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MM Patients (mm + patient)
Selected AbstractsContribution of genetic factors for melanoma susceptibility in sporadic US melanoma patientsEXPERIMENTAL DERMATOLOGY, Issue 5 2009M. Laurin Council To examine the contribution of rare and common variation within known MM genes in sporadic US MM patients, coding regions of known MM susceptibility genes [cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 4, melanocortin 1 receptor (MC1R) and tyrosinase (TYR)] were resequenced in 109,135 MM cases. The significance of variants was examined by comparing their frequencies in 390 cancer-free controls. Potential deleterious mutations in CDKN2A were found in two patients and two others had variants of unknown significance. Cases were more likely than controls to harbour the MC1R,R' variants known or predicted to alter its function (P = 0.002), particularly the R160W variant (P = 0.0035). The associated TYR R402Q variant (rs1126809*A) was found in 29% of cases, similar to what has been described previously. One MM patient with a family history of MM, who had developed other skin cancers, was homozygous for a novel TYR variant (P406L) of unknown significance. Hence, rare variants in TYR may be important risk factors for skin cancer. [source] Long-term effects of idiotype vaccination on the specific T-cell response in peripheral blood and bone marrow of multiple myeloma patientsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2007Amir Osman Abdalla Abstract Objectives:, To elucidate long-term effects of idiotype (Id) vaccination on Id-specific T cells of multiple myeloma (MM) patients and compare Id-specific T-cell responses of peripheral blood with those of bone marrow (BM). Materials and methods:, Id-specific T-cell responses of peripheral blood mononuclear cells (PBMC) were compared with those of BM mononuclear cells (BMMC) in 10 MM patients vaccinated with the Id protein at a median time of 41 months since the last immunization. The PBMC responses at late follow-up were also compared with those during active immunization. The responses were assessed by a proliferation assay, enzyme-linked immunospot (ELISPOT) (,-interferon), cytometric bead array (CBA) for secreted cytokines and quantitative real-time polymerase chain reaction (QRT-PCR) for cytokine gene expression. Results:, At the late testing time, an Id-specific response was detected in PBMC of five patients (ELISPOT, CBA, QRT-PCR) and in BMMC of four patients (CBA, QRT-PCR). A response in both compartments was noted only in three patients. The cytokines gene profile was consistent with a predominance of Th2 cells [interleukin (IL)-4, IL-5, IL-10]. Comparison of the Id-specific responses of PBMC during active immunization with those at the late follow-up showed that the frequency and magnitude of the responses had decreased significantly by time (proliferation/ELISPOT) (P < 0.02) and shifted at the gene level from a Th1 to a Th2 profile (P < 0.05). Conclusion:, Id-specific T cells may decline overtime and shift toward a Th2 response and may be found at a similar frequency of patients in blood and BM. [source] Multiple myeloma in elderly patients: prognostic factors and outcomeEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2005Athanasios Anagnostopoulos Abstract:,Objectives:,Purpose of this study was to compare prognostic factors and outcome of patients with multiple myeloma (MM) aged >70 yr at diagnosis with those of younger patients. We also applied the recently proposed International Staging System (ISS) for MM in these patients. Patients and methods:,Among 1,162 newly diagnosed, symptomatic MM patients included in our database, 357 (31%) were >70 yr of age. Clinical and laboratory variables were evaluated in patients >70 yr and in younger patients and were assessed for possible correlation with survival in patients >70 yr of age. Results:,Most clinical and laboratory features were similar in the two groups of patients but older patients presented more frequently with advanced ISS (P = 0.02). Despite similar response rates to primary treatment, younger patients survived longer than patients >70 yr of age (40 vs. 28 months, P = 0.001). There was a longer survival of younger patients than that of older patients diagnosed with ISS stage 1 (median 71 vs. 54 months, P = 0.007) and ISS stage-2 patients (median: 38 vs. 26 months, P = 0.0008) but for patients with ISS stage 3 median survival was similarly poor in the younger and older age group (21 and 20 months, P = 0.283). Other variables associated with impaired prognosis were severe anemia, extensive bone marrow plasmacytosis and elevated serum LDH. Conclusions:,Older patients with MM present more often with advanced ISS and have significantly shorter survival than younger patients. The ISS retained its prognostic significance within the group of elderly patients. [source] Frequency and prognostic relevance of cyclin D1 dysregulation in multiple myelomaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5-6 2001Thomas Rasmussen Abstract:Objective: Cyclin D1 dysregulation has been found with varying frequencies in multiple myeloma (MM) and has been suggested to be associated with a poor prognosis. The aim of this study was to investigate the frequency of cyclin D1 dysregulation in patients being treated for MM and to test whether cyclin D1 dysregulation is a prognostic factor for MM patients. Methods: To achieve the above aims we designed a highly sensitive and reproducible real-time reverse-transcription polymerase chain reaction (RT-PCR) assay for quantitation of cyclin D1 mRNA. Using this assay, 110 diagnostic bone marrow (BM) samples from patients with MM were screened for cyclin D1 dysfuntion. Results: The real-time assay was able to detect the presence of 0.01% cyclin D1 positive cells allowing a safe detection in MM BM samples. In 42% (46/110) of MM BM samples a ,,3-fold increase in cyclin D1 mRNA was observed compared to the cyclin D1 level in normal BM. In the remaining group of MM patients the cyclin D1 mRNA levels were comparable to normal donors. Follow-up of 76 MM patients showed no significant (P = 0.35) difference in survival between cyclin D1 positive and negative MM patients. In addition, cyclin D1 dysregulation did not correlate with known prognostic factors. Conclusion: The developed real-time RT-PCR assay for detection of cyclin D1 mRNA levels offers a fast and safe screening for cyclin D1 dysfunction. When a large cohort of MM patients was screened, the cyclin D1 gene was found to be frequently dysregulated, but there was no significant correlation to survival or known prognostic parameters. [source] Contribution of genetic factors for melanoma susceptibility in sporadic US melanoma patientsEXPERIMENTAL DERMATOLOGY, Issue 5 2009M. Laurin Council To examine the contribution of rare and common variation within known MM genes in sporadic US MM patients, coding regions of known MM susceptibility genes [cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 4, melanocortin 1 receptor (MC1R) and tyrosinase (TYR)] were resequenced in 109,135 MM cases. The significance of variants was examined by comparing their frequencies in 390 cancer-free controls. Potential deleterious mutations in CDKN2A were found in two patients and two others had variants of unknown significance. Cases were more likely than controls to harbour the MC1R,R' variants known or predicted to alter its function (P = 0.002), particularly the R160W variant (P = 0.0035). The associated TYR R402Q variant (rs1126809*A) was found in 29% of cases, similar to what has been described previously. One MM patient with a family history of MM, who had developed other skin cancers, was homozygous for a novel TYR variant (P406L) of unknown significance. Hence, rare variants in TYR may be important risk factors for skin cancer. [source] Patients with bisphosphonates-associated osteonecrosis of the jaw have reduced circulating endothelial cellsHEMATOLOGICAL ONCOLOGY, Issue 4 2007A Allegra Abstract Osteonecrosis of the jaws (ONJ) associated with the use of bisphosphonates is a newly described entity. To elucidate the mechanism leading to ONJ and to test the hypothesis that in patients with ONJ the bisphosphonates may interfere with endothelial cell proliferation, using flow cytometric analysis we evaluated the number of circulating endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) in eight patients with bisphosphonate treatment and osteonecrosis, eight multiple myeloma (MM) patients with bisphosphonates treatment without ONJ and five normal subjects. MM patients showed an increase of CD34+ cells with respect the control subjects and ONJ subjects. EPCs and CECs were higher in MM patients compared to controls and ONJ patients. ONJ patients showed a decrease of EPCs compared to control subjects while CECs were similar to the controls group. Our results seem to show the possibility that bisphosphonates could have a antiangiogenic effect and a suppressive effect on CECs of patients with ONJ. Copyright © 2007 John Wiley & Sons, Ltd. [source] Relevance of Ras gene mutations in the context of the molecular heterogeneity of multiple myelomaHEMATOLOGICAL ONCOLOGY, Issue 1 2007Daniela Intini Abstract Ras gene mutations are a recurrent genetic lesion in multiple myeloma (MM). Here, we report a mutation analysis of N- and K- Ras genes in purified plasma cell populations from a panel of 81 newly diagnosed MM patients stratified according to the most frequent genetic and molecular features associated with the neoplasia. Ras gene mutations, mostly involving the N- Ras gene, were detected in 20% of the patients. Ras mutations did not correlate with the presence of chromosome 13q deletion, trisomy of chromosome 11, 1q amplification or hyperdiploidy. In addition, despite an appreciable association with tumours overexpressing Cyclin D1, Ras mutations did not correlate at significant levels with any of the proposed groups in the TC classification, based on the presence of the major IgH chromosomal translocations and expression of Cyclin D genes. Finally, transcription analyses revealed the presence of differentially expressed transcripts in human multiple myeloma cell lines carrying the Ras gene mutations but not in primary tumours. Overall, these data suggest that Ras gene mutations are not likely to represent a master lesion in MM but its relevance needs to be considered in the context of other genetic abnormalities. Copyright © 2006 John Wiley & Sons, Ltd. [source] Urinary N-telopeptide levels in multiple myeloma patients, correlation with Tc-99m-sestaMIBI scintigraphy and other biochemical