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Bart Barlogie

Publications and source records attributed to Bart Barlogie.

At least 37 records · Page 2Linked to original sources
PubMed2006

Fibroblast activation protein (FAP) is upregulated in myelomatous bone and supports myeloma cell survival.

The microenvironment plays a critical role in facilitating cancer progression and metastasis. We previously demonstrated the ability of osteoclasts to support primary myeloma plasma cell (MM PC) growth. Our study on the role of the bone marrow (BM) microenvironment in myeloma, using global gene expression profiling, has identified fibroblast activation protein (FAP) as one of 28 genes significantly overexpressed in cocultured osteoclasts. Because FAP has been previously implicated in tumorigenesis and shown to be selectively expressed by the reactive stroma of epithelial tumours, we focused our study on the role of this serine protease in myeloma. Using quantitative polymerase chain reaction amplification, we demonstrated upregulation of FAP by cocultured osteoclasts and mesenchymal stem cells, and in whole myelomatous human bone in SCID-hu mice. Immunohistochemical analysis of myelomatous bone sections revealed FAP expression by osteoclasts, osteogenic cells, fibrotic stroma and certain adipocytes and vascular endothelial cells. FAP was not expressed in PCs by all these methods. Inhibition of FAP expression with the use of small-interference RNA reduced MM PC survival in cocultures. Our results indicate that FAP is critical for the interaction of MM cells with the BM microenvironment--a potential therapeutic target in myeloma.

Adipocytes↗
PubMed2006

Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism.

Acquired activated protein C resistance (aAPCR), not associated with factor V Leiden, has been described in cancer patients with an increased risk of venous thromboembolism (VTE). APCR was determined in 1178 myeloma patients using an activated partial thromboplastin time-based resistance assay in the presence of excess of factor V-deficient plasma; polymerase chain reaction amplification of genomic DNA was used to detect factor V Leiden mutation. A total of 109 patients were found to have abnormal APCR and one-third of them were carriers for the mutation. With a median follow-up of 40 months, the presence of aAPCR was associated with a significantly increased risk of thrombosis (P < or = 0.001). APCR was measured again after treatment in 31 patients with abnormal baseline values and had normalised in 30 of them. This study indicates that aAPCR is the most common single transitory baseline coagulation abnormality associated with VTE in myeloma patients.

Activated Protein C Resistance↗
PubMed2006

Superior 12-year survival after at least 4-year continuous remission with tandem transplantations for multiple myeloma.

BACKGROUND: Complete response has been considered a surrogate for favorable long-term outcome in multiple myeloma. Data on the impact of the duration of response on prognosis are lacking. PATIENTS AND METHODS: Of the 899 patients enrolled in Total Therapy trials (Total Therapy 1, N = 231; Total Therapy 2, N = 668), 254 survived for > 5 years. The prognostic impact of continuous (Rc) versus discontinuous (Rd) 4-year remission after 5-year survival was examined along with laboratory features present at baseline and at 5 years. RESULTS: Most baseline prognostic features were evenly distributed among Rc and Rd groups; however, a greater proportion of Rc patients were enrolled in Total Therapy 2 (60%) compared with Rd (19%; P < 0.001). Twelve-year survival (7 years after the 5-year landmark) was 66% with Rc and only 30% with Rd. Hypodiploidy and deletion 13, present in 24 patients at baseline, were associated with a 12-year survival of only 20%. Among the 200 patients lacking these cytogenetic abnormalities, Rc (n = 141) defined a superior 12-year survival rate of 70% versus 35% among those with Rd (n = 59). Initial quality of response (complete response) or having received the scheduled tandem transplantations did not affect post-5-year survival. CONCLUSION: Five-year Rc appears to be an important prerequisite for prolonged subsequent overall survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Inhibitory effects of osteoblasts and increased bone formation on myeloma in novel culture systems and a myelomatous mouse model.

