrogen assimilation, particularly photosynthesis, gluconeogenesis, and photorespiration. Water-deficit-treated plants appear to have a higher demand than salinized plants to adjust osmotically, detoxify free radicals (reactive oxygen species), and cope with photoinhibition.

Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients

International Nuclear Information System (INIS)

Walker, B A; Wardell, C P; Brioli, A; Boyle, E; Kaiser, M F; Begum, D B; Dahir, N B; Johnson, D C; Ross, F M; Davies, F E; Morgan, G J

2014-01-01

Secondary MYC translocations in myeloma have been shown to be important in the pathogenesis and progression of disease. Here, we have used a DNA capture and massively parallel sequencing approach to identify the partner chromosomes in 104 presentation myeloma samples. 8q24 breakpoints were identified in 21 (20%) samples with partner loci including IGH, IGK and IGL, which juxtapose the immunoglobulin (Ig) enhancers next to MYC in 8/23 samples. The remaining samples had partner loci including XBP1, FAM46C, CCND1 and KRAS, which are important in B-cell maturation or myeloma pathogenesis. Analysis of the region surrounding the breakpoints indicated the presence of superenhancers on the partner chromosomes and gene expression analysis showed increased expression of MYC in these samples. Patients with MYC translocations had a decreased progression-free and overall survival. We postulate that translocation breakpoints near MYC result in colocalization of the gene with superenhancers from loci, which are important in the development of the cell type in which they occur. In the case of myeloma these are the Ig loci and those important for plasma cell development and myeloma pathogenesis, resulting in increased expression of MYC and an aggressive disease phenotype

Chalazia development in multiple myeloma: a new complication associated with bortezomib therapy

Directory of Open Access Journals (Sweden)

Charles Yun

2015-06-01

Full Text Available Multiple myeloma (MM is a neoplasm of plasma cells within the bone marrow. A major impact on improving survival in MM has been the use of the boronic acid-derived proteasome inhibitor bortezomib, a first-in-class selective inhibitor of the 26S proteasome. Ocular side effects of bortezomib are rare. In this report, we present 2 patients with active MM in whom persistent chalazia became a therapy-interfering complication of treatment with bortezomib. Both patients had relapsed ISS III B kappa light chain myeloma, and they were responding to treatment with bortezomib until chalazia − which caused intolerable discomfort − started. In both patients discontinuation of bortezomib was necessary for chalazia to heal, and restarting of bortezomib was associated with relapse of chalazia.

Unsuspected multiples myeloma presenting as bilateral pleural effusion – a cytological diagnosis

Directory of Open Access Journals (Sweden)

Dhingra Kajal

2007-01-01

Full Text Available Abstract Background Multiple Myeloma presenting as a pleural effusion is extremely rare. It is usually a late complication and is associated with a poor prognosis. Case Presentation A 40-year-old male presented with dyspnea and fever of six months duration. Clinical diagnosis of pulmonary tuberculosis was considered. X-ray chest showed bilateral pleural effusion. Pleural cytology revealed numerous plasma cells, some of which were binucleated and atypical. Cytological differential diagnosis included: Myelomatous effusion and Non-Hodgkin's Lymphoma deposit (Immunoblastic type. Bone marrow biopsy, serum protein electrophoresis and bone scan confirmed the diagnosis of multiple myeloma (Plasmablastic type. Conclusion Myelomatous pleural effusion as an initial presentation although extremely rare, should always be considered in presence of atypical plasma cells irrespective of age.

Oxidative stress responses in gills of tilapia (Oreochromis niloticus) at different salinities

Science.gov (United States)

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.

Multiple myeloma in Nigeria: An insight to the clinical, laboratory ...

African Journals Online (AJOL)

... the clinician to investigate along the lines of MM. Majority of patients have osteolytic lesions on X‑ray and pathological fractures, and benefit from melphalan based combinations in situations where facilities for transplant are not available. Key words: Clinical features, chemotherapy, laboratory features, multiple myeloma, ...

PI3K/Akt inhibitor LY294002 potentiates homoharringtonine antimyeloma activity in myeloma cells adhered to stromal cells and in SCID mouse xenograft.

Science.gov (United States)

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.

Science.gov (United States)

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.

Multiple myeloma presenting with a maxillary lesion as the first sign

Energy Technology Data Exchange (ETDEWEB)

Ramaiah, Kiran Kumar Kotagudda; Joshi, Vajendra; Thayi, Shilpa Ravishankar; Sathyanarayana, Pathalapate; Patil, Prashant [Dept. of Oral Medicine and Radiology, Navodaya Dental College and Hospital, Raichur (Korea, Republic of); Ahmed, Zaheer [Dept. of Public Health Dentistry, Navodaya Dental College and Hospital, Raichur (Korea, Republic of)

2015-03-15

Multiple myeloma is a clonal neoplastic proliferation of terminally differentiated B-lymphocytes involving the skeletal system in a multifocal fashion. Its oral manifestations are less common in the maxilla than in the mandible due to the lower amount of hemopoietic bone marrow in the maxilla. We report the case of a 50-year-old man who presented with a mass in the left maxillary alveolar region with tooth mobility. The mass had become enlarged after the teeth were extracted 15 days previously. Radiographs demonstrated multiple punched-out radiolucent lesions in the skull and pelvic region. Computed tomography images showed a soft tissue density mass in the left maxilla, eroding the floor and walls of the maxillary sinus. Although several analytical techniques were used to characterize the lesion, it was finally confirmed as multiple myeloma through immunohistochemistry.

Local radiotherapy for palliation in multiple myeloma patients with symptomatic bone lesions

International Nuclear Information System (INIS)

Lee, Jeong Won; Lee, Jeong Eun

2016-01-01

To evaluate the clinical outcomes of symptomatic bone lesions in patients with multiple myeloma (MM) who received local radiotherapy (LRT). Fifty-one patients with 87 symptomatic bone lesions treated via LRT were analyzed. LRT was delivered at a median total dose of 21 Gy (range, 12 to 40 Gy) in a median of 7 fractions (range, 4 to 20 fractions). The clinical outcomes of LRT and the factors affecting treatment response were assessed. After a median follow-up time of 66.7 weeks, symptom relief was achieved for 85 of 87 lesions (97.7%). The median time to symptom relief was 7 days from the start of LRT (range, 1 to 67 days). The duration of in-field failure-free survival ranged from 1.1 to 450.9 weeks (median, 66.7 weeks). The radiation dose or use of previous and concurrent chemotherapy was not significantly associated with in-field failure for LRT (p = 0.354, 0.758, and 0.758, respectively). Symptomatic bone lesions in patients with MM can be successfully treated with LRT. A higher radiation dose or the use of concurrent chemotherapy may not influence the in-field disease control. A relatively low radiation dose could achieve remission of symptoms in patients with MM