markers of disease activityHEMATOLOGICAL ONCOLOGY, Issue 1 2003M. G. Alexandrakis Abstract Urinary cross-linked N-telopeptide of type I collagen (NTx) has been reported to be a sensitive and specific marker of bone resorption in multiple myeloma (MM). In this study, we measured the levels of NTx in 30 newly diagnosed MM patients and 25 controls. We examined its association with the overall score of skeletal involvement measured by Tc-99m-MIBI scintigraphy and other biochemical markers of bone disease (tumour necrosis factor a (TNF-a), serum calcium and creatinine). We further studied the correlation of NTx with the stage of disease (according to Durie,Salmon criteria) and bone marrow infiltration by plasma cells. High levels of NTx, bone marrow infiltration, TNF-,, calcium and creatinine were noted at advanced stages of disease (p,<,0.05). NTx and TNF-a were found at significantly higher concentrations in patients with a high overall score (3 and 4) in Tc-99m-sestaMIBI in comparison to a low score (0, 1 and 2; p,<,0.05). Positive correlations were found between NTx and TNF-a, as well as between bone infiltration and TNF-a or calcium. In conclusion, NTx is a useful marker for the monitoring of bone resorption in MM and correlates with imaging findings on Tc-99m-sestaMIBI and other biochemical markers of disease activity. Copyright © 2002 John Wiley & Sons, Ltd. [source] Proliferative activity of plasma cells is the most relevant prognostic factor in elderly multiple myeloma patientsINTERNATIONAL JOURNAL OF CANCER, Issue 5 2004R. García-Sanz Abstract Although multiple myeloma (MM) is predominantly a disease of the elderly, few studies have focused on the identification of prognostic factors in this group of patients. Four hundred twenty five MM patients >65 years were uniformly treated with chemotherapy (MP or VCMP/VBAD). Multivariate analysis identified 4 factors with independent unfavorable prognostic influence: high percentage of S-phase bone marrow plasma cells (>2.5%); elevated ,2 microglobulin (B2M) (>4 mg/L); age >80 years old; and LDH serum levels (above normal limit). The S-phase value was the most powerful independent prognostic factor to discriminate subgroups of patients with different prognosis. Thus, 3 main risk categories could be identified according to S-phase values: ,1%, 1,3% and >3%, with median survivals of 34, 22 and 12 months, respectively (p < 0.0001). Our study also proved the value for elderly patients of the recently developed International Score System (ISS) based on B2M and albumin. Furthermore, the number of S-phase cells helped to subdivide the ISS III Group identifying a subset of patients with very poor prognosis defined by an additional high S-phase, who displayed a median survival of only 8 months. These results demonstrate that elderly patients can be accurately classified according to prognosis, which may be particularly valuable when comparing the efficacy of new treatment strategies. Moreover, our results underline the high prognostic value of proliferative activity of PC, a parameter that should be considered in routine laboratory investigations of MM. © 2004 Wiley-Liss, Inc. [source] Peripheral blood stem cell collection in multiple myeloma: A retrospective analysis of 6 years leukapheresis activity in 109 patients treated at the Istituto Nazionale dei Tumori of MilanJOURNAL OF CLINICAL APHERESIS, Issue 4 2009Paola Coluccia Abstract Double autologous stem cell transplantation is the standard treatment in newly diagnosed multiple myeloma (MM) patients younger than 65 years; therefore, optimization of leukapheresis is crucial. We performed a retrospective analysis of 297 leukaphereses comparing semiautomated (V4.7 in 20% of collections) versus automated (V6.0 in 80%) Caridian (COBE) Spectra versions and analyzing the influence of M-protein on the outcome. Both methods gave comparable collection efficiencies (CE%) (53.4% vs. 55.7% in V6.0 and V4.7, respectively) with similar leukapheresis time and processed volume. Harvest volume was higher in V4.7 (P < 0.0001) with similar contamination of red blood cells (RBCs) (P = 0.77) and platelets (P = 0.09) when compared with V6.0. In patients with higher peripheral white blood cells (WBCs), V6.0 with adjusted harvest volume (<700 mL), achieved similar CD34+ CE% (P = 0.39) and better enrichment of nucleated cells (P < 0.0,002) but higher RBCs (P < 0.0,001) and platelets contamination (P = 0.001), when compared with a larger cycle volume in patients with lower WBCs. In hard to mobilize patients, CD34+ CE% was significantly more efficient with V4.7 than V6.0 (P < 0.0,001). CD34+ CE% was unaffected by serologic M-protein, but platelet CE% was higher in the absence of M-protein (P = 0.0,003), without any reduction in peripheral patients platelets. We, therefore, conclude that in the setting of MM patients with a high WBCs count and/or low percentage of peripheral CD34+ cells, collections with V4.7 or adjusted cycle volume V6.0 gave comparable result in CD34+ CE%. RBCs and platelets contamination is higher if low cycle volume is chosen. In hard to mobilize patients, V4.7 is advisable. J. Clin. Apheresis, 2009. © 2009 Wiley-Liss, Inc. [source] Lenalidomide in the treatment of multiple myeloma: a reviewJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2008X. Armoiry PharmD