BACKGROUND AND OBJECTIVES: Multiple myeloma (MM) growth in the bone marrow is associated with increased osteoclast activity and a reduced number of osteoblasts. Experimental studies suggest that bone disease drives the progression of MM. Whereas those studies focused on the critical role of myeloma-induced osteoclastogenesis in disease progression, little is known about the impact of osteoblasts and increased bone formation on MM. DESIGN AND METHODS: We investigated the effect of isolated osteoblasts and osteoclasts on survival and proliferation of primary MM plasma cells (PC) in co-cultures and triple-cultures, and tested the effect of mesenchymal stem cells (MSC) on bone mineral density and MM growth in myelomatous human bones of SCID-hu mice. RESULTS: Whereas osteoclasts promoted survival and proliferation of MM PC, osteoblasts supported or inhibited MM PC, depending on the source of the MM cells. In triple-cultures osteoblasts attenuated the effect of osteoclasts on MM PC in 18 of 24 experiments. The anti-MM response to osteoblasts correlated with advanced clinical stage. Injection of MSC into myelomatous bones resulted in marked inhibition of tumor growth in three of nine experiments and stabilization of disease in two additional experiments. The anti-MM response of MSC was associated with increased human bone mineral density. Immunohistochemical analysis indicated that the MSC were well engrafted and, in responding mice, differentiated into osteogenic cells. INTERPRETATION AND CONCLUSIONS: MM PC from the majority of patients are susceptible to growth inhibition by osteoblasts; however, growth of MM PC from certain patients is accelerated by osteoblasts. In vivo, increased bone formation is associated with reduced myeloma burden.

Animals↗
PubMed2006

Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone.

BACKGROUND AND OBJECTIVES: The efficacy and safety of added dexamethasone were assessed in patients with relapsed and/or refractory multiple myeloma who had a suboptimal response to bortezomib alone. DESIGN AND METHODS: In two previously reported, open-label, multicenter phase 2 studies, bortezomib 1.0 or 1.3 mg/m2 was administered intravenously twice weekly for 2 weeks of a 3-week cycle for up to 8 cycles to patients who had failed either > or = 2 lines of therapy (SUMMIT, n=202) or first-line therapy (CREST, n=54). Patients with progressive disease after the first two cycles or stable disease after four cycles of bortezomib were eligible for addition of oral dexamethasone 20 mg on the day of and after each bortezomib dose. Responses were assessed by an Independent Review Committee using European Group for Blood and Marrow Transplantation criteria. RESULTS: Addition of dexamethasone to bortezomib was associated with improved responses in 13 of 74 evaluable patients (18%) in SUMMIT and 9 of 27 (33%) in CREST; eight of these 22 patients had been previously refractory to dexamethasone. There were 2 complete, 8 partial, and 12 minimal responses. Dexamethasone did not appear to alter the type or number of adverse events. Treatment-emergent adverse events reported in > or = 20% of patients receiving combination therapy were fatigue (25%), thrombocytopenia (24%), insomnia (21%), and nausea (20%). INTERPRETATION AND CONCLUSIONS: Addition of dexamethasone to bortezomib in patients with relapsed and/or refractory myeloma who had suboptimal responses to bortezomib alone was associated with improvement in responses without prohibitive toxicity.

Adult↗
PubMed2006

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

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.

Biopsy↗
PubMed2005

Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies.

Patients with myeloma, treated on the thalidomide arm of total therapy 2 (TT2), had a higher complete response (CR) rate and improved event-free survival (EFS) but not overall survival (OS). To evaluate the benefit of TT2's posttandem autotransplant consolidation chemotherapy and dexamethasone maintenance, outcomes were compared on TT2 without thalidomide (n = 345; median follow-up, 3.5 years) and on predecessor trial TT1 (n = 231; median follow-up, 11.5 years). CR rates were similar (43% vs 41%); however, 5-year estimates of continuous CR (45% vs 32%, P < .001) and 5-year EFS (43% vs 28%, P < .001) were superior with TT2, with a trend for improved OS (62% vs 57%; P = .11). OS was also superior among patients achieving CR and receiving the second transplantation early after the first transplantation. Superior EFS and OS with TT2 versus TT1 was noted in the two thirds presenting without cytogenetic abnormalities (CAs); 4-year posttandem transplantation OS for patients with CAs was 47% with TT1 and 76% with TT2 when combination chemotherapy rather than DEX was applied for consolidation (P = .040). Thus, TT2 (without thalidomide) improved OS of patients without CAs; those with CAs benefited from posttransplantation consolidation chemotherapy. The favorable effects of CR and rapidly sequenced second transplantation attest to the validity of a melphalan dose-response effect in myeloma.

