1
UI - 11955031
AU - Imrie K; Esmail R; Meyer RM; Members of the Hematology Disease Site
TI - Group of the Cancer Care Ontario Practice Guidelines Initiative The role of high-dose chemotherapy and stem-cell transplantation in patients with multiple myeloma: a practice guideline of the Cancer Care Ontario Practice Guidelines Initiative.
SO - Ann Intern Med 2002 Apr 16;136(8):619-29
AD - Cancer Care Ontario Program in Evidence-Based Care, Ontario, Canada.
The Hematology Disease Site Group of the Cancer Care Ontario Practice Guidelines Initiative has systematically reviewed the published literature and, through a consensus process, developed an evidence-based practice guideline assessing the role of stem-cell transplantation in patients with multiple myeloma. The conclusions were validated by solicited feedback from 221 practitioners across Ontario, Canada. The guideline comprises six recommendations: 1) Autologous transplantation is recommended for patients with stage II or III myeloma and good performance status. Evidence of benefit is strongest for patients who are younger than 55 years of age and have a serum creatinine level less than 150 micromol/L (<1.7 mg/dL). Physicians must use clinical judgment in recommending transplantation to other patients. 2) Allogeneic transplantation is not recommended as routine therapy. 3) Patients potentially eligible for transplantation should be referred for assessment early after diagnosis and should not be extensively exposed to alkylating agents before collection of stem cells. 4) Autologous peripheral blood stem cells should be harvested early in the patient's treatment course. The best available data suggest that transplantation is most advantageous when performed as part of initial therapy. 5) The comparative data addressing the specifics of the transplantation process are insufficient to allow definitive recommendations. In the absence of such data, a single transplant with high-dose melphalan, with or without total-body irradiation, is suggested for patients undergoing transplantation outside a clinical trial. 6) At this time, no conclusions can be reached about the role of interferon therapy after transplantation.

2
UI - 11771050
AU - Campis P; Frenkiel S; Glikstein R; Mohr G
TI - Unilateral sixth cranial nerve palsy caused by skull base mass lesions: case series.
SO - J Otolaryngol 2001 Jun;30(3):184-6
AD - Department of Otolaryngology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec.

3
UI - 11920166
AU - San Miguel JF; Lahuerta JJ; Garcia-Sanz R; Alegre A; Blade J; Martinez
TI - R; Garcia-Larana J; De La Rubia J; Sureda A; Vidal MJ; Escudero A; Perez-Esquiza E; Conde E; Garcia-Ruiz JC; Cabrera R; Caballero D; Moraleda JM; Leon A; Besalduch J; Hernandez MT; Rifon J; Hernandez F; Solano C; Palomera L; Parody R; Gonzalez JD; Mataix R; Maldonado J; Constela J; Carrera D; Bello JL; De Pablos JM; Perez-Simon JA; Torres JP; Olanguren J; Prieto E; Acebede G; Penarrubia MJ; Torres P; Diez-Martin JL; Rivas A; Sanchez JM; Diaz-Mediavilla J Are myeloma patients with renal failure candidates for autologous stem cell transplantation?
SO - Hematol J 2000;1(1):28-36
AD - Spanish Registry for Transplant in Multiple Myeloma, Grupo Espanol de Trasplante Hematopoyetico (GETH), Spain. sanmigiz@gugu.usal.es
INTRODUCTION: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insufficiency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. MATERIALS AND METHODS: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were defined: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. RESULTS AND CONCLUSION: Patients from groups BA and BB presented with a significantly higher number of adverse prognostic factors, reflecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insufficiency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was significantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent influence on TRM: poor performance status (ECOG 3), hemoglobin <9.5 g/dl and serum creatinine > or =5 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine < 2 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically significant difference favoring group AA (P<0.01). PFS did not differ significantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high beta(2)-microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insufficiency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (>5 mg/dl).

4
UI - 11920177
AU - Sundblad A; Coutinho A; Bjorkholm M; Holm G
TI - V-region-specific alterations of serum IgM production in multiple myeloma of IgG class.
SO - Hematol J 2000;1(2):102-10
AD - Division of Hematology, Department of Medicine, Karolinska Institute and Hospital, Stockholm, Sweden. anne.sunblad@cmm.ki.se
INTRODUCTION: Multiple myeloma is accompanied by decreased polyclonal serum immunoglobulin concentrations. This suppression might be due to non-specific effects on the polyclonal lymphocyte populations as previously suggested, or it could include specific variable region-dependent mechanisms. Thus, differentiation, survival and activation to Ig secretion of B-lineage cells are dependent on the expression and signalling through the variable Ig receptor. The present study addresses the question whether such variable region-specific alterations were present in the peripheral repertoire of IgM antibodies in patients with IgG-secreting MM. MATERIALS AND METHODS: IgM reactivity repertoires towards a large panel of antigens in extracts of homologous tissues (liver, brain, stomach and heart muscle) and bacteria (Bacillus macquarensis) were analysed in sera from 22 patients diagnosed with IgG1 MM. Healthy, matched volunteers served as control donors. A modified Western assay was used, and values obtained from area integration by image analyses were submitted to multiparametric statistics. RESULTS AND CONCLUSION: The results confirm previous observations on the depression of serum IgM concentrations in multiple myeloma, and demonstrate concentration-independent, patient- and V-region-specific alterations in the polyclonal reactivity repertoires. Since the scoring of IgM reactivities by this technique is independent of IgG and because the deviations of IgM reactivity are not coincident with reactivities of (myeloma) IgG in the individual sera, the results indicate that the immunological syndrome of MM includes significant V-region-specific alterations in the polyclonal repertoires of IgM antibodies.