Local radiotherapy for palliation in multiple myeloma patients with symptomatic bone lesions

Energy Technology Data Exchange (ETDEWEB)

Lee, Jeong Won; Lee, Jeong Eun [Dept. of Radiation Oncology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu (Korea, Republic of)

2016-03-15

To evaluate the clinical outcomes of symptomatic bone lesions in patients with multiple myeloma (MM) who received local radiotherapy (LRT). Fifty-one patients with 87 symptomatic bone lesions treated via LRT were analyzed. LRT was delivered at a median total dose of 21 Gy (range, 12 to 40 Gy) in a median of 7 fractions (range, 4 to 20 fractions). The clinical outcomes of LRT and the factors affecting treatment response were assessed. After a median follow-up time of 66.7 weeks, symptom relief was achieved for 85 of 87 lesions (97.7%). The median time to symptom relief was 7 days from the start of LRT (range, 1 to 67 days). The duration of in-field failure-free survival ranged from 1.1 to 450.9 weeks (median, 66.7 weeks). The radiation dose or use of previous and concurrent chemotherapy was not significantly associated with in-field failure for LRT (p = 0.354, 0.758, and 0.758, respectively). Symptomatic bone lesions in patients with MM can be successfully treated with LRT. A higher radiation dose or the use of concurrent chemotherapy may not influence the in-field disease control. A relatively low radiation dose could achieve remission of symptoms in patients with MM.

The potentiality of Trichoderma harzianum in alleviation the adverse effects of salinity in faba bean plants.

Science.gov (United States)

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.

Translocation t(11;14 (q13;q32 and genomic imbalances in multi-ethnic multiple myeloma patients: a Malaysian study

Directory of Open Access Journals (Sweden)

Ivyna Bong Pau Ni

2012-09-01

Full Text Available More than 50% of myeloma cases have normal karyotypes under conventional cytogenetic analysis due to low mitotic activity and content of plasma cells in the bone marrow. We used a polymerase chain reaction (PCR-based translocation detection assay to detect BCL1/JH t(11;14 (q13;q32 in 105 myeloma patients, and randomly selected 8 translocation positive samples for array comparative genomic hybridization (aCGH analysis. Our findings revealed 14.3% of myeloma samples were positive for BCL1/JH t(11;14 (q13;q32 translocation (n=15 of 105. We found no significant correlation between this translocation with age (P=0.420, gender (P=0.317, ethnicity (P=0.066 or new/relapsed status of multiple myeloma (P=0.412 at 95% confidence interval level by x2 test. In addition, aCGH results showed genomic imbalances in all samples analyzed. Frequent chromosomal gains were identified at regions 1q, 2q, 3p, 3q, 4p, 4q, 5q, 7q, 9q, 11q, 13q, 15q, 21q, 22q and Xq, while chromosomal losses were detected at 4q and 14q. Copy number variations at genetic loci that contain NAMPT, IVNS1ABP and STK17B genes are new findings that have not previously been reported in myeloma patients. Besides fluorescence in situ hybridization, PCR is another rapid, sensitive and simple technique that can be used for detecting BCL1/JH t(11;14(q13;q32 translocation in multiple myeloma patients. Genes located in the chromosomal aberration regions in our study, such as NAMPT, IVNS1ABP, IRF2BP2, PICALM, STAT1, STK17B, FBXL5, ACSL1, LAMP2, SAMSN1 and ATP8B4 might be potential prognostic markers and therapeutic targets in the treatment and management of multiple myeloma patients positive for BCL1/JH t(11;14 (q13;q32 translocation.

Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma.

Science.gov (United States)

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.

Treatment of inflammatory bowel disease associated E. coli with ciprofloxacin and E. coli Nissle in the streptomycin-treated mouse intestine

DEFF Research Database (Denmark)

Petersen, Andreas Munk; Schjørring, Susanne; Gerstrøm, Sarah Choi

2011-01-01

E. coli belonging to the phylogenetic group B2 are linked to Inflammatory Bowel Disease (IBD). Studies have shown that antimicrobials have some effect in the treatment of IBD, and it has been demonstrated that E. coli Nissle has prophylactic abilities comparable to 5-aminosalicylic acid (5-ASA......) therapy in ulcerative colitis. The objective of this study was to test if ciprofloxacin and/or E. coli Nissle could eradicate IBD associated E. coli in the streptomycin-treated mouse intestine....

New techniques to control salinity-wastewater reuse interactions in golf courses of the Mediterranean regions

Science.gov (United States)

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

T-Stimulator effect on cotton protein composition and synthesis in salinization stress

International Nuclear Information System (INIS)

Ibragimova, E.A.; Nazirova, E.R.; Samarkhodjaeva, N.R.; Nalbandyan, A.A.; Babaev, T.A.

2004-01-01

Full text: T-stimulator was established to possess a wide spectrum of physiological effects, to enhance plant adaptation to thermal stress and to increase plant resistance to pathogens. Plant adaptation to unfavorable conditions manifests in changes in many links of metabolism, that of proteins included. We studied effect of cottonseed treatment with T-stimulator on composition and synthesis of plasma membrane proteins upon chloride salinization by means of the radioisotope method. Electrophoretic fractionation of cottonseed plasma membrane proteins showed absence of more than 40 polypeptides with molecular mass from 10 to more than 100 kDa in the cotton root membranes. Major fractions-polypeptides with molecular mass of 61, 53, 46, 25, 21, 20 and 18 kDa constitute about 50% of the total polypeptide composition. The salinization significantly affects the total membrane protein output, proportion of some polypeptides and their synthesis rate. Analysis of phoreogram radioautographs showed that 2-hour exposition of cotton roots to 35 S methionine suppresses synthesis of major polypeptides with molecular mass of 63, 61 and 53 kDa, that of low molecular polypeptides (46, 20, 18 kDa) increasing. Changes in the proportion of major polypeptides in cotton plasma membranes, reduction in rate of biosynthesis of high molecular fractions with the general suppression of label inclusion in the membrane fraction are the evidence for a disturbance in biosynthesis of some membrane proteins in cotton tissue cells upon salinization. The inhibiting effect of salinization on the protein-synthesizing system was observed in plants treated with T-stimulator, but the rate of synthesis in plasma membranes of the treated plants was found significantly higher. The activation of some plasma membrane proteins under T-stimulator effect suggests an association with the increase in adaptation of the treated plants to the disturbing effect of salinization

Validation of interphase fluorescence in situ hybridization (iFISH for multiple myeloma using CD138 positive cells