Aged↗
PubMed2005

Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma.

BACKGROUND: Bortezomib, a first-in-class proteasome inhibitor, is active with manageable toxicities in relapsed and/or refractory myeloma. METHODS: Bortezomib 1.0 or 1.3 mg/m2 was administered Days 1, 4, 8, and 11 every 21 days for up to 8 cycles to patients with relapsed and/or refractory myeloma participating in two Phase II trials. Dexamethasone could be added because of progressive disease after 2 cycles or stable disease after 4 cycles. Continuation of or retreatment with bortezomib was offered to patients who, in the investigator's opinion, would benefit from extended treatment. RESULTS: Sixty-three patients with relapsed/refractory myeloma treated in this extension trial received a median of 7 additional cycles of therapy, for a total of 14 cycles (range, 7-32) over a median duration of therapy of 45.1 weeks in the parent and extension studies. Seventy-eight percent of patients completed this study at the same or higher bortezomib dose than they started on during this study, and the treatment schedule of twice-weekly administration remained unchanged in 89%. Overall, 75% of patients received dexamethasone in combination with bortezomib for a median of 5 cycles starting either in the parent or extension study. The safety profile was similar between the extension and parent trials, with no evidence of new cumulative toxicity. The most commonly reported Grade 3/4 toxicities were thrombocytopenia (29%), with a consistent pattern of recovery during the rest period of each cycle, diarrhea (11%), anemia (11%), and neutropenia (10%). Neuropathy was reported less frequently. CONCLUSIONS: Retreatment with or continuation of bortezomib +/- dexamethasone beyond 6 months was safe, and toxicities were manageable, in patients with relapsed and/or refractory myeloma.

Adult↗
PubMed2005

Protein transduction of dendritic cells for NY-ESO-1-based immunotherapy of myeloma.

Myeloma vaccines, based on dendritic cells pulsed with idiotype or tumor lysate, have been met with limited success, probably in part due to insufficient cross-priming of myeloma antigens. A powerful method to introduce myeloma-associated antigens into the cytosol of dendritic cells is protein transduction, a process by which proteins fused with a protein transduction domain (PTD) freely traverse membrane barriers. NY-ESO-1, an immunogenic antigen by itself highly expressed in 60% of high-risk myeloma patients, was purified to near homogeneity both alone and as a recombinant fusion protein with a PTD, derived from HIV-Tat. Efficient entry of PTD-NY-ESO-1 into dendritic cells, confirmed by microscopy, Western blotting, and intracellular flow cytometry, was achieved without affecting dendritic cell phenotype. Experiments with amiloride, which inhibits endocytosis, and N-acetyl-l-leucinyl-l-norleucinal, a proteasome inhibitor, confirmed that PTD-NY-ESO-1 entered dendritic cells by protein transduction and was degraded by the proteasome. Tetramer analysis indicated superior generation of HLA-A2.1, CD8+ T lymphocytes specific for NY-ESO-1(157-165) with PTD-NY-ESO-1 compared with NY-ESO-1 control protein (44% versus 2%, respectively). NY-ESO-1-specific T lymphocytes generated with PTD-NY-ESO-1 secreted IFN-gamma indicative of a Tc1-type cytokine response. Thus, PTD-NY-ESO-1 accesses the cytoplasm by protein transduction, is processed by the proteasome, and NY-ESO-1 peptides presented by HLA class I elicit NY-ESO-1-specific T lymphocytes.

Amiloride↗
PubMed2005

ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma.