5
UI - 11920187
AU - Troussard X; Avet-Loiseau H; Macro M; Mellerin MP; Malet M; Roussel M;
TI - Sola B Cyclin D1 expression in patients with multiple myeloma.
SO - Hematol J 2000;1(3):181-5
AD - Laboratoire d'Hematologie, CHU Caen, France, and UPRES-EA 2128, UFR de Medecine, Caen, France. troussard-x@chu-caen.fr
INTRODUCTION: Chromosomal abnormalities are detected in 50 to 70% of patients with multiple myeloma (MM). By conventional cytogenetic analysis, a t(11;14)(q13;q32) is observed at a frequency of 3 to 14%. MATERIALS AND METHODS: To demonstrate a cyclin D1 expression in MM patients or MM cell lines, 14 patients with multiple myeloma (MM) and nine human multiple myeloma cell lines (HMCL) were screened by a competitive RT-PCR and/or Northern blot analysis for cyclin D1 expression. Furthermore, we screened 10 MM patients with FISH to demonstrate a relationship between the cyclin D1 expression and the presence of the t(11;14). RESULTS: Five HMCL had a cyclin D1 overexpression: three of them had a t(11;14)(q13;q32) and two had extra copies of chromosome 11. A cyclin D1 expression was found at diagnosis in seven out of 14 untreated MM patients (50%). Out of 14 MM patients, FISH studies were performed in 10 patients. A t(11;14) was detected in three out of 10 patients and extra copies of chromosome 11 were found in two additional patients. CONCLUSION: Cyclin D1 expression is a common event in MM patients (50%) and is associated either with a t(11;14)(q13;q32) or extra copies of chromosome 11. The prognostic role of the cyclin D1 expression and the level of this expression, as compared to other B-cell chronic lymphoproliferative disorders such as mantle cell lymphoma or hairy cell leukemia, remains to be determined in the pathogenesis of multiple myeloma.

6
UI - 11920188
AU - Yakoub-Agha I; Moreau P; Leyvraz S; Berthou C; Payen C; Dumontet C;
TI - Grosbois B; Beris P; Duguet C; Attal M; Harousseau JL; Facon T; (on behalf of the Intergroupe Francophone du Myelome (IFM)) Thalidomide in patients with advanced multiple myeloma.
SO - Hematol J 2000;1(3):186-9
AD - Service des Maladies du Sang, CHU, Lille, France.
INTRODUCTION: Recently, a report has suggested the efficacy and safety of thalidomide in refractory multiple myeloma. In an attempt to assess the efficacy and tolerance of thalidomide in advanced multiple myeloma (on behalf of the Intergroupe Franchophone dy Myelome (IFM)), we report the preliminary experience of the IFM with this drug. MATERIALS AND METHODS: Patients with advanced multiple myeloma (n=27) were treated with an oral dose of thalidomide (median 400 mg/day). At the start of treatment, all patients had active disease and 20 patients had received at least one autologous transplantation. RESULTS: Median follow-up was 105 days from the first administration. The serum and/or urine levels of the M-component were reduced by at least 75% in four patients including one patient with a >90% reduction, by at least 50% in five patients and by at least 25% in three patients, giving a total response rate of 45% (12 out of 27 patients). Nine patients had stable disease and six patients had progressed disease. Short-term side-effects of thalidomide were generally moderate. CONCLUSION: This study confirms that thalidomide is an effective agent in patients with advanced myeloma.