Directory of Open Access Journals (Sweden)

Renata Kiyomi Kishimoto

2016-06-01

Full Text Available ABSTRACT BACKGROUND: Multiple myeloma is a plasma cell neoplasm with acquired genetic abnormalities of clinical and prognostic importance. Multiple myeloma differs from other hematologic malignancies due to a high fraction of low proliferating malignant plasma cells and the paucity of plasma cells in bone marrow aspiration samples, making cytogenetic analysis a challenge. An abnormal karyotype is found in only one-third of patients with multiple myeloma and interphase fluorescence in situ hybridization is the most useful test for studying the chromosomal abnormalities present in almost 90% of cases. However, it is necessary to study the genetic abnormalities in plasma cells after their identification or selection by morphology, immunophenotyping or sorting. Other challenges are the selection of the most informative FISH panel and determining cut-off levels for FISH probes. This study reports the validation of interphase fluorescence in situ hybridization using CD138 positive cells, according to proposed guidelines published by the European Myeloma Network (EMN in 2012. METHOD: Bone marrow samples from patients with multiple myeloma were used to standardize a panel of five probes [1q amplification, 13q14 deletion, 17p deletion, t(4;14, and t(14;16] in CD138+ cells purified by magnetic cell sorting. RESULTS: This test was validated with a low turnaround time and good reproducibility. Five of six samples showed genetic abnormalities. Monosomy/deletion 13 plus t(4;14 were found in two cases. CONCLUSION: This technique together with magnetic cell sorting is effective and can be used in the routine laboratory practice. In addition, magnetic cell sorting provides a pure plasma cell population that allows other molecular and genomic studies.

Multiple myeloma in Nigeria: An insight to the clinical, laboratory ...

African Journals Online (AJOL)

The average percentage of bone marrow plasmacytosis at diagnosis ... of autologous stem cell transplantation (ASCT) for white, black, and ... Hospital Cancer Registry and Data Collation Institute. .... Figure 1: (a) Kaplan‑Meier survival curve for all myeloma patients, (b) Kaplan‑Meier survival curve for the different sexes b a ...

Bacteria as a target of human milk and myeloma IgA

Czech Academy of Sciences Publication Activity Database

Přibylová, Jaroslava; Moldoveanu, Z.; Mestecky, J.; Tlaskalová, Helena

2009-01-01

Roč. 39, - (2009), s. 760-760 ISSN 0014-2980. [European Congress of Immunology /2./. 13.09.2009-16.09.2009, Berlin] Institutional research plan: CEZ:AV0Z50200510 Keywords : human milk * myeloma IgA Subject RIV: EC - Immunology

Reassessment of the relationship between M-protein decrement and survival in multiple myeloma.

Science.gov (United States)

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.

Science.gov (United States)

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

A novel signaling pathway associated with Lyn, PI 3-kinase and Akt supports the proliferation of myeloma cells

Energy Technology Data Exchange (ETDEWEB)

Iqbal, Mohd S. [Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505 (Japan); Enteric and Food Microbiology Laboratory, Laboratory Sciences Division, International Center for Diarrhoeal Disease Research, Bangladesh, P.O. Box 128, Dhaka 1000 (Bangladesh); Tsuyama, Naohiro [Department of Analytical Molecular Medicine and Devices, Division of Frontier Medical Science, Graduate School of Medical Sciences, Hiroshima University, Hiroshima, Hiroshima 734-8553 (Japan); Obata, Masanori [Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505 (Japan); Ishikawa, Hideaki, E-mail: hishika@yamaguchi-u.ac.jp [Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505 (Japan)

2010-02-12

Interleukin-6 (IL-6) is a growth factor for human myeloma cells. We have recently found that in myeloma cells the activation of both signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase (ERK) 1/2 is not sufficient for the IL-6-induced proliferation, which further requires the activation of the src family kinases, such as Lyn. Here we showed that the Lyn-overexpressed myeloma cell lines had the higher proliferative rate with IL-6 and the enhanced activation of the phosphatidylinositol (PI) 3-kinase and Akt. The IL-6-induced phosphorylation of STAT3 and ERK1/2 was not up-regulated in the Lyn-overexpressed cells, indicating that the Lyn-PI 3-kinase-Akt pathway is independent of these pathways. The PI 3-kinase was co-precipitated with Lyn in the Lyn-overexpressed cells of which proliferation with IL-6 was abrogated by the specific inhibitors for PI 3-kinase or Akt, suggesting that the activation of the PI 3-kinase-Akt pathway associated with Lyn is indeed related to the concomitant augmentation of myeloma cell growth. Furthermore, the decreased expression of p53 and p21{sup Cip1} proteins was observed in the Lyn-overexpressed cells, implicating a possible downstream target of Akt. This study identifies a novel IL-6-mediated signaling pathway that certainly plays a role in the proliferation of myeloma cells and this novel mechanism of MM tumor cell growth associated with Lyn would eventually contribute to the development of MM treatment.

Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma.

Science.gov (United States)

Canitano, Andrea; Iessi, Elisabetta; Spugnini, Enrico Pierluigi; Federici, Cristina; Fais, Stefano

2016-07-01

Multiple Myeloma (MM) is the second most common hematological malignancy and is responsive to a limited number of drugs. Unfortunately, to date, despite the introduction of novel drugs, no relevant increase in survival rates has been obtained. Proton pump inhibitors (PPIs) have been shown to have significant antitumor action as single agents as well as in combination with chemotherapy. This study investigates the potential anti-tumor effectiveness of two PPIs, Lansoprazole and Omeprazole, against human MM cells. We found that Lansoprazole exerts straightforward efficacy against myeloma cells, even at suboptimal concentrations (50 µM), while Omeprazole has limited cytotoxic action. The Lansoprazole anti-MM effect was mostly mediated by a caspase-independent apoptotic-like cytotoxicity, with only a secondary anti-proliferative action. This study provides clear evidence supporting the use of Lansoprazole in the strive against MM with an efficacy proven much higher than current therapeutical approaches and without reported side effects. It is however conceivable that, consistent with the results obtained in other human tumors, Lansoprazole may well be combined with existing anti-myeloma therapies with the aim to improve the low level of efficacy of the current strategies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci.

Science.gov (United States)

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 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.

The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma

NARCIS (Netherlands)

Lokhorst, Henk M.; Wu, Kalung; Verdonck, Leo F.; Laterveer, Laurens L.; van de Donk, Niels W. C. J.; van Oers, Marinus H. J.; Cornelissen, Jan J.; Schattenberg, Anton V.