PhD Summary Lenalidomide is an immunomodulatory drug derived from thalidomide. It was developed to maximize the anti-inflammatory and anti-neoplasic properties of thalidomide and to reduce its toxicity. The molecular mechanism of action of lenalidomide is unclear, but its therapeutic activity is mainly due to its well defined anti-inflammatory, immunomodulatory, anti-proliferative and anti-angiogenic properties. In relapsed or refractory multiple myeloma (MM), lenalidomide, combined with standard dose dexamethasone, is superior to dexamethasone alone in terms of time to progression, response rate and overall survival. The most commonly reported adverse events include haematological toxicity with manageable neutropenia and thrombopenia. Lenalidomide does not trigger the limiting toxicities of thalidomide: somnolence, neuropathy and constipation. Lenalidomide, in combination with dexamethasone, is indicated for the treatment of MM patients who have received at least one prior therapy and is administered orally at the dose of 25 mg q.d. for 21 days of 28-day cycles. The drug is being investigated for the treatment of newly diagnosed MM. In this review, we summarize the pharmacokinetic, pharmacodynamic and clinical trial data on lenalidomide. [source] Bortezomib plus intermediate-dose dexamethasone and thalidomide in elderly untreated patients with multiple myeloma: A Chinese experience,AMERICAN JOURNAL OF HEMATOLOGY, Issue 7 2010Hongfeng Guo Bortezomib has proven to be active in patients with multiple myeloma (MM), including elderly patients. The aim of this study was to evaluate the efficacy and toxicity of bortezomib in combination with intermediate-dose dexamethasone (Dex) and thalidomide in untreated MM patients aged ,65 years in a Chinese single center. In this study, 18 patients were treated with bortezomib at 1.3 mg/m2 IV on Days 1, 4, 8, and 11 and Dex at 20 mg/day IV on Days 1,4 and 8,11 simultaneously. Thalidomide at dose of 100 mg/day was given everyday. The mean number of cycles of bortezomib treatment was 2.06. Three patients (17%) achieved a complete response (CR), four (22%) a very good partial response (VGPR), and nine (50%) a PR, resulting in an overall response rate of 89%. The median time to response was 22 days (range 14,50 days). The duration of response was significantly longer in patients achieving a CR/VGPR with respect to those achieving only a PR (8.5 vs. 4.2 months, P = 0.03). Grade 3,4 toxicities occurring in patients comprised weakness, thrombocytopenia, diarrhea, infection, and neuropathy. Only one patient suffered from deep vein thrombosis. This preliminary experience in Chinese patients indicated that bortezomib-Dex-thalidomide is highly effective in elderly untreated patients with MM, even in patients with poor prognostic features. Am. J. Hematol. 2010. © 2010 Wiley-Liss, Inc. [source] Non-myeloablative conditioning and allogeneic transplantation for multiple myeloma,AMERICAN JOURNAL OF HEMATOLOGY, Issue 4 2010Keren Osman In multiple myeloma (MM), allogeneic stem cell transplantation (alloHCT) carries a lower relapse risk than autologous transplantation but a greater transplant-related mortality. Nonmyeloablative conditioning for allogeneic transplantation (NST) reduces transplant-related toxicity. Results are encouraging when used during first remission in low-risk patients, but less-so in relapsed or refractory disease. This is a single-center retrospective analysis of 20 previously treated MM patients who underwent NST from matched-related or matched-unrelated donors from 2000,2006. Median age was 52.7 years (37.2,68.0). Twenty-five percent had advanced or high-risk disease. Eleven still had active disease prior to NST. Conditioning was total body irradiation 200 cGy on a single fraction on day ,5, followed by antithymocyte globulin (ATG) 1.5 mg/kg/day and fludarabine 30 mg/m2/day on days ,4 to ,2. All received immunosuppression, most commonly with oral mycofenylate mofetil and cyclosporine beginning on day ,5. At day 100, 50% had achieved complete remission. Transplant-related mortality was 25%. Median overall survival (OS) was 21.2 months (0.6,90+) and progression-free survival (PFS) 6.6 months (0.6,90+). Both OS and PFS were 24% at 3 years. OS was significantly greater for patients with age <52 years (median 27 months vs. 7.9 months, P = 0.031), and there was a trend toward greater OS for those with ,2 microglobulin <2.5 mg/l (median 27 months vs. 7.7 months, P = 0.08). Donor characteristics and Ig type had no significant effect on survival. These data suggest a benefit of NST in relapsed/refractory MM. Randomized trials must be performed to confirm and further qualify this benefit. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] Retrospective comparison of mobilization methods for autologous stem cell transplantation in multiple myeloma,AMERICAN JOURNAL OF HEMATOLOGY, Issue 12 2009Hideki Nakasone The combination of cyclophosphamide and granulocyte-colony stimulating factor (G-CSF) has widely been used to mobilize hematopoietic stem cells (HSCs) for autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Recently, however, alternative approaches such as G-CSF alone or etoposide followed by G-CSF have been investigated. We, therefore, retrospectively analyzed the effects of these mobilization methods on collection yield and disease outcome in ASCT for MM. We reviewed 146 MM patients from whom we intended to collect stem cells. For mobilization, 67, 58, and 21 patients received cyclophosphamide and G-CSF, etoposide and G-CSF, and G-CSF alone (including nonmyelosuppressive chemotherapy followed by G-CSF), respectively. Among them, 136 achieved the target number of HSCs (at least 2 × 106/kg). Lower creatinine and higher albumin levels at diagnosis were significantly associated with successful yield. A lower number of infused HSCs, use of the etoposide for mobilization and high ISS were associated with delayed hematopoietic recovery. The mobilization methods did not significantly affect either the successful collection of more than 2 × 106 CD34-positive cells/kg or PFS after ASCT. G-CSF alone was sufficient for stem cell mobilization for a single ASCT. The optimal approach to collect HSCs in MM remains to be elucidated. Am. J. Hematol., 2010. © 2009 Wiley-Liss, Inc. [source] Acute weight gain and diastolic dysfunction as a potent risk complex for post stem cell transplant atrial fibrillation,AMERICAN JOURNAL OF HEMATOLOGY, Issue 8 2009Kaniz Fatema The management of atrial fibrillation (AF) following stem cell transplant (SCTX) is often challenging because of the universal presence of profound bone marrow suppression. The incidence of and risk factors for AF/flutter following SCTX are not well known. A total of 395 multiple myeloma (MM) patients consecutively underwent SCTX between 2002 and 2005 at the Mayo Clinic, and 383 of whom, mean age 57 ± 9 years, had no history of evidence of AF/flutter constituted the study population. During 1,002 person-years of follow up, 39 (10%) patients developed first AF/flutter (incidence of 39 per 1,000 person years), and 28 of these (72%) occurred within 21 days of SCTX. In multivariable-adjusted analyses, weight gain of ,7% in the 1st week post-SCTX (HR 3.68; P = 0.0120) and presence of diastolic dysfunction at MM diagnosis (HR 2.294; P = 0.0082) were independent predictors of AF/flutter. The risk of AF/flutter post-SCTX increased by about ninefold when both factors were present. Compared to age and sex-matched MM patients without SCTX, the risk of AF/flutter differed significantly only over the 1st year after MM diagnosis, during which SCTX was performed for the majority. Beyond the 1st year, there was no significant difference in risk of AF/flutter between the two groups. The data suggested that SCTX was associated with significantly increased risk of first AF/flutter, which typically occurred within the first 21 days of the transplant. Weight gain of ,7% was strongly predictive of first AF/flutter, and the risk was augmented by the presence of diastolic dysfunction at baseline. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Impact of vitamin D deficiency on the clinical presentation and prognosis of patients with newly diagnosed multiple myeloma,,AMERICAN JOURNAL OF HEMATOLOGY, Issue 7 2009Alvin C. Ng Vitamin D is a fundamental mediator of skeletal metabolism. It also has important nonskeletal actions. We hypothesized that vitamin D deficiency may play an important role in skeletal morbidity and clinical outcomes in MM. We studied 148 newly diagnosed MM patients from January 1, 2004 through December 31, 2008 who had a serum 25-hydroxyvitamin D [25(OH)D] obtained within 14 days of diagnosis. Subjects with vitamin D deficiency [25(OH)D level less than 50 nmol/L (20 ng/mL)] had higher mean values of serum C-reactive protein (CRP) (2.40 mg/L vs. 0.84 mg/L, P = 0.02) and creatinine (1.75 mg/dL vs. 1.24 mg/dL, P = 0.03) and lower serum albumin values (3.12 g/dL vs. 3.39 g/dL, P = 0.003) compared to subjects without vitamin D deficiency. The prevalence of vitamin D deficiency increased in parallel with International Staging System (ISS): 16% of subjects in Stage I, 20% in Stage II, and 37% in Stage III (P = 0.03) were vitamin D deficient. No differences were detected between the two groups in terms of skeletal morbidity. Association of vitamin D deficiency with higher serum CRP, serum creatinine and ISS stage at time of diagnosis suggests that vitamin D deficiency may portend poorer outcomes in subjects with MM. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] Familial myeloma and monoclonal gammopathy: A report of eight African American families,AMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2009Maneesh Jain Previous descriptions of familial myeloma have been mainly of Caucasian families. We report here eight African American families with familial multiple myeloma and monoclonal gammopathy identified over a 30 year period. Six patients with multiple myeloma (MM) and two with monoclonal gammopathy of unknown significance (MGUS) reported a family history of MM or had family members with MGUS found on screening. A pedigree compiled for each family included a history of other cancers. In the eight families, 21 of 58 first degree relatives had a plasma cell dyscrasia including 12 MM, eight MGUS, and one amyloidosis patient(s). The age of the MM patients ranged from 50 to 78 years (median 61 years). Four families had two members with MM, including one mother,son and three sibling pairs. Two MM families each had two additional first degree relatives with MGUS, with three generations involved in one family. Anticipation