7
UI - 11971193
AU - Wang YD; De Vos J; Jourdan M; Couderc G; Lu ZY; Rossi JF; Klein B
TI - Cooperation between heparin-binding EGF-like growth factor and interleukin-6 in promoting the growth of human myeloma cells.
SO - Oncogene 2002 Apr 11;21(16):2584-92
AD - INSERM U475 and Unit for Cellular Therapy, CHU Montpellier, 99 Rue Puech Villa, 34197 Montpellier, France.
Interleukin-6 (IL-6) is a major survival and proliferation factor of human malignant plasma cells and IL-6 dependent myeloma cell lines can be obtained from patients with terminal disease. We show here that mutated diphtheria toxin, a specific inhibitor of heparin-binding epidermal growth factor-like growth factor (HB-EGF), blocked the IL-6-induced growth of two myeloma cell lines (XG-1 and XG-14) and did not significantly affect that of two other cell lines (XG-6 and XG-13). The IL-6 mediated growth of myeloma cells was also inhibited by antibodies to ErbB1, a receptor for HB-EGF. The XG-1 and XG-14 cell lines that are sensitive to HB-EGF inhibitors overexpressed HB-EGF and EGF receptor (ErbB1) genes. They also overexpressed CD9, a tetraspanin that binds to the heparin-binding domain of HB-EGF and is critical for promoting ErbB1 activation by HB-EGF. The XG-6 and XG-13 myeloma cells that were not significantly sensitive to HB-EGF antagonists, poorly expressed HB-EGF, ErbB1 and CD9 genes or proteins. We demonstrated that recombinant HB-EGF supported the long-term growth of myeloma cells, as did IL-6. The myeloma cell growth factor activity of HB-EGF was completely inhited by antibodies to ErbB1, but also by antibodies to gp130 IL-6 transducer or to IL-6. These data indicate that in the XG-1 and XG-14 IL-6-dependent myeloma cell lines, the CD9/HB-EGF/erbB1 and the IL-6/IL-6R/gp130 pathways cooperate synergistically to trigger myeloma cell growth. They suggest that inhibitors of the EGF receptor or HB-EGF may be useful for inducing myeloma cell apoptosis in patients with multiple myeloma.

8
UI - 11380408
AU - Blade J; Perales M; Rosinol L; Tuset M; Montoto S; Esteve J; Cobo F;
TI - Villela L; Rafel M; Nomdedeu B; Montserrat E Thalidomide in multiple myeloma: lack of response of soft-tissue plasmacytomas.
SO - Br J Haematol 2001 May;113(2):422-4
AD - Institute of Haematology and Oncology, Department of Haematology, Postgraduate School of Haematology Farreras-Valenti, Barcelona, Spain. jblade@clinic.ub.es
Thalidomide is active in patients with refractory myeloma. Seventeen patients (nine men/eight women, median age 73 years) with multiple myeloma (MM) were treated with thalidomide. Fifteen patients had refractory disease and two untested relapse. The median dose of thalidomide was 500 mg (range, 200-800 mg). Nine of the 17 patients (53%) responded. The response rate was significantly higher in patients with no extramedullary disease than in those with soft tissue masses (75% CI: 43-95% versus 0%; P = 0.01)). Of note, no decrease in the size of soft tissue plasmacytomas was observed in all the five patients who had extramedullary involvement. This data suggests that the mechanism of action and effectiveness of thalidomide might depend on the site of the tumour cells.

9
UI - 11722443
AU - Myers B; Grimley C; Crouch D; Dolan G
TI - Lack of response to thalidomide in plasmacytomas.
SO - Br J Haematol 2001 Oct;115(1):234

10
UI - 11792416
AU - Semenov I; Akyuz C; Roginskaya V; Chauhan D; Corey SJ
TI - Growth inhibition and apoptosis of myeloma cells by the CDK inhibitor flavopiridol.
SO - Leuk Res 2002 Mar;26(3):271-80
AD - Department of Pediatrics (Hematology-Oncology), Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA.
Although myeloma shows responsiveness in intensive chemotherapy, overall survival remains less than 40% at 2 years. Since myeloma appears to be dependent on cytokines, such as IL-6, we hypothesized that targeting signal transduction molecules could effectively treat myeloma. Two myeloma cell lines U266 and RPMI-8226 and CD38+ myeloma cells were studied by immune complex kinase assay or anti-phosphotyrosine blot for evidence of constitutive activation of tyrosine kinases. Growth arrest and apoptosis were evaluated in these two cell lines following their treatment with specific kinase inhibitors. We found that a variety of Src and Janus kinases were present and constitutively active in U266 and RPMI-8226 cells. Inhibitors of both Src and Janus kinases were inferior to the cyclin-dependent kinase inhibitor, flavopiridol, in inducing both growth arrest with GI50 of 100 nM and apoptosis in both cell lines and CD38+ myeloma cells. Although, flavopiridol did not affect cyclin D1 and cyclin A levels, it inhibited Mcl-1 and Bcl-2 protein levels and cyclin-dependent kinase 2 activity. Flavopiridol is a well-tolerated drug, currently in phase I-II trials for a variety of tumors. A clinical trial using flavopiridol should be performed in patients with myeloma. Its mechanism of action may involve targets other than the cyclin-dependent kinases.

11
UI - 11829241
AU - Muzio LL; Pannone G; Bucci P
TI - Early clinical diagnosis of solitary plasmacytoma of the jaws: a case report with a six year follow-up.
SO - Int J Oral Maxillofac Surg 2001 Dec;30(6):558-60
AD - Institute of Dental Sciences, University of Ancona, Italy. lomuziol@tin.it
The authors reported a case of a solitary mandibular plasmacytoma in a 53-year-old male Caucasian patient. The histological examination of the specimen was positive for a plasmacytoma with anaplastic appearance. Since the patient refused a demolitive surgical treatment, he was treated with a local radiation therapy of 4000 rads over a 20-day period and polychemotherapy with cyclophosphamide, prednisone and melphalan. Six years after starting radiation treatment the patient is free of recurrent primary disease and not affected by multiple localization. In conclusion, the solitary bone plasmacytoma represents an initial stage of the multiple myeloma rather than a distinct clinical pathology. Unfortunately, the diagnosis of the plasmacytoma is only rarely carried out in the early phases of the disease. The importance of the identification of the initial stage without a clear M component, as in the reported case, is self-evident, since the prognosis is related to the mass of plasmacytoma cells that are present at the time of the diagnosis. The purpose of this study is to report an extremely rare case of solitary bone plasmacytoma with a mandibular localization treated with radio- and polychemotherapy.