2004-01-01

The graft-versus-myeloma (GVM) effect of donor lymphocyte infusions (DLIs) is well established. We now report the outcome of DLI in 54 patients with relapsed myeloma following allogeneic transplantation. Twenty-eight patients (52%) responded, 19 patients (35%) with a partial response and 9 patients

Attenuation of prostaglandin E2 elimination across the mouse blood-brain barrier in lipopolysaccharide-induced inflammation and additive inhibitory effect of cefmetazole

Directory of Open Access Journals (Sweden)

Akanuma Shin-ichi

2011-10-01

Full Text Available Abstract Background Peripheral administration of lipopolysaccharide (LPS induces inflammation and increases cerebral prostaglandin E2 (PGE2 concentration. PGE2 is eliminated from brain across the blood-brain barrier (BBB in mice, and this process is inhibited by intracerebral or intravenous pre-administration of anti-inflammatory drugs and antibiotics such as cefmetazole and cefazolin that inhibit multidrug resistance-associated protein 4 (Mrp4/Abcc4-mediated PGE2 transport. The purpose of this study was to examine the effect of LPS-induced inflammation on PGE2 elimination from brain, and whether antibiotics further inhibit PGE2 elimination in LPS-treated mice. Methods [3H]PGE2 elimination across the BBB of intraperitoneally LPS-treated mice was assessed by the brain efflux index (BEI method. Transporter protein amounts in brain capillaries were quantified by liquid chromatography-tandem mass spectrometry. Results The apparent elimination rate of [3H]PGE2 from brain was lower by 87%, in LPS-treated mice compared with saline-treated mice. The Mrp4 protein amount was unchanged in brain capillaries of LPS-treated mice compared with saline-treated mice, while the protein amounts of organic anion transporter 3 (Oat3/Slc22a8 and organic anion transporting polypeptide 1a4 (Oatp1a4/Slco1a4 were decreased by 26% and 39%, respectively. Either intracerebral or intravenous pre-administration of cefmetazole further inhibited PGE2 elimination in LPS-treated mice. However, intracerebral or intravenous pre-administration of cefazolin had little effect on PGE2 elimination in LPS-treated mice, or in LPS-untreated mice given Oat3 and Oatp1a4 inhibitors. These results indicate that peripheral administration of cefmetazole inhibits PGE2 elimination across the BBB in LPS-treated mice. Conclusion PGE2 elimination across the BBB is attenuated in an LPS-induced mouse model of inflammation. Peripheral administration of cefmetazole further inhibits PGE2 elimination in LPS-treated

Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells.

Science.gov (United States)

Kiraz, Yağmur; Neergheen-Bhujun, Vidushi S; Rummun, Nawraj; Baran, Yusuf

2016-02-01

Multiple myeloma is of great concern since existing therapies are unable to cure this clinical condition. Alternative therapeutic approaches are mandatory, and the use of plant extracts is considered interesting. Punica granatum and its derived products were suggested as potential anticancer agents due to the presence of bioactive compounds. Thus, polypenolic-rich extracts of the non-edible parts of P. granatum were investigated for their antiproliferative and apoptotic effects on U266 multiple myeloma cells. We demonstrated that there were dose-dependent decreases in the proliferation of U266 cells in response to P. granatum extracts. Also, exposure to the extracts triggered apoptosis with significant increases in loss of mitochondrial membrane potential in U266 cells exposed to the leaves and stem extracts, while the flower extract resulted in slight increases in loss of MMP. These results were confirmed by Annexin-V analysis. These results documented the cytotoxic and apoptotic effects of P. granatum extracts on human U266 multiple myeloma cells via disruption of mitochondrial membrane potential and increasing cell cycle arrest. The data suggest that the extracts can be envisaged in cancer chemoprevention and call for further exploration into the potential application of these plant parts.

Expression of Mucin-1 in multiple myeloma and its precursors

DEFF Research Database (Denmark)

Andrulis, Mindaugas; Ellert, Elena; Mandel, Ulla

2014-01-01

AIMS: Recent reports suggest a possible role for extracellular (MUC1N) and transmembrane (MUC1C) subunits of Mucin 1 (MUC1) in the pathogenesis of multiple myeloma (MM). Nuclear translocation of MUC1C is involved in activation of various oncogenic signalling pathways and both MUC1 subunits...

Multiple myeloma, leukemia, and breast cancer among the US radium dial workers

International Nuclear Information System (INIS)

Stebbings, J.H.; Lucas, H.F.; Stehney, A.F.

1984-01-01

The relationships of radium exposure to mortality from multiple myeloma, leukemia, and breast cancer were studied in three cohorts of female dial workers defined by year of first employment. A three-fold excess risk of multiple myeloma occurred in the pre-1930 cohort; however, analyses of body burdens and durations of employment suggest that external radiation was more likely to have been responsible than was internal radium. Leukemia incidence and mortality have not been elevated overall among the female dial workers, either in the pre-1930 or the post-1930 cohorts, but cases have tended to occur early and in subjects with higher body burdens of radium. Extensive analyses of breast cancer data have uncovered several observations weighing against a causal interpretation of the association between radium body burdens and breast cancer

Twelve cases of multiple myeloma in Nagasaki (especially seven atomic bombing casualty cases). [In Japanese

Energy Technology Data Exchange (ETDEWEB)

Ichimaru, M; Yasuhi, S; Ouchuru, S

1963-12-01

Since 1958, there have been 12 cases of multiple myeloma in Nagasaki, and among them were 7 cases representing atomic bombing casualties, with 3 cases being with 2 km distance from the hypocenter. The age of onset was between 51 and 69 years, and the sex ratio was 8:4, it occurring mostly in males. Symptoms were predominantly low back pain and chest pain caused by the bone changes in 8 cases. Two cases complained of general malaise and palpitation which resulted from anemia. One developed persistent epistaris, and another complained of diplopia caused by the paralysis of the oculomotor nerve. Peripheral blood in all cases showed anemia, 9 with hyperchromic and 3 with normochromic or hypochromic anemia. Low platelet counts were seen in 3 cases. All showed leukopenia. All cases showed typical ..gamma..-globulin change with a myeloma peak, and in 4 cases showed an increase of ..beta..-globulin. Bence-Jones proteinuria was present in 5 cases. Average course was 1 year 4 months. Among complications, myeloma nephrosis, aplastic anemia, and pneumonia were the most important ones.