was suggested in two families with parent,child pairs with monoclonal gammopathy. The eight pedigrees had 66 members, 21 of whom had a diagnosis of cancer, including non-Hodgkin lymphoma and Hodgkin disease, or a clonal myeloproliferative disorder other than MM. Although the mode of genetic transmission and anticipation cannot be confirmed due to the small sample size, the increased number of MM and MGUS family members suggests underlying genetic susceptibility factors for plasma cell dyscrasias and possibly for other cancers in these families. Am. J. Hematol., 2009. © 2008 Wiley-Liss, Inc. [source] Vitamin D and systemic cancer: is this relevant to malignant melanoma?BRITISH JOURNAL OF DERMATOLOGY, Issue 2 2002J.E. Osborne Summary 1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1,-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-, and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-, or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express the VDR, and the antiproliferative and prodifferentiation effects of 1,25(OH)2D3 have been shown in cultured melanocytes, MM cells and MM xenografts. Recently, an inhibitory effect on the spread of MM cells has been demonstrated, low serum levels of 1,25(OH)2D3 have been reported in MM patients and the VDR polymorphisms have been shown to be associated with both the occurrence and outcome of MM. The relationship between solar irradiation and MM is more complex than for the systemic cancers. As in other cancers, there is evidence of a protective effect of vitamin D3 in MM, but ultraviolet radiation, which is a principal source of vitamin D3, is mutagenic. Further work is necessary on the influence of serum vitamin D3 levels on the occurrence and prognosis of MM, the effects of sun protection measures on serum vitamin D3 levels in temperate climates and epidemiological studies on geographical factors and skin type on the prognosis of MM. Meanwhile, it would seem mandatory to ensure an adequate vitamin D3 status if sun exposure were seriously curtailed, certainly in relation to carcinoma of breast, prostate and colon and probably also MM. [source] Prediction of survival using absolute lymphocyte count for newly diagnosed patients with multiple myeloma: a retrospective studyBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2008Hilmi Ege Summary Absolute lymphocyte count (ALC) recovery after autologous stem cell transplantation for multiple myeloma (MM) has been reported to be an independent prognostic factor for clinical outcome. The role of ALC on survival in newly diagnosed untreated MM patients is unknown. Between 1994 and 2002, we analysed retrospectively 537 MM patients of 1835 consecutive MM patients that were neither uniformly treated nor part of a clinical trail, but originally diagnosed and followed at the Mayo Clinic. The primary endpoint was to assess the role of ALC at the time of MM diagnosis on overall survival (OS). The median follow-up was 35·1 months (range: 1,152·5 months). ALC, as a continuous variable, was identified as prognostic factor for OS (Hazard ratio = 0·473, 95% confidence interval = 0·359,0·618, P < 0·0001). MM patients with an ALC ,1·4 × 109/l experienced superior OS compared with MM patients with an ALC <1·4 × 109/l (65 vs. 26 months, P < 0·0001). Multivariate analysis identified ALC as an independent prognostic factor for OS. This study showed that, in newly diagnosed MM, ALC is an independent prognostic factor for OS, suggesting a significant role of host immune status in the survival of MM. [source] Serum pleiotrophin levels are elevated in multiple myeloma patients and correlate with disease statusBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2006Howard S. Yeh Summary Pleiotrophin (PTN), a tightly regulated angiogenic and mitogenic heparin-binding protein, is markedly elevated in a variety of aggressive solid tumours. The role of PTN in haematological malignancies, however, has not been previously evaluated. This study demonstrated that PTN serum levels were elevated in multiple myeloma (MM) patients when compared with healthy subjects (P < 0·0001). Serum levels of this protein significantly increased during progression of disease, and decreased during response to anti-MM therapy (P < 0·001). These results suggest that serum PTN may be a new biomarker for monitoring the disease status and therapeutic response of MM patients. [source] Either interleukin-12 or interferon-, can correct the dendritic cell defect induced by transforming growth factor ,1 in patients with myelomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2004Ross Brown Summary The poor response to immunotherapy in patients with multiple myeloma (MM) indicates that a better understanding of any defects in the immune response in these patients is required before effective therapeutic strategies can be developed. Recently we reported that high potency (CMRF44+) dendritic cells (DC) in the peripheral blood of patients with MM failed to significantly up-regulate the expression of the B7 co-stimulatory molecules, CD80 and CD86, in response to an appropriate signal from soluble trimeric human CD40 ligand. This defect was caused by transforming growth factor ,1 (TGF,1) and interleukin (IL)-10, produced by malignant plasma cells, and the defect was neutralized in vitro with anti-TGF,1. As