12
UI - 11948073
AU - Dooley KE; Sinha SR; Haponik E; Conwit R; Sevransky JE
TI - A 39-year-old man with hip pain and respiratory failure.
SO - Chest 2002 Apr;121(4):1345-9
AD - Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224-6801, USA.

13
UI - 11968583
AU - Adam Z; Pour L; Svobodnik A; Scudla V; Salajka F; Vytrasova M; Bacovsky
TI - J; Schutzova M; Koza V; Sumna E; Frankova H; Lehanka F; Gumulec J; Stavarova Y; Cahova S; Vranova M; Dostalova V; Kessler P; Walterova L; Meluzinova I; Seifertova N; Slama O; Buchler T; Krejci M; Bencikova V; Nykodymova V; Dusek L; Hajek R; Czech Myeloma Group [Quality of life and tolerance of maintenance therapy in patients with multiple myeloma]
SO - Vnitr Lek 2002 Mar;48(3):216-29
AD - Interni hematoonkologicka klinika FN Brno, pracoviste Bohunice, Brno.
Questionnaires on the quality of life and tolerance of different parts of maintenance treatment were sent to a total of 83 patients with multiple myeloma. All patients were for more than one year on maintenance treatment which involved either interferon alpha monotherapy (I), 3 million u. three times per week till signs of relapse developed or sequence administration of interferon alpha and dexamethazone 40 mg on day 1 to 4, 10 to 13 and 20 to 23 and then after a four-week interval again interferon alpha, again till progression of the disease occurred. The patients evaluated the presence or absence of different undesirable effects of treatment during the first two weeks of treatment and throughout the year and listed their intensity into four categories defined in the questionnaire. The quality of life was evaluated by means of a basic module of the questionnaire of the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30). The results of the questionnaire are to a certain extent surprising as from the patients' answers ensues that this maintenance treatment is associated with more numerous undesirable effects than the physicians realized when in contact with the patient. In this summary we can list only the most frequent effects (deterioration of eyesight, impaired sleep, depressions, irritability and unrest, chill, pain in muscles and joints, general weakness and dyspnoea). From the questionnaires on the quality of life ensues a markedly poorer quality of life of these patients as compared with the healthy population. There are however no basic differences between individual groups. The questionnaires were handed only to patients who had maintenance treatment for more than one year and thus patients were eliminated where maintenance treatment was discontinued because of undesirable effects. To give a general idea of the tolerance of the above maintenance treatment the authors mention that to the date of Aug. 31, 2001 113 patients were randomized into one of the branches of maintenance treatment. Maintenance treatment had to be discontinued in 6% patients (in two instances on account of severe hypothyroidism, in one case on account of hallucinations, in three instances on account of severe mental depression caused by this treatment). Reduction of interferon doses in 20% patients usually because of cytopenia but also on account of psychic problem. To the question what length of prolongation of life compensates the undesirable effects of maintenance treatment the following replies were obtained from patients receiving ID, possibly I: 3 months--47.6 and 38.3%, 6 months--4.3 and 10.6%, 9 months--0 and 4.3%, 12 months--47.6 and 46.8% of the addressed patients. In reply to the question whether the patients would prefer, assuming equal effectiveness, a maintenance monotherapy with interferon alpha or dexamethazone more patients preferred interferon to dexamethasone. For practice ensues from this article informing on undesirable effects of maintenance treatment and the effect of maintenance treatment on the quality of life: 1. the necessity of thorough knowledge of physicians of all possible undesirable effects as only a doctor knowing possible undesirable effects of treatment can recognize them, 2. regular monitoring not only of the activity of the basic disease, but also undesirable effects of maintenance treatment and the influence of treatment on the patients' quality of life, 3. the necessity to assess the quality of life in clinical trials as an important parameter for deciding on the way of treatment.

14
UI - 11893981
AU - Wein RO; Topf P; Sham RL
TI - Subglottic plasmacytoma: a case report and review of the literature.
SO - Am J Otolaryngol 2002 Mar-Apr;23(2):112-8
AD - Division of Otolaryngology, University of Rochester Medical Center, Rochester, NY 14642, USA.