Intramuscular manifestation of non-Hodgkin lymphoma and myeloma: Prevalence, clinical signs, and computed tomography features

Energy Technology Data Exchange (ETDEWEB)

Surov, Alexey; Spielmann, Rolf-Peter; Behrmann, Curd (Dept. of Radiology, Martin Luther Univ., Halle-Wittenberg (Germany)), e-mail: alex.surow@medizin.uni-halle.de; Holzhausen, Hans-Juergen (Dept. of Hematology/Oncology, Martin Luther Univ., Halle-Wittenberg (Germany)); Arnold, Dirk (Dept. of Pathology, Martin Luther Univ., Halle-Wittenberg (Germany)); Schmidt, Joerg (Dept. of Medical Statistics and Controlling, Martin Luther Univ., Halle-Wittenberg (Germany))

2010-01-15

Background: Intramuscular manifestations of malignant immuno proliferative diseases (IMMID) are very rare. Purpose: To determine the prevalence and the clinical features of IMMID in a large series of patients, and to analyze their radiological appearances. Material and Methods: Between 1997 and 2007, 20 patients with IMMID (non-Hodgkin lymphoma [NHL], n=14, and myeloma, n=6) were identified. All patients underwent computed tomography (CT). In five cases, magnetic resonance imaging (MRI) was additionally performed. Results: Clinically, 16 patients presented with local pain and soft-tissue swelling. In four patients, IMMID was found incidentally. The most common site was the erector spinae muscle, followed by the iliopsoas and pelvic muscles. In 13 cases of IMMID, diffuse mass-forming muscle infiltration was found. Focal intramuscular masses were identified in seven cases. Conclusion: NHL mostly manifests as diffuse muscle enlargement, whereas myelomas form focal intramuscular masses. Nevertheless, CT and MR appearances are nonspecific and can be misinterpreted as muscle sarcoma or inflammatory disease. Although rare, muscle involvement should be considered in the differential diagnosis of muscle disorders in patients with non-Hodgkin lymphoma and myeloma

N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

NARCIS (Netherlands)

Groen, Richard W. J.; de Rooij, Martin F. M.; Kocemba, Kinga A.; Reijmers, Rogier M.; de Haan-Kramer, Anneke; Overdijk, Marije B.; Aalders, Linda; Rozemuller, Henk; Martens, Anton C. M.; Bergsagel, P. Leif; Kersten, Marie José; Pals, Steven T.; Spaargaren, Marcel

2011-01-01

Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays

N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

NARCIS (Netherlands)

Groen, R.W.J.; de Rooij, M.F.M.; Kocemba, K.A.; Reijmers, R.M.; de Haan-Kramer, A.; Overdijk, M.B.; Aalders, L.; Rozemuller, H.; Martens, A.C.M.; Bergsagel, P.L.; Kersten, M.J.; Pals, S.T.; Spaargaren, M.

2011-01-01

Background Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

DEFF Research Database (Denmark)

Drent, Esther; Groen, Richard W. J.; Noort, Willy A. Noort

2016-01-01

Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody...... sequences to generate second-generation retroviral CD38- chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence......, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite...

Cytotoxic Effect on Human Myeloma Cells and Leukemic Cells by the Agaricus blazei Murill Based Mushroom Extract, Andosan™

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Jon-Magnus Tangen

2017-01-01

Full Text Available Agaricus blazei Murill is an edible mushroom of the Basidiomycetes family, which has been found to contain a number of compounds with antitumor properties, such as proteoglycans and ergosterol. In the present investigation, we show that the commercial mushroom product Andosan, which contains 82.4% Agaricus blazei Murill, together with medicinal mushrooms Hericium erinaceus (14.7% and Grifola frondosa (2.9%, has a cytotoxic effect on primary myeloma cells, other myeloma cell lines, and leukemia cell lines in vitro. Although the exact content and hence the mechanisms of action of the Andosan extract are unknown, we have found in this investigation indications of cell cycle arrest when myeloma cell lines are cultivated with Andosan. This may be one of the possible explanations for the cytotoxic effects of Andosan.

Recent advances in multiple myeloma: a Korean perspective.

Science.gov (United States)

Hong, Junshik; Lee, Jae Hoon

2016-09-01

Epidemiologically, multiple myeloma (MM) is a malignant disorder of plasma cells with a higher incidence among Western populations than among Asians. However, there is growing evidence of a recent increase in the age-standardized incidence rate (ASR) of MM in Asian countries, particularly Korea. Application of novel agents has resulted in significant improvement of treatment outcomes, and the advances are ongoing with the recent introduction and U.S. Food and Drug Administration's approval of newer agents, including carfilzomib, ixazomib, elotuzumab, and daratumumab. In concert with the technical advances in the cytogenetic and molecular diagnostics of MM, modifications of its diagnosis and staging system have been attempted for better risk stratification. The modified diagnostic criteria from the International Myeloma Working Group in 2014 enabled a strategy of more active treatment for some patients with smoldering MM, with an ultra-high risk of progression, and fine-tuned the definition of end-organ damage, known as CRAB (hypercalcemia, renal insufficiency, anemia, and bone lesions). Considering Korea's trend of aging at an unprecedented rate, we can expect that the ASR of MM will maintain a gradual increase for many years to come; therefore, MM will be a cancer of critical importance from both medical and socioeconomic perspectives in Korea.

Influence of intramuscular granisetron on experimentally induced muscle pain by acidic saline.

Science.gov (United States)

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 granisetron on pain duration was significant only in women (P granisetron has a pain-reducing effect on experimentally induced muscle pain by repeated acidic saline injection. © 2013 John Wiley & Sons Ltd.

Progress in decontamination by halophilic microorganisms in saline wastewater and soil

International Nuclear Information System (INIS)

Zhuang Xuliang; Han Zhen; Bai Zhihui; Zhuang Guoqiang; Shim Hojae

2010-01-01

Environments with high-salt concentrations are often populated by dense microbial communities. Halophilic microorganisms can be isolated from different saline environments and different strains even belonging to the same genus have various applications. Wastewater and soil rich in both organic matter and salt are difficult to treat using conventional microorganisms typically found in wastewater treatment and soil bioremediation facilities. Studies on decontaminative capabilities and decontamination pathways of organic contaminants (i.e., aromatic compounds benzoate, cinnamate, 3-phenylpropionate, 4-hydroxybenzoic acid), heavy metals (i.e., tellurium, vanadium), and nutrients in the biological treatment of saline wastewater and soil by halophilic microorganisms are discussed in this review. - Review on the decontaminative capabilities of halophilic microorganisms in saline wastewater and soil.

