Images in cardiovascular medicine. Intermittent loss of second heart sound.
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Anti-Arrhythmia Agents↗
Biomedical subjects
Amin Rahemtulla
Publications and source records attributed to Amin Rahemtulla.
Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation.
Dickkopf-1 (DKK-1) protein, a soluble inhibitor of Wnt signalling, has been implicated in the pathogenesis of myeloma bone disease through the suppression of osteoblast differentiation. In this study, serum concentrations of DKK-1 were measured in 50 myeloma patients (32 at diagnosis and 18 before and after autologous stem cell transplantation (ASCT), 18 patients with monoclonal gammopathy of undetermined significance (MGUS), and 22 healthy controls. Serum DKK-1 levels were increased in MM at diagnosis compared with MGUS (mean +/- SD: 67 +/- 54 ng/mL vs. 38 +/- 13 ng/mL; p = 0.006) and controls (31 +/- 11 ng/mL; p = 0.02), while there was no difference between MGUS patients and controls. Although patients with stage 2 and 3 myeloma had higher DKK-1 values than stage 1 patients (79 +/- 63 vs. 40 +/- 13; p = 0.005), no significant correlation between serum DKK-1 and myeloma bone disease was observed. Myeloma patients before ASCT also had increased levels of DKK-1 (63 +/- 77 ng/mL; p = 0.03) compared with controls, supporting the notion that DKK-1 may be responsible for the suppressed osteoblast activity even in patients with low tumor burden. After ASCT, there was a sustained decrease in DKK-1 levels over time, while bone formation markers elevated, suggesting that the reduction of DKK-1 levels after ASCT may correlate with the normalization of osteoblast function. These results could provide the basis for developing agents that block DKK-1, thus restoring osteoblast function and counteracting the increased osteoclastogenesis observed in myeloma.
Adult↗
The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British Society of Blood and Marrow Transplantation study.
The outcome of high-dose chemotherapy (HDT) was evaluated retrospectively in 27 patients with myeloma and four patients with AL amyloidosis with severe renal impairment. Twenty-three patients were receiving dialysis and the rest had a creatinine clearance of <20 ml/min. The median melphalan dose was 140 mg/m2 (range: 60-200 mg/m2), but 10 patients (37%) received 200 mg/m2. Myeloid and platelet engraftment were similar to that seen in patients without renal failure. Five of 27 patients died of transplant-related toxicity before the day 100. Twenty of 27 patients had a response (70%). The median time to disease progression was 32 months (range: 6-54 months) and the median time to best response was 6.5 months. Four of 17 evaluable patients (24%) became dialysis-independent at a median of 5 months post-HDT/stem cell transplantation. At a median follow-up of 70 months, 7/23 patients with myeloma were alive but three of these seven patients had progressive disease. Two of the four patients with amyloidosis have survived. HDT is feasible in these patients and results in 5-year survival in about one-third of patients.
Adult↗
Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma.
The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma.
Acid Phosphatase↗
Human invariant NKT cells are required for effective in vitro alloresponses.
NKT cells are a small subset of regulatory T cells conserved in humans and mice. In humans they express the Valpha24Jalpha18 invariant chain (hence invariant NKT (iNKT) cells) and are restricted by the glycolipid-presenting molecule CD1d. In mice, iNKT cells may enhance or inhibit anti-infectious and antitumor T cell responses but suppress autoimmune and alloreactive responses. We postulated that iNKT cells might also modulate human alloreactive responses. Using MLR assays we demonstrate that in the presence of the CD1d-presented glycolipid alpha-galactosylceramide (alphaGC) alloreactivity is enhanced (37 +/- 12%; p < 0.001) in an iNKT cell-dependent manner. iNKT cells are activated early during the course of the MLR, presumably by natural ligands. In MLR performed without exogenous ligands, depletion of iNKT cells significantly diminished the alloresponse in terms of proliferation (58.8 +/- 24%; p < 0.001) and IFN-gamma secretion (43.2 +/- 15.2%; p < 0.001). Importantly, adding back fresh iNKT cells restored the reactivity of iNKT cell-depleted MLR to near baseline levels. CD1d-blocking mAbs equally reduced the reactivity of the iNKT cell-replete and -depleted MLR compared with IgG control, indicating that the effect of iNKT cells in the in vitro alloresponse is CD1d-dependent. These findings suggest that human iNKT cells, although not essential for its development, can enhance the alloreactive response.
Antigens, CD1↗
No evidence of mutations of the PSMB5 (beta-5 subunit of proteasome) in a case of myeloma with clinical resistance to Bortezomib.
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Aged↗
The role of markers of bone remodeling in multiple myeloma.
Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. A characteristic feature of myeloma bone disease is that the lesions rarely heal and bone scans are often negative in myeloma patients who have extensive lytic lesions, offering very little in the follow-up of bone disease. X-rays are also of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone turnover, such as N- and C-terminal cross-linking telopeptide of type I collagen (NTX, CTX/ICTP, respectively), and newer ones such as the tartrate resistant acid phosphatase isoform 5b, provide information on bone dynamics that in turn may reflect disease activity in bone. Several studies have shown bone markers to be elevated in myeloma patients and reflect the extent of bone disease, while in some of them bone resorption markers correlate with survival. These markers may also be helpful in identifying those patients likely to respond to bisphosphonate treatment, and monitoring the effectiveness of bisphosphonate therapy in the management of myeloma bone disease. This review attempts to summarize the existing data for the role of markers of bone remodeling in assessing the extent of bone destruction in myeloma and monitoring bone turnover during specific anti-myeloma treatment. We also discuss some novel markers that may be of particular interest in the near future.