15
UI - 11973972
AU - Jarvelainen H; Remes K; Viikari J
TI - [A severe osteoporosis in a middle-aged man]
SO - Duodecim 1999;115(22):2473-6
AD - TYKS:n sisatautien klinikka Kiinamyllynkatu 4-8 20520 Turku. hannu.jarvelainen@utu.fi

16
UI - 11594143
AU - Garcia Montesinos R; Avisbal Portillo N; Velasco Garrido JL; Rueda Rios
TI - C; Bujalance Zafra J; Ramirez Ramirez G [Pleural effusion as presentation form of multiple myeloma]
SO - Rev Clin Esp 2001 Jul;201(7):424-5

17
UI - 11917503
AU - Kishi Y; Kashiwagi T; Kaneko T; Hayashi M; Shimizu M; Matsunobu S; Iino
TI - Y; Katayama Y; Ohashi R [Multiple myeloma light chain deposition with specific pathological change]
SO - Nippon Naika Gakkai Zasshi 2002 Feb 10;91(2):749-51
AD - Second Department of Internal Medicine, Nippon Medical School, Tokyo.

18
UI - 11861260
AU - Van Ness B
TI - Defining the genetic chaos in myeloma.
SO - Blood 2002 Mar 1;99(5):1504
AD - University of Minnesota, USA.

19
UI - 11861292
AU - Zhan F; Hardin J; Kordsmeier B; Bumm K; Zheng M; Tian E; Sanderson R;
TI - Yang Y; Wilson C; Zangari M; Anaissie E; Morris C; Muwalla F; van Rhee F; Fassas A; Crowley J; Tricot G; Barlogie B; Shaughnessy J Jr Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells.
SO - Blood 2002 Mar 1;99(5):1745-57
AD - Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.
Bone marrow plasma cells (PCs) from 74 patients with newly diagnosed multiple myeloma (MM), 5 with monoclonal gammopathy of undetermined significance (MGUS), and 31 healthy volunteers (normal PCs) were purified by CD138(+) selection. Gene expression of purified PCs and 7 MM cell lines were profiled using high-density oligonucleotide microarrays interrogating about 6800 genes. On hierarchical clustering analysis, normal and MM PCs were differentiated and 4 distinct subgroups of MM (MM1, MM2, MM3, and MM4) were identified. The expression pattern of MM1 was similar to normal PCs and MGUS, whereas MM4 was similar to MM cell lines. Clinical parameters linked to poor prognosis, abnormal karyotype (P =.002) and high serum beta(2)-microglobulin levels (P =.0005), were most prevalent in MM4. Also, genes involved in DNA metabolism and cell cycle control were overexpressed in a comparison of MM1 and MM4. In addition, using chi(2) and Wilcoxon rank sum tests, 120 novel candidate disease genes were identified that discriminate normal and malignant PCs (P <.0001); many are involved in adhesion, apoptosis, cell cycle, drug resistance, growth arrest, oncogenesis, signaling, and transcription. A total of 156 genes, including FGFR3 and CCND1, exhibited highly elevated ("spiked") expression in at least 4 of the 74 MM cases (range, 4-25 spikes). Elevated expression of these 2 genes was caused by the translocation t(4;14)(p16;q32) or t(11;14)(q13;q32). Thus, novel candidate MM disease genes have been identified using gene expression profiling and this profiling has led to the development of a gene-based classification system for MM.

20
UI - 11861305
AU - San Miguel JF; Almeida J; Mateo G; Blade J; Lopez-Berges C; Caballero D;
TI - Hernandez J; Moro MJ; Fernandez-Calvo J; Diaz-Mediavilla J; Palomera L; Orfao A Immunophenotypic evaluation of the plasma cell compartment in multiple myeloma: a tool for comparing the efficacy of different treatment strategies and predicting outcome.
SO - Blood 2002 Mar 1;99(5):1853-6
AD - Servicio de Hematologia, Hospital Clinico Universitario, Salamanca, Spain. sanmigiz@gugu.usal.es
Multiparametric immunophenotyping can be a sensitive method for analyzing the plasma cell (PC) compartment in patients with multiple myeloma because it discriminates between myelomatous and normal PCs. Using this approach, we compared the efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) with that of conventional chemotherapy. We found that ASCT provided a significantly greater reduction in the level of residual tumor PCs and with better recovery of normal PCs. This profile of coexistence of normal PCs and myelomatous PCs resembled that observed in monoclonal gammopathy of undetermined significance. We also found that treatment-induced changes in the PC compartment correlated with disease outcome. Thus, patients in whom at least 30% of gated PCs had a normal phenotype after treatment had a significantly longer progression-free survival (60 +/- 6 months versus 34 +/- 12 months; P =.02).