Progress in decontamination by halophilic microorganisms in saline wastewater and soil

Energy Technology Data Exchange (ETDEWEB)

Zhuang Xuliang, E-mail: xlzhuang@rcees.ac.c [Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Haidian District, Beijing 100085 (China); Bureau of Science and Technology for Resources and Environment, Chinese Academy of Sciences, Beijing 100864 (China); Han Zhen [Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Haidian District, Beijing 100085 (China); Graduate University of Chinese Academy of Sciences, Beijing 100049 (China); Bai Zhihui; Zhuang Guoqiang [Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, Haidian District, Beijing 100085 (China); Shim Hojae [Department of Civil and Environmental Engineering, Faculty of Science and Technology, University of Macau, Macau (China)

2010-05-15

Environments with high-salt concentrations are often populated by dense microbial communities. Halophilic microorganisms can be isolated from different saline environments and different strains even belonging to the same genus have various applications. Wastewater and soil rich in both organic matter and salt are difficult to treat using conventional microorganisms typically found in wastewater treatment and soil bioremediation facilities. Studies on decontaminative capabilities and decontamination pathways of organic contaminants (i.e., aromatic compounds benzoate, cinnamate, 3-phenylpropionate, 4-hydroxybenzoic acid), heavy metals (i.e., tellurium, vanadium), and nutrients in the biological treatment of saline wastewater and soil by halophilic microorganisms are discussed in this review. - Review on the decontaminative capabilities of halophilic microorganisms in saline wastewater and soil.

Development of a mouse-feline chimeric antibody against feline tumor necrosis factor-alpha

Science.gov (United States)

DOKI, Tomoyoshi; TAKANO, Tomomi; HOHDATSU, Tsutomu

2016-01-01

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. PMID:27264736

Whole-Body MRI versus PET in assessment of multiple myeloma disease activity.

LENUS (Irish Health Repository)

Shortt, Conor P

2009-04-01

The purpose of this study was to compare FDG PET; whole-body MRI; and the reference standard, bone marrow aspiration and biopsy, to determine the best imaging technique for assessment of disease activity in multiple myeloma.

Recent advances in multiple myeloma: a Korean perspective

OpenAIRE

Hong, Junshik; Lee, Jae Hoon

2016-01-01

Epidemiologically, multiple myeloma (MM) is a malignant disorder of plasma cells with a higher incidence among Western populations than among Asians. However, there is growing evidence of a recent increase in the age-standardized incidence rate (ASR) of MM in Asian countries, particularly Korea. Application of novel agents has resulted in significant improvement of treatment outcomes, and the advances are ongoing with the recent introduction and U.S. Food and Drug Administration?s approval of...

CG13250, a novel bromodomain inhibitor, suppresses proliferation of multiple myeloma cells in an orthotopic mouse model

International Nuclear Information System (INIS)

Imayoshi, Natsuki; Yoshioka, Makoto; Chauhan, Jay; Nakata, Susumu; Toda, Yuki; Fletcher, Steven; Strovel, Jeffrey W.; Takata, Kazuyuki; Ashihara, Eishi

2017-01-01

Multiple myeloma (MM) is characterized by the clonal proliferation of neoplastic plasma cells. Despite a stream of new molecular targets based on better understanding of the disease, MM remains incurable. Epigenomic abnormalities contribute to the pathogenesis of MM. bromodomain 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, binds to acetylated histones during M/G1 transition in the cell cycle promoting progression to S phase. In this study, we investigated the effects of a novel BET inhibitor CG13250 on MM cells. CG13250 inhibited ligand binding to BRD4 in a dose-dependent manner and with an IC 50 value of 1.1 μM. It inhibited MM proliferation in a dose-dependent manner and arrested cells in G1, resulting in the induction of apoptosis through caspase activation. CG13250 inhibited the binding of BRD4 to c-MYC promoter regions suppressing the transcription of the c-MYC gene. Administered in vivo, CG13250 significantly prolonged survival of an orthotopic MM-bearing mice. In conclusion, CG13250 is a novel bromodomain inhibitor that is a promising molecular targeting agent against MM. - Highlights: • A novel bromodomain inhibitor CG13250 suppresses MM cell proliferation. • CG13250 decreases C-MYC expression, resulting in the induction of apoptosis. • CG13250 prolongs the survivals of MM-bearing mice.

MULTIPLE MYELOMA-LIKE SPINAL MRI FINDINGS IN SKELETAL FLUOROSIS: AN UNUSUAL PRESENTATION OF FLUORIDE TOXICITY IN HUMAN

Directory of Open Access Journals (Sweden)

Javed Ahsan Quadri

2016-11-01

Full Text Available Endemic fluorosis is a worldwide environmental problem due to excessive fluoride, commonly due to increased drinking water fluoride levels but sometimes due to other sources such food with high fluoride content. In India, 21 of the 35 states are known to have health problems associated with fluoride toxicity. The present report is a case of a 50-year-old female who was seen with progressive spinal complications and a MRI of the spine suggestive of multiple myeloma. The MRI of the lumbo-sacral spine showed a diffuse and heterogeneous marrow signal of the lower dorsal and lumbo-sacral vertebrae. The MRI was also suggestive of coarse trabeculation and appeared predominantly hypointanse on the T1W image and had mixed signal intensity on the T2W image. These findings were suggestive of neoplastic bone marrow infiltration and the presence of a proliferative disorder, with multiple myeloma being the most likely. During the patient workup, it was found that other family members were also having similar complications and, after investigation of these family members, it was found that they are suffering from systemic fluorosis. The patient was then evaluated for skeletal fluorosis and this condition was found to be present. Multiple myeloma was ruled out by the finding of a negative serum protein electrophoresis. The spinal complications appeared to be mainly due to the compression of the spinal cord and nerve roots by protruding osteophytes, thickening of the posterior longitudinal ligament, and thickening of the ligamentum flavum resulting in a compressive myeloradiculopathy and compressive myelopathy. The finding of multiple myeloma- like findings on the spinal MRI in association with skeletal fluorosis was considered to be a very rare event. This case report underlines the need to consider the presence of spinal skeletal fluorosis when evaluating spinal complications with unusual pseudo-multiple myeloma-like changes on the spinal MRI.

Treatment of patients with multiple myeloma over 65 yr: more tolerability or better response?

Science.gov (United States)

Tarkun, Pinar; Atalay, Figen; Atesoglu, Elif Birtas; Mehtap, Ozgur; Simsek, Melih; Terzi, Esra; Geduk, Ayfer; Balli, Fatih; Batman, Adnan; Baydemir, Canan; Hacihanefioglu, Abdullah

2015-05-01

Two-thirds of newly diagnosed patients with multiple myeloma (MM) are over 65 yr and/or physically unfit. Such patients are not eligible for high-dose chemotherapy or stem cell transplantation. The treatment aims in these patients should be to prolong survival by obtaining the best possible response, while maintaining good tolerability. The aim of our study was to evaluate the response to treatment and treatment-related toxicities in patients treated with conventional and novel protocols. The records of 138 elderly (≥65 yr) patients with MM were retrospectively evaluated. The median overall survival(OS) of the patients was 46 months. The median progression-free survival (PFS) was 18 months. The OS and PFS of the patients treated with the conventional protocols did not differ significantly from those treated with the novel protocols. The statistical analysis of the quality of the response to the treatment with the conventional and novel therapies showed that complete remission (CR), combined with a very good partial response (VGPR), was significantly higher in the latter. However, the toxicities were higher in the novel treatment group. The novel drug protocols significantly increased the quality of the responses of elderly patients with MM to therapy, but they did not increase the patients' tolerability. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial

DEFF Research Database (Denmark)

Gimsing, Peter; Carlson, Kristina; Turesson, Ingemar

2010-01-01

Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effec...