ARK5, AMP-activated protein kinase (AMPK)-related protein kinase mediating Akt signals, is closely involved in tumor progression, and its stage-associated expression was observed in colorectal cancer. In this study, we found ARK5 expression in multiple myeloma cell lines expressing c-MAF and MAFB. In addition, gene expression profiling of 351 clinical specimens revealed ARK5 expression in primary myelomas expressing c-MAF and MAFB, suggesting that ARK5 may be a transcriptional target of the Large-MAF family. Sequence analysis of the ARK5 gene promoter revealed that it contains two putative MAF-recognition element (MARE) sequences. In support of this hypothesis, ARK5 was induced when an MAFB or c-MAF expression vector was introduced into non-ARK5-expressing colon cancer cells. Furthermore, ARK5 promoter activity was dramatically decreased by mutation or deletion of MARE sequences. Chromatin immunoprecipitation assays revealed an interaction between the Large-MAF family proteins and MARE sequences in the ARK5 promoter. Moreover, in ARK5 mRNA-expressing multiple myeloma lines, but not in ARK5-negative lines, insulin-like growth factor (IGF)-1 increased invasion activity. IGF-1-induced invasion was reproduced when ARK5 was overexpressed in Burkitt's lymphoma and plasmacytoma lines. Based on results, we conclude that ARK5 is a transcriptional target of the Large-MAF family through MARE sequence and that ARK5 may in part mediate the aggressive phenotype associated with c-MAF- and MAFB-expressing myelomas.

Base Sequence↗
PubMed2005

Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma.

Bortezomib, a proteasome inhibitor with efficacy in multiple myeloma, is associated with thrombocytopenia, the cause and kinetics of which are different from those of standard cytotoxic agents. We assessed the frequency, kinetics, and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m2 in 228 patients with relapsed and/or refractory myeloma in 2 phase 2 trials. The mean platelet count decreased by approximately 60% during treatment but recovered rapidly between treatments in a cyclic fashion. Among responders, the pretreatment platelet count increased significantly during subsequent cycles of therapy. The mean percent reduction in platelets was independent of baseline platelet count, M-protein concentration, and marrow plasmacytosis. Plasma thrombopoietin levels inversely correlated with platelet count. Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity, ploidy, or morphology. These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors. The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown but it is unlikely to be related to marrow injury or decreased thrombopoietin production.

Adult↗
PubMed2005

Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma.

Bortezomib, a potent and reversible proteasome inhibitor, affects the myeloma cell and its microenvironment, resulting in down-regulation of growth and survival signaling pathways and durable responses in patients with relapsed and refractory myeloma. Potential associations between baseline parameters and outcomes with bortezomib were explored in 202 patients who received bortezomib 1.3 mg/m2 twice weekly for 2 weeks every 3 weeks for up to 8 cycles in a phase 2 trial. Using European Group for Blood and Marrow Transplantation criteria, the response rate (complete or partial response) to bortezomib alone was 27% and was not associated with sex, race, performance status, isotype, chromosome 13 deletion, number or type of previous therapies, or concentration of hemoglobin or beta2-microglobulin. By multivariate analysis, factors associated with lower response were being age 65 or older versus younger than 65 (19% vs 32%; P < .05) and plasma-cell infiltration in bone marrow greater than 50% versus 50% or less (20% vs 35%; P < .05). Factors that may be indicative of tumor burden (bone marrow plasma-cell infiltration greater than 50%, hypoalbuminemia, thrombocytopenia) were predictive of overall survival. Chromosome 13 deletion and elevated beta2-microglobulin, generally considered poor prognostic factors, were not predictive of poor outcome with bortezomib in this study.

Aged↗
PubMed2005

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.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adult↗
PubMed2005

International staging system for multiple myeloma.

PURPOSE: There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. PATIENTS AND METHODS: Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies. RESULTS: Serum beta2-microglobulin (Sbeta2M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sbeta2M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sbeta2M less than 3.5 mg/L plus serum albumin > or = 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sbeta2M > or = 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and > or = 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. CONCLUSION) The new ISS is simple, based on easy to use variables (Sbeta2M and serum albumin), and recommended for early adoption and widespread use.

Age Factors↗
PubMed2005

Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impared renal function.