21
UI - 11847486
AU - Gado K; Rimanoczi E; Hasitz A; Gigler G; Toth BE; Nagy GM; Paloczi K;
TI - Domjan G Elevated levels of serum prolactin in patients with advanced multiple myeloma.
SO - Neuroimmunomodulation 2001;9(4):231-6
AD - National Institute of Haematology and Immunology, Budapest, Hungary. gadok@freemail.hu
BACKGROUND AND OBJECTIVE: The role of prolactin in immunoregulation and normal hemopoiesis is well known. However, prolactin also seems to be involved in the pathomechanism of malignancies and autoimmune diseases. Elevated serum prolactin levels were reported in patients with malignant lymphoma, colon and breast carcinoma, systemic lupus erythematosus and rheumatoid arthritis. Recently we demonstrated prolactin immunostaining in bone marrow cells of patients with multiple myeloma. DESIGN AND METHODS: Serum prolactin levels of 56 patients with multiple myeloma, as well as serum beta(2)-microglobulin, and interleukin-6 concentrations were determined in this study. RESULTS: Patients with advanced disease showed a significant increase in serum prolactin concentration, while patients with a clinical stage of I and II, and also control patients had normal values. The concentration of serum beta(2)-microglobulin and interleukin-6 changed in parallel with that of serum prolactin in patients with multiple myeloma. Determining serum prolactin levels several times during the disease process in a given patient clearly showed that the prolactin concentration was increasing during the disease progression. INTERPRETATION AND CONCLUSIONS: Our results indicate a role of prolactin in disease progression in multiple myeloma. Copyright 2002 S. Karger AG, Basel

22
UI - 11966603
AU - Ajithkumar TV; Sivasankar C; Ramachandran K
TI - Orbital multiple myeloma: case report and review of computed tomography features.
SO - Australas Radiol 2002 Mar;46(1):119-20
AD - Regional Cancer Centre, Trivandrum, India. tvajilh@hotmail.com
Orbital involvement at diagnosis in multiple myeloma is rare. Only a few a cases are reported with computed tomographic features. We report a case of orbital myeloma, and relevant medical reviews on computed tomography features are discussed.

23
UI - 11769964
AU - Bergsagel DE
TI - Myeloma: what have we learned?
SO - Biomed Pharmacother 2001 Nov;55(9-10):548-9
AD - University of Toronto, ON, Canada. daniel.bergsagel@utoronto.ca

24
UI - 11769965
AU - Alexanian R; Weber D
TI - Recent advances in treatment of multiple myeloma and Waldenstrom's macroglobulinemia.
SO - Biomed Pharmacother 2001 Nov;55(9-10):550-2
AD - University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

25
UI - 11869932
AU - Tosi P; Cavo M
TI - Thalidomide in multiple myeloma: state of art.
SO - Haematologica 2002 Mar;87(3):233-4

26
UI - 11869949
AU - Corso A; Lorenzi A; Orlandi E; Astori C; Mangiacavalli S; Lazzarino M
TI - Advantages of using thalidomide for the management of refractory myeloma patients.
SO - Haematologica 2002 Mar;87(3):327-8
A group of 11 heavily pretreated patients receiving low-dose thalidomide was compared with a similar group of 10 patients with refractory myeloma treated with a convention-al oral chemotherapy. This study shows that thalidomide is not only effective in controlling the neoplastic clone but more-over, thanks to its low toxicity, allows out-patient management of these subjects.

27
UI - 11877256
AU - Zhang B; Gojo I; Fenton RG
TI - Myeloid cell factor-1 is a critical survival factor for multiple myeloma.
SO - Blood 2002 Mar 15;99(6):1885-93
AD - University of Maryland Greenebaum Cancer Center, Bressler Research Building, 655 W Baltimore St., Rm 7-023, Baltimore, MD 21201, USA.
Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow caused primarily by failure of normal homeostatic mechanisms to prevent the expansion of postgerminal center plasma cells. We have examined the molecular mechanisms that promote the survival of MM cells and have identified a key role for myeloid cell factor-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family. These experiments were initiated by the observation that MM cells were exquisitely sensitive to culture in the presence of actinomycin D: caspase activation occurred within 3 hours of treatment and cells were not protected by interleukin-6, the main MM cell growth and survival factor. Actinomycin D-induced apoptosis was blocked by proteasome inhibitors, suggesting that a labile protein was required for MM cell survival. Further analysis demonstrated that Mcl-1 was likely to be the labile factor governing MM cell survival. Mcl-1 protein levels decreased rapidly after culture in the presence of actinomycin D in concordance with effector caspase activation, but addition of proteasome inhibitors reversed the loss of Mcl-1 and maintained cell viability. The levels of other antiapoptotic proteins, including Bcl-2 and members of the inhibitors-of-apoptosis family, were unaffected by these interventions. Furthermore, Mcl-1 antisense oligonucleotides caused a rapid down-regulation of Mcl-1 protein levels and the coincident induction of apoptosis, whereas overexpression of Mcl-1 delayed actinomycin D-induced apoptosis with kinetics that correlated with expression levels of Mcl-1. These data indicate that Mcl-1 expression is required for the survival of MM cells and may represent an important target for future therapeutics.