The myeloma stem cell concept, revisited: From phenomenology to operational terms

NARCIS (Netherlands)

H.E. Johnsen (Hans); M. Bøgsted (Martin); A. Schmitz; Bødker, J.S. (Julie Støve); El-Galaly, T.C. (Tarec Christoffer); Johansen, P. (Preben); P. Valent (Peter); Zojer, N. (Niklas); E. van Valckenborgh (Els); Vanderkerken, K. (Karin); M. van Duin (Mark); P. Sonneveld (Pieter); M. Perez-Andres; A. Orfao (Alberto); K. Dybkær (Karen)

2016-01-01

textabstractThe concept of the myeloma stem cell may have important therapeutic implications, yet its demonstration has been hampered by a lack of consistency in terms and definitions. Here, we summarize the current documentation and propose single-cell in vitro studies for future translational

Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma

Directory of Open Access Journals (Sweden)

Larysa Sanchez

2016-06-01

Full Text Available Abstract Daratumumab is a human monoclonal antibody that targets CD38, a cell surface protein that is overexpressed on multiple myeloma (MM cells. Preclinical studies have shown that daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC, antibody-dependent cell-mediated cytotoxicity (ADCC, antibody-dependent cellular phagocytosis (ADCP, and apoptosis. Given the encouraging efficacy and acceptable safety profile of daratumumab demonstrated in clinical trials, daratumumab has emerged as a novel treatment option for myeloma and became the first monoclonal antibody approved by the FDA for the treatment of MM.

Oral carcinogenesis is not achieved in different carcinogen-treated PAI-1 transgenic and wild-type mouse models.

Science.gov (United States)

Avgoustidis, Dimitris; Nisyrios, Themistoklis; Nkenke, Emeka; Lijnen, Roger; Ragos, Vassilis; Perrea, Despina; Donta, Ismini; Vaena, Apostolia; Yapijakis, Christos; Vairaktaris, Eleftherios

2012-01-01

In an effort to assess the role of plasminogen activator inhibitor-1 (PAI-1) in oral squamous cancer development and progression, two different carcinogen treatment protocols were conducted. Protocol I included mice from a PAI-1 transgenic (Tg) breed (n=56) and their wild-type (WT) counterparts (n=56), divided into one control group and two main experimental groups, treated with 7,12-dimethylbenz[a]anthracene (DMBA) for 8 and 16 weeks, respectively. Protocol II included the same number and types of animals and groups, which were similarly treated with 4-Nitroquinoline 1-oxide (4-NQO) in drinking water. Two drugs that affect plasma PAI-1 levels, enalapril and pravastatin, were administered to certain subgroups of animals in both protocols. None of the animals developed macroscopically-visible oral cancer lesions. Eleven animals under Protocol I and 52 animals under Protocol II died. Skin lesions were noted only in DMBA-treated animals (n=9). Almost all animals administered with 4-NQO developed alopecia and lost weight, while two of them developed stomach tumours, and one female mouse developed a large ovarian cyst. Transgenic mice may respond differently when used in well-established carcinogen models and oral carcinogenesis is hard to achieve in these rodents.

Do laboratory salinity tolerances of freshwater animals correspond with their field salinity?

Energy Technology Data Exchange (ETDEWEB)

Kefford, Ben J.; Papas, Phil J.; Metzeling, Leon; Nugegoda, Dayanthi

2004-06-01

The degree to which laboratory derived measures of salinity tolerance reflect the field distributions of freshwater biota is uncertain. In this paper we compare laboratory-derived acute salinity tolerance (LC{sub 50} values) of freshwater macroinvertebrates (range 5.5-76 mS/cm) and fish (range 2.7-82 mS/cm) from southeastern Australia with the salinity from which they have been collected in the field. Only 4% of the macroinvertebrates were collected at salinity levels substantially higher than their 72-h LC{sub 50} obtained from directly transferring animals from low salinity water to the water they were tested (direct transfer LC{sub 50}). This LC{sub 50} value was correlated with the maximum salinity at which a species had been collected. For common macroinvertebrates, the maximum field salinity was approximated by the direct transfer 72-h LC{sub 50}. For adult freshwater fish, 21% of species were collected at salinities substantially greater than their acute direct transfer LC{sub 50} and there was a weak relationship between these two variables. Although there was a weak correlation between the direct transfer LC{sub 50} of early life stages of freshwater fish and the maximum field salinity, 58% of the field distribution were in higher than their LC{sub 50} values. In contrast, LC{sub 50} determined from experiments that acclimated adult fish to higher salinity (slow acclimation) provided a better indication of the field distribution: with only one fish species (7%) being in conflict with their maximum field salinity and a strong positive relationship between these variables. This study shows that laboratory measures of acute salinity tolerance can reflect the maximum salinity that macroinvertebrate and fish species inhabit and are consistent with some anecdotal observations from other studies. - Acute laboratory salinity tolerances relate to maximum salinity where organisms occur in nature.

Do laboratory salinity tolerances of freshwater animals correspond with their field salinity?

International Nuclear Information System (INIS)

Kefford, Ben J.; Papas, Phil J.; Metzeling, Leon; Nugegoda, Dayanthi

2004-01-01

The degree to which laboratory derived measures of salinity tolerance reflect the field distributions of freshwater biota is uncertain. In this paper we compare laboratory-derived acute salinity tolerance (LC 50 values) of freshwater macroinvertebrates (range 5.5-76 mS/cm) and fish (range 2.7-82 mS/cm) from southeastern Australia with the salinity from which they have been collected in the field. Only 4% of the macroinvertebrates were collected at salinity levels substantially higher than their 72-h LC 50 obtained from directly transferring animals from low salinity water to the water they were tested (direct transfer LC 50 ). This LC 50 value was correlated with the maximum salinity at which a species had been collected. For common macroinvertebrates, the maximum field salinity was approximated by the direct transfer 72-h LC 50 . For adult freshwater fish, 21% of species were collected at salinities substantially greater than their acute direct transfer LC 50 and there was a weak relationship between these two variables. Although there was a weak correlation between the direct transfer LC 50 of early life stages of freshwater fish and the maximum field salinity, 58% of the field distribution were in higher than their LC 50 values. In contrast, LC 50 determined from experiments that acclimated adult fish to higher salinity (slow acclimation) provided a better indication of the field distribution: with only one fish species (7%) being in conflict with their maximum field salinity and a strong positive relationship between these variables. This study shows that laboratory measures of acute salinity tolerance can reflect the maximum salinity that macroinvertebrate and fish species inhabit and are consistent with some anecdotal observations from other studies. - Acute laboratory salinity tolerances relate to maximum salinity where organisms occur in nature