this defect could impact on immunotherapeutic strategies and may be a major cause of the failure of recent trials, it was important to identify a more clinically useful agent that could correct the defect in vivo. In this study of 59 MM patients, the relative and absolute numbers of blood DC were only significantly decreased in patients with stage III disease and CD80 up-regulation was reduced in both stage I and stage III. It was demonstrated that both IL-12 and interferon- , neutralized the failure to stimulate CD80 up-regulation by huCD40LT in vitro. IL-12 did not cause a change in the distribution of DC subsets that were predominantly myeloid (CD11c+ and CDw123,) suggesting that there would be a predominantly T-helper cell type response. The addition of IL-12 or interferon- , to future immunotherapy trials involving these patients should be considered. [source] Occurrence of dysregulated oncogenes in primary plasma cells representing consecutive stages of myeloma pathogenesis: indications for different disease entitiesBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2003Thomas Rasmussen Summary. This study investigated the expression pattern in primary plasma cells (PCs) of putative oncogenes suggested to be involved in multiple myeloma (MM) development. cDNA archives were generated by global reverse transcription polymerase chain reaction from CD38++/CD19,/CD56,/++ aberrant PCs of a prospective cohort of 96 subjects, including healthy individuals, patients with monoclonal gammopathies of undetermined significance (MGUS), MM and MM with extramedullary manifestations (ExMM). The cDNA archives were analysed quantitatively for expression of the cyclin D1, fibroblast growth factor receptor 3 (FGFR3), C-MYC, C-MAF and cyclin D3 oncogenes. In addition, all patients were screened for IGH,MMSET hybrid transcripts. None of the analysed oncogenes was randomly distributed. C-MYC and cyclin D3 expression increased at the extramedullary transformation stage. Furthermore, C-MYC and cyclin D3 expression in CD56+ MM was similar to MGUS, whereas CD56, MM was similar to ExMM. FGFR3/IGH,MMSET was only observed among CD56+ MM patients, whereas an increased frequency of C-MAF dysregulation was seen among CD56, MM. High cyclin D1 expression levels were identified at similar frequencies at all stages, whereas the frequency of patients with low cyclin D1 levels increased during MM development. These data support the stepwise transformation model accumulating genetic alterations and proliferative capacity during MM initiation and development resulting in different clinical entities. [source] Soluble urokinase-type plasminogen activator receptor (suPAR) as an independent factor predicting worse prognosis and extra-bone marrow involvement in multiple myeloma patientsBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2003Gian Matteo Rigolin Summary. The urokinase-type plasminogen activator (uPA) system, which consists of a proteinase (uPA), a receptor (uPAR or CD87) and inhibitors, is involved in proteolysis, cell migration, tissue remodelling, angiogenesis and cell adhesion. Recent findings suggest that malignant plasma cells express uPA and uPAR. The expression of these factors could represent a process by which myeloma plasma cells interact with the bone marrow (BM) environment and influence important biological events such as bone matrix degradation, plasma cell invasion and homing and, possibly, clinical evolution. We evaluated uPAR (CD87) and its soluble form (suPAR) in 49 multiple myeloma (MM) patients and correlated their expression and levels with clinico-biological characteristics of the disease. Flow cytometric analysis demonstrated that CD87 was expressed in all MM patients. High CD87 expression was associated with higher intensity of expression of CD56 (P = 0·038), CD38 (P = 0·058) and CD138 (P = 0·054) and CD45bright positivity (P = 0·014). suPAR levels correlated positively with soluble serum CD138 (P = 0·001), creatinine (P = 0·001), beta2 -microglobulin (P < 0·001), disease stage (P = 0·017) and extra-BM involvement (P = 0·002). In the 46 evaluable patients, multivariate analysis showed that high levels of suPAR (P = 0·0214) and disease stage (P = 0·0064) were predictive of extra-BM involvement. In multivariate Cox analysis, 13q deletion (P = 0·0278), high soluble serum CD138 (P = 0·0201) and high suPAR (P = 0·0229) were the only parameters that independently affected survival. We conclude that CD87 is expressed on myeloma plasma cells and that suPAR, which predicts extra-BM involvement and poor prognosis, possibly represents a molecule with a relevant role in the biology of MM. [source] A pooled analysis of karyotypic patterns, breakpoints and imbalances in 783 cytogenetically abnormal multiple myelomas reveals frequently involved chromosome segments as well as significant age- and sex-related differencesBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2003Thérèse Nilsson Summary. The cytogenetic features (ploidy, complexity, breakpoints, imbalances) were ascertained in 783 abnormal multiple myeloma (MM) cases to identify frequently involved chromosomal regions as well as a possible impact of age/sex. The series included MM patients from the Mitelman Database of Chromosome Aberrations in Cancer and from our own laboratory. Hyperdiploidy