28
UI - 11877293
AU - Mitsiades N; Mitsiades CS; Poulaki V; Anderson KC; Treon SP
TI - Intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human multiple myeloma cells.
SO - Blood 2002 Mar 15;99(6):2162-71
AD - Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Mayer Bldg., Boston, MA 02115, USA.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2 ligand) effectively kills multiple myeloma (MM) cells in vitro irrespective of refractoriness to dexamethasone and chemotherapy. Because clinical trials with this anticancer agent are expected shortly, we investigated the signaling pathway of TRAIL-induced apoptosis in MM. We detected rapid cleavage of caspases-8, -9, -3, and -6, as well as the caspase substrates poly(ADP-ribose) polymerase (PARP) and DNA fragmentation factor-45 (DFF45), but not caspase-10, upon TRAIL treatment in sensitive MM cells, pointing to caspase-8 as the apical caspase of TRAIL signaling in MM cells. These phenomena were not observed or were significantly delayed in TRAIL-resistant MM cells, suggesting that resistance may arise from inhibition at the level of caspase-8 activation. Higher levels of expression for various apoptosis inhibitors, including FLICE-inhibitory protein (FLIP), and lower procaspase-8 levels were present in TRAIL-resistant cells and sensitivity was restored by the protein synthesis inhibitor cycloheximide (CHX) and the protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM), which both lowered FLIP and cellular inhibitor of apoptosis protein-2 (cIAP-2) protein levels. Forced expression of procaspase-8 or FLIP antisense oligonucleotides also sensitized TRAIL-resistant cells to TRAIL. Moreover, the cell permeable nuclear factor (NF)-kappaB inhibitor SN50, which sensitizes TRAIL-resistant cells to TRAIL, also inhibited cIAP2 protein expression. Finally, CHX, BIM, and SN50 facilitated the cleavage and activation of procaspase-8 in TRAIL-resistant cells, confirming that inhibition of TRAIL-induced apoptosis occurs at this level and that these agents sensitize MM cells by relieving this block. Our data set a framework for the clinical use of approaches that sensitize MM cells to TRAIL by agents that inhibit FLIP and cIAP-2 expression or augment caspase-8 activity.

29
UI - 11877294
AU - Ishikawa H; Tsuyama N; Abroun S; Liu S; Li FJ; Taniguchi O; Kawano MM
TI - Requirements of src family kinase activity associated with CD45 for myeloma cell proliferation by interleukin-6.
SO - Blood 2002 Mar 15;99(6):2172-8
AD - Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan.
Specific intracellular signals mediated by interleukin-6 (IL-6) receptor complexes, such as signal transducer and activator of transcription 3 (STAT 3) and extracellular signal-regulated kinase (ERK) 1/2, are considered to be responsible for inducing a variety of cellular responses. In multiple myeloma, IL-6 only enhanced the proliferation of CD45+ tumor cells that harbored the IL-6-independent activation of src family kinases even though STAT3 and ERK1/2 could be activated in response to IL-6 in both CD45+ and CD45(minus sign) cells. Furthermore, the IL-6-induced proliferation of CD45+ U266 myeloma cells was significantly suppressed by Lyn-specific antisense oligodeoxynucleotides or a selective src kinase inhibitor. These results indicate that the activation of both STAT3 and ERK1/2 is not enough for IL-6-induced proliferation of myeloma cell lines that require src family kinase activation independent of IL-6 stimulation. Thus, the activation of the src family kinases associated with CD45 expression is a prerequisite for the proliferation of myeloma cell lines by IL-6. We propose a mechanism for IL-6-induced cell proliferation that is strictly dependent upon the cellular context in myelomas.

30
UI - 11877296
AU - Avet-Loiseau H; Facon T; Grosbois B; Magrangeas F; Rapp MJ; Harousseau
TI - JL; Minvielle S; Bataille R; Intergroupe Francophone du Myelome Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation.
SO - Blood 2002 Mar 15;99(6):2185-91
AD - Laboratory and Clinical Department of Hematology, University Hospital, 9 quai Moncousu, 44093 Nantes, France. havetloiseau@chu-nantes.fr
Multiple myeloma (MM) is a plasma-cell malignancy characterized by marked epidemiological, biological, and clinical heterogeneity. The goal of this study was to find a genetic basis for this heterogeneity. Using fluorescence in situ hybridization, we analyzed a prospective cohort of 901 patients with various plasma-cell disorders--monoclonal gammopathies of undetermined significance, smoldering MM, MM, and primary plasma-cell leukemia--for genetic abnormalities involving the 13q14 and 14q32 chromosomal regions; the patients were consecutively enrolled in the Intergroupe Francophone du Myelome clinical trials, We performed statistical analyses comparing these chromosomal abnormalities in terms of immunological (ie, immunoglobulin types and light-chain subtypes) and clinical status and, to some extent, prognostic features. It was found that 14q32 translocations and del(13) are the most frequent chromosomal abnormalities, observed in 75% and 45% of the patients, respectively, and are not randomly distributed, but interconnected. Second, correlations between them allowed us to define 4 major genetic categories of patients: (1) patients lacking any 14q32 abnormality (25%) and generally also lacking del(13); (2) patients presenting either t(4;14) or t(14;16), almost always associated with a del(13) (15% of patients); (3) patients with other 14q32 abnormalities and presenting del(13) (25%); and (4) patients with other 14q32 abnormalities but not presenting del(13) (35%). Third, we show that this genetic stratification is highly correlated with immunological status and clinical presentation and with some major prognostic factors. For the first time, this study gives genetic support to the heterogeneity observed in patients with MM and demonstrates that the 14q32 and 13q chromosomal abnormalities are not randomly distributed. The strong correlations we found might be the basis for a novel genetic classification of MM, as has been previously demonstrated for leukemias and lymphomas. Furthermore, our study supports different models for MM oncogenesis.