No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

International Nuclear Information System (INIS)

Vangsted, Annette J; Rasmussen, Henrik B; Søeby, Karen; Klausen, Tobias W; Abildgaard, Niels; Andersen, Niels F; Gimsing, Peter; Gregersen, Henrik; Vogel, Ulla; Werge, Thomas

2010-01-01

The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the potential influence of different polymorphisms in the CYP enzymes on the outcome of treatment. Data was analyzed from 348 patients undergoing high-dose treatment and stem cell support in Denmark in 1994 to 2004. Clinical information on relapse treatment in 243 individual patients was collected. The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion), *6, and CYP2D6 gene duplication. In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment. We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome

Uptake of yeast (Saccharomyces boulardii) in normal and rotavirus treated intestine.

Science.gov (United States)

Cartwright-Shamoon, J; Dickson, G R; Dodge, J; Carr, K E

1996-01-01

BACKGROUND: There has recently been a growing interest in the use of the non-pathogenic yeast Saccharomyces boulardii, in the treatment of gastrointestinal disorders, including diarrhoea. The full effects of administration of the yeast are not fully understood. AIMS: To investigate the morphological effects of inoculated S boulardii on mouse intestinal villi, both in control animals and those treated with rotavirus. METHODS: Seven day old BALB/c seronegative mice were intubated with either rotavirus (30 microliters orally) or S boulardii (1.5 g/kg) or both rotavirus and S boulardii administered together. Control animals were given saline only. Animals were killed by decapitation 48 hours post-treatment. The middle region of the small intestine was studied using light microscopy and transmission and scanning electron microscopy, including backscattered electron imaging. RESULTS: Animals treated with rotavirus with or without S boulardii developed severe diarrhoea and showed morphological villous changes such as stromal separation and increased epithelial vacuolation. Specimens treated with S boulardii contained yeast particles within the mucosal tissues. CONCLUSION: The administration of S boulardii did not influence the changes produced by rotavirus, but yeast particles appeared to be taken up by the villous mucosa, with the predominant route apparently being uptake between adjacent epithelial cells. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8991857

Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.

Science.gov (United States)

Dimopoulos, Meletios A; Oriol, Albert; Nahi, Hareth; San-Miguel, Jesus; Bahlis, Nizar J; Usmani, Saad Z; Rabin, Neil; Orlowski, Robert Z; Komarnicki, Mieczyslaw; Suzuki, Kenshi; Plesner, Torben; Yoon, Sung-Soo; Ben Yehuda, Dina; Richardson, Paul G; Goldschmidt, Hartmut; Reece, Donna; Lisby, Steen; Khokhar, Nushmia Z; O'Rourke, Lisa; Chiu, Christopher; Qin, Xiang; Guckert, Mary; Ahmadi, Tahamtan; Moreau, Philippe

2016-10-06

Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10 5 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened

Effects of imidacloprid on soil microbial communities in different saline soils.

Science.gov (United States)

Zhang, Qingming; Xue, Changhui; Wang, Caixia

2015-12-01

The effects of imidacloprid in the soil environment are a worldwide concern. However, the impact of imidacloprid on soil microorganisms under salt stress is almost unknown. Therefore, an indoor incubation test was performed, and the denaturing gradient gel electrophoresis (DGGE) approach was used to determine the response of different saline soil bacterial and fungal community structures to the presence of imidacloprid (0.4, 2, 10 mg kg(-1)). The results showed that the soil bacterial diversity slightly declined with increasing imidacloprid concentration in soils with low salinity. In moderately saline soils, a new band in the DGGE profile suggested that imidacloprid could improve the soil bacterial diversity to some degree. An analysis of variance indicated that the measured soil bacterial diversity parameters were significantly affected by dose and incubation time. Compared with the control, the soil fungal community structure showed no obvious changes in low and moderately saline soils treated with imidacloprid. The results of these observations provide a basic understanding of the potential ecological effects of imidacloprid on different microorganisms in saline soils.

Iodine-based contrast media, multiple myeloma and monoclonal gammopathies: literature review and ESUR Contrast Media Safety Committee guidelines.

Science.gov (United States)

Stacul, Fulvio; Bertolotto, Michele; Thomsen, Henrik S; Pozzato, Gabriele; Ugolini, Donatella; Bellin, Marie-France; Bongartz, Georg; Clement, Olivier; Heinz-Peer, Gertraud; van der Molen, Aart; Reimer, Peter; Webb, Judith A W

2018-02-01

Many radiologists and clinicians still consider multiple myeloma (MM) and monoclonal gammopathies (MG) a contraindication for using iodine-based contrast media. The ESUR Contrast Media Safety Committee performed a systematic review of the incidence of post-contrast acute kidney injury (PC-AKI) in these patients. A systematic search in Medline and Scopus databases was performed for renal function deterioration studies in patients with MM or MG following administration of iodine-based contrast media. Data collection and analysis were performed according to the PRISMA statement 2009. Eligibility criteria and methods of analysis were specified in advance. Cohort and case-control studies reporting changes in renal function were included. Thirteen studies were selected that reported 824 iodine-based contrast medium administrations in 642 patients with MM or MG, in which 12 unconfounded cases of PC-AKI were found (1.6 %). The majority of patients had intravenous urography with high osmolality ionic contrast media after preparatory dehydration and purgation. MM and MG alone are not risk factors for PC-AKI. However, the risk of PC-AKI may become significant in dehydrated patients with impaired renal function. Hypercalcaemia may increase the risk of kidney damage, and should be corrected before contrast medium administration. Assessment for Bence-Jones proteinuria is not necessary. • Monoclonal gammopathies including multiple myeloma are a large spectrum of disorders. • In monoclonal gammopathy with normal renal function, PC-AKI risk is not increased. • Renal function is often reduced in myeloma, increasing the risk of PC-AKI. • Correction of hypercalcaemia is necessary in myeloma before iodine-based contrast medium administration. • Bence-Jones proteinuria assessment in myeloma is unnecessary before iodine-based contrast medium administration.