was most common, followed by hypodiploidy, pseudodiploidy and tri-/tetraploidy. Most cases were complex, with a median of eight changes per patient. The distribution of modal numbers differed between younger and older patients, but was not related to sex. No sex- or age-related differences regarding the number of anomalies were found. The most frequent genomic breakpoints were 14q32, 11q13, 1q10, 8q24, 1p11, 1q21, 22q11, 1p13, 1q11, 19q13, 1p22, 6q21 and 17p11. Breaks in 1p13, 6q21 and 11q13 were more common in the younger age group. The most frequent imbalances were +,9, ,,13, +,15, +,19, +,11 and ,,Y. Trisomy 11 and monosomy 16 were more common among men, while ,X was more frequent among women. Loss of Y as the sole change and +,5 were more common in elderly patients, and ,,14 was more frequent in the younger age group. The present findings strongly suggest that some karyotypic features of MM are influenced by endogenous and/or exogenous factors. [source] Extent of disease burden determined with magnetic resonance imaging of the bone marrow is predictive of survival outcome in patients with multiple myelomaCANCER, Issue 1 2010Sikander Ailawadhi MD Abstract BACKGROUND: Multiple myeloma (MM) remains an incurable cancer. Treatment often is initiated at the time patients experience a progressive increase in tumor burden. The authors of this report investigated magnetic resonance imaging of the bone marrow (BM-MRI) as a novel approach to quantify disease burden and validated a staging system by correlating BM-MRI with common clinical and laboratory parameters. METHODS: The extent of bone marrow involvement was evaluated by BM-MRI. Clinical and laboratory parameters were assessed in patients with active MM, and correlations between variables were assessed statistically. Bone marrow involvement by BM-MRI was defined as stage A (0%), stage B (<10%), stage C (10%-50%), and stage D (>50%). RESULTS: In total, 170 consecutive patients were evaluated (77 women and 93 men), including 144 patients who had active MM. The median age was 61 years (age range, 35-83 years). Advance stage disease (stage >I) based on Durie-Salmon (DS) staging or International Staging System (ISS) criteria was observed in 122 patients (84%) and 77 patients (53%), respectively. Lytic bone disease was noted in 120 patients (83%). There was a significant association between BM-MRI involvement and DS stage (P = .0006), ISS stage (P = .0001), the presence of lytic bone disease (P < .0001) and mean ,-2 microglobulin levels (P < .0001). Among the patients with previously untreated MM, there was a significant association between BM-MRI stage and overall survival (OS) (univariate P = .013; multivariate P = .045). Plasmacytosis on bone marrow biopsy at diagnosis was not predictive of OS (P = .91). CONCLUSIONS: BM-MRI is a novel approach for quantifying disease burden in patients with MM. The current investigation in a large cohort of nontransplantion MM patients demonstrated that the extent of bone marrow involvement determined by BM-MRI correlates accurately with other conventional parameters of disease burden and can independently predict survival in patients with MM at the time of initial diagnosis. Cancer 2010. © 2010 American Cancer Society. [source] Characterization of bone marrow T cells in monoclonal gammopathy of undetermined significance, multiple myeloma, and plasma cell leukemia demonstrates increased infiltration by cytotoxic/Th1 T cells demonstrating a squed TCR-V, repertoireCANCER, Issue 6 2006Martin Pérez-Andres M.D. Abstract BACKGROUND The majority of studies published to date regarding the role of the bone marrow (BM) microenvironment in the pathogenesis of monoclonal gammopathies (MG) have focused on the interaction between stroma cells and plasma cells, whereas information concerning the lymphocytes infiltrating the tumor microenvironment is scanty. METHODS The authors measured the distribution, TCR-V, repertoire, immunophenotype, and functional characteristics of different subsets of BM T lymphocytes from 61 nontreated patients with MG (30 patients with MG of undetermined significance [MGUS], 27 patients with multiple myeloma [MM], and 4 patients with plasma cell leukemia [PCL]). RESULTS The authors found a significantly increased rate of BM infiltration by T cells in all patient groups, at the expense of CD4+CD8, and CD4,CD8, T lymphocytes and both CD4+CD28, and CD8+CD28, cytotoxic/effector T cell subsets, and associated with TCR-V, expansions in both CD4+ and CD8+ BM T cells in the majority of patients with MGUS, MM, and PCL. Moreover, the percentage of T cells secreting interferon (IFN)-, was found to be increased (P , 0.05) both in CD4+ and CD8+ T cells in MGUS and MM patients, and a higher plasma concentration of IFN-, was found in patients with MM. It is interesting to note that a positive correlation was noted between the proportion of CD28, and both the percentage of IFN-,,secreting cells and the proportion of expanded TCR-V, lymphocytes within the total BM CD4+ T cells. CONCLUSIONS The results of the current study demonstrated an increased infiltration of BM by T cells associated with frequent TCR-V, expansions and a more prominent cytotoxic/Th1 phenotype in all the patient groups studied. Cancer 2006. © 2006 American Cancer Society. [source] | |||||||||||||||||||||||||