31
UI - 11902142
AU - Alkan S; Izban KF
TI - Immunohistochemical localization of phosphorylated AKT in multiple myeloma.
SO - Blood 2002 Mar 15;99(6):2278-9

32
UI - 11990854
AU - Kuehl WM; Bergsagel PL
TI - Multiple myeloma: evolving genetic events and host interactions.
SO - Nature Rev Cancer 2002 Mar;2(3):175-87
AD - Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda Naval Hospital, Maryland 20889-5105, USA. wmk@helix.nih.gov
Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers. Unlike most haematopoietic cancers, multiple myeloma often has complex chromosomal abnormalities that are reminiscent of epithelial tumours. What causes full-blown myeloma? And can our molecular understanding of this common haematological malignancy be used to develop effective preventive and treatment strategies?

33
UI - 11991600
AU - Michopoulos S; Petraki K; Petraki C; Dimopoulos MA
TI - Light chain deposition disease of the liver without renal involvement in a patient with multiple myeloma related to liver failure and rapid fatal outcome.
SO - Dig Dis Sci 2002 Apr;47(4):730-4
AD - Gastroenterology Unit, Alexandra University Hospital, Athens, Greece.
We describe a 36-year-old man with advanced multiple myeloma (Salmon and Durie stage III) who developed jaundice and severe cholestasis after a first cure with systemic chemotherapy of vincristine, doxorubicin, and oral dexamethasone (VAD). Serology for hepatitis A, B, and C and for CMV was negative. A liver ultrasound and CT scan showed mild hepatomegaly without evidence of extrahepatic or intrahepatic biliary tree dilatation. A percutaneous liver biopsy revealed perisinusoidal deposits of an abundant slightly eosinophilic, PAS-positive amorphous substance. Immunohistochemistry showed positivity for kappa-light chains and was negative for lambda-light chains, for IgA, IgG, IgM, and IgD immunoglobulins as well as for AA and AL proteins and for amyloid P component. A diagnosis of light chain deposition disease (LCDD) of the liver was made. The patient developed rapid deterioration of liver function, leading to a multisystem dysfunction and death. The occurrence of LCDD in multiple myeloma is close to 5% and myeloma is the underlying disease in two thirds of patients with LCDD. The kidneys are involved in almost all cases of LCDD and renal dysfunction usually reveals the disease. Only three patients with LCDD of the liver without overt renal involvement have been reported so far. This is the first observation of LCDD presenting with jaundice and severe cholestasis shortly after the diagnosis of high tumor mass myeloma, without overt renal involvement, leading rapidly to the patient's death.

34
UI - 11279146
AU - Ghosh N; Gyory I; Wright G; Wood J; Wright KL
TI - Positive regulatory domain I binding factor 1 silences class II transactivator expression in multiple myeloma cells.
SO - J Biol Chem 2001 May 4;276(18):15264-8
AD - H. Lee Moffitt Cancer Center, Interdisciplinary Oncology Program and the Department of Biochemistry and Molecular Biology, University of South Florida, Tampa, Florida 33612, USA.
The major histocompatibility complex (MHC) class II transactivator (CIITA) acts as a master switch to activate expression of the genes required for MHC-II antigen presentation. During B-cell to plasma cell differentiation, MHC-II expression is actively silenced, but the mechanism has been unknown. In plasma cell tumors such as multiple myeloma the repression of MHC-II is associated with the loss of CIITA. We have identified that positive regulatory domain I binding factor 1 (PRDI-BF1), a transcriptional repressor, inhibits CIITA expression in multiple myeloma cell lines. Repression of CIITA depends on the DNA binding activity of PRDI-BF1 and its specific binding site in the CIITA promoter. Deletion of a histone deacetylase recruitment domain in PRDI-BF1 does not inhibit repression of CIITA nor does blocking histone deacetylase activity. This is in contrast to PRDI-BF1 repression of the c-myc promoter. Repression of CIITA requires either the N-terminal acidic and conserved PR motif or the proline-rich domain. PRDI-BF1 has been shown to be a key regulator of B-cell and macrophage differentiation. These findings now indicate that PRDI-BF1 has at least two mechanisms of repression whose function is dependent on the nature of the target promoter. Importantly, PRDI-BF1 is defined as the key molecule in silencing CIITA and thus MHC-II in multiple myeloma cells.

35
UI - 11841448
AU - Nagy M; Chapuis B; Matthes T
TI - Expression of transcription factors Pu.1, Spi-B, Blimp-1, BSAP and oct-2 in normal human plasma cells and in multiple myeloma cells.

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