BACKGROUND: Bortezomib is a potent, reversible proteasome inhibitor that has been approved for the treatment of recurrent and/or refractory multiple myeloma, but its activity in patients with renal impairment has not been studied to date. METHODS: Response rates, safety, and 20S proteasome activity were assessed in relation to baseline creatinine clearance (CrCl) among patients with recurrent and/or refractory myeloma (n = 256 patients) who were treated with bortezomib in 2 Phase II trials. Bortezomib was administered by intravenous bolus on Days 1, 4, 8, and 11 of a 21-day cycle at 2 doses, 1.0 mg/m2 (n = 28 patients) and 1.3 mg/m2 (n = 228 patients). RESULTS: Of 10 patients with CrCl < or = 30 mL/minute, 7 patients completed the protocol-specified 8 cycles of treatment; 4 patients received the 1.3 mg/m2 bortezomib dose, and 3 patients received the 1.0 mg/m2 bortezomib dose. Using the European Group for Blood and Marrow Transplantation criteria, responses were assigned by an independent committee to 3 of the 10 patients (2 partial responses and 1 minimal response), a response rate similar to that of the overall treated population. Patients with CrCl > 80 mL/minute (n = 105 patients), 51-80 mL/minute (n = 99 patients), and < or = 50 mL/minute (n = 52 patients) had similar rates of discontinuation and similar adverse event profiles. Renal function did not appear to affect the 1-hour postdose proteasome inhibition or its recovery. CONCLUSIONS: Clinical experience in a limited number of patients with impaired renal function suggests that bortezomib provides clinical benefit with manageable toxicities in this high-risk population.

Adult↗
PubMed2005

Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma.

Two oncogenic pathways have been hypothesized for multiple myeloma (MM) and premalignant monoclonal gammopathy of undetermined significance (MGUS) tumors: a nonhyperdiploid pathway associated with a high prevalence of IgH translocations and a hyperdiploid pathway associated with multiple trisomies of 8 chromosomes. Cyclin D1, D2, or D3 expression appears to be increased and/or dysregulated in virtually all MM tumors despite their low proliferative capacity. Translocations can directly dysregulate CCND1 (11q13) or CCND3 (6p21), or MAF (16q23) or MAFB (20q11) transcription factors that target CCND2. Biallelic dysregulation of CCND1 occurs in nearly 40% of tumors, most of which are hyperdiploid. Other tumors express increased CCND2, either with or without a t(4;14) translocation. Using gene expression profiling to identify 5 recurrent translocations, specific trisomies, and expression of cyclin D genes, MM tumors can be divided into 8 TC (translocation/cyclin D) groups (11q13, 6p21, 4p16, maf, D1, D1+D2, D2, and none) that appear to be defined by early, and perhaps initiating, oncogenic events. However, despite subsequent progression events, these groups have differing gene expression profiles and also significant differences in the prevalence of bone disease, frequency at relapse, and progression to extramedullary tumor.

Bone Diseases↗
PubMed2005

Genomic instability in multiple myeloma: evidence for jumping segmental duplications of chromosome arm 1q.

Multiple myeloma (MM) is a malignant plasma cell disorder characterized by complex karyotypes and chromosome 1 instability at the cytogenetic level. Chromosome 1 instability generally involves partial duplications, whole-arm translocations, or jumping translocations of 1q, identified by G-banding. To characterize this instability further, we performed spectral karyotyping and fluorescence in situ hybridization with probes for satII/III (1q12), BCL9 (1q21), and IL6R (1q21) on the karyotypes of 44 patients with known 1q aberrations. In eight patients, segmental duplication of 1q12-21 and adjacent bands occurred on nonhomologous chromosomes. In five cases, the 1q first jumped to a nonhomologous chromosome, after which the 1q12-21 segment again duplicated itself 1-3 times. In three other cases, segmental duplications occurred after the 1q first jumped to a nonhomologous chromosome, where the proximal adjacent nonhomologous chromosome segment was duplicated prior to the 1q jumping or inserting itself into a new location. These cases demonstrate that satII/III DNA sequences are not only associated not only with the duplication of adjacent distal chromosome segments after translocation, but are also associated with the duplication and jumping/insertion of proximal nonhomologous chromosome segments. We have designated this type of instability as a jumping segmental duplication.

Adult↗