Bone Remodeling↗
Significance of macrophage inflammatory protein-1 alpha (MIP-1alpha) in multiple myeloma.
Macrophage inflammatory protein-1 alpha (MIP-1alpha) is a member of the CC chemokine family and is primarily associated with cell adhesion and migration. It is produced by myeloma (MM) cells and directly stimulates osteoclast formation and differentiation in a dose dependent way. MIP-1alpha protein levels were elevated in the bone marrow plasma of MM patients and correlated with disease stage and activity. MIP-1alpha was also elevated in the serum of myeloma patients with severe bone disease and correlated positively with bone resorption markers providing evidence for a causal role of MIP-1alpha in the development of lytic bone lesions in MM. MIP-1alpha has also been found to stimulate proliferation, migration and survival of plasma cells. Mice, which were inoculated with myeloma cells and treated with a monoclonal rat anti-mouse MIP-1alpha antibody, showed a reduction of both paraprotein and lytic lesions. In addition, MIP-1alpha enhanced adhesive interactions between myeloma and marrow stromal cells, increasing the expression of RANKL and IL-6, which further increased bone destruction and tumor burden. Myeloma patients with high MIP-1alpha serum levels have poor prognosis. The positive correlation between MIP-1alpha and beta(2)-microglobulin that has been observed in MM patients at diagnosis further supports the notion that MIP-1alpha is not only a chemokine with osteoclast activity function but is also implicated in myeloma growth and survival. Therefore, MIP-1alpha pathway may serve as a target for the development of novel anti-myeloma therapies.
Animals↗
Plasmacytoma relapses in the absence of systemic progression post-high-dose therapy for multiple myeloma.
Autologous (ASCT) and allogeneic stem cell transplantations (alloBMT) are well-established therapies for multiple myeloma. However, patients continue to relapse at a constant rate. We present here 15 out of 163 patients who underwent SCT and relapsed with plasmacytomas only without evidence of bone marrow disease progression (14/147 post-ASCT and 1/16 post-alloBMT). The median time from SCT to plasmacytoma relapse was 24 months. The sites of plasmacytoma included bone, skin, rectum, and testicles. Five patients were treated with local radiotherapy, while seven patients received a combination of radiotherapy and chemotherapy or thalidomide, and two patients received chemotherapy alone with or without thalidomide. The recipient of alloBMT was initially treated with VAD-chemotherapy and local radiotherapy followed by a mini-allograft from the original donor. Eleven patients died at a median of 10 months following diagnosis of the plasmacytoma. Four are still alive, 12-20 months post-plasmacytoma diagnosis. These cases of unconventional disease recurrence are likely to be seen due to sub-clinical seeding of tumour cells suggestive of the presence of an extramedullary (EM) clone of plasma cells with a high degree of chemoresistance. We also review all the available data in the literature for the optimal therapy for patients with isolated EM relapse.
Aged↗
Anti-angiogenic effect of bortezomib in patients with multiple myeloma.
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Adult↗
Current treatment options for myeloma.
In most cases multiple myeloma is an incurable plasma cell malignancy. Despite the use of conventional therapy or high-dose chemotherapy with autologous stem cell transplantation (ASCT), patients continue to relapse at a constant rate. A small minority of patients are cured by allogeneic transplantation. Novel drugs targeting not only the myeloma cell but also its interactions with the malignant microenvironment have recently been used in patients with relapsed/refractory disease. So far, ASCT has been the treatment of choice for eligible myeloma patients. However, many questions regarding the management of myeloma patients remain unanswered. How safe is ASCT in elderly patients? Is there a role for non-myeloablative allogeneic transplantation in multiple myeloma? What is the role of novel agents, such as thalidomide, its analogues and bortezomib, in the treatment of newly diagnosed patients or as maintenance post-ASCT? This review summarises all available data for the current treatment options for myeloma providing a useful algorithm for its management.
Age Factors↗
Centromeric repositioning of coreceptor loci predicts their stable silencing and the CD4/CD8 lineage choice.
The differentiation of CD4(+) CD8(+) double positive (DP) thymocytes requires the irreversible choice between two alternative lineages, distinguished by the mutually exclusive expression of either CD4 or CD8. Differentiating DP cells transiently down-regulate both CD4 and CD8, and this has complicated the debate whether the mechanism of CD4/CD8 lineage choice is instructive, stochastic/selective, or more complex in nature. Using fluorescence in situ hybridization, we show that the stable silencing of coreceptor loci, and ultimately lineage choice, is predicted by the spatial repositioning of coreceptor alleles to centromeric heterochromatin domains. These data provide evidence that lineage-specific developmental programs are established early during the transition from the DP to the single positive stage.
Alleles↗
Tumour lysis syndrome in multiple myeloma after bortezomib (VELCADE) administration.
Bortezomib (VELCADE) is a proteasome inhibitor, which has been recently used for the treatment of relapsed/refractory multiple myeloma (MM) with encouraging results. Tumour lysis syndrome (TLS) has been described during chemotherapy for many haematological malignancies, such as acute lymphoblastic leukaemia and high-grade lymphomas. TLS is very rare in MM with ten reported cases, including approximately 1% of patients receiving high-dose chemotherapy with stem cell support (ASCT). We report here a patient with refractory MM and deletion 13q, who had received more than four lines of previous treatment, including two ASCT, and had relapsed. The patient received bortezomib, as a single agent, at a dose of 1.3 mg/m(2) twice per week for 2 weeks, in a 3-week cycle, and developed TLS after the second dose of cycle one. Bortezomib therapy, due to the rapidity of its action, may result in TLS in myeloma patients who have rapidly proliferative disease with a high tumour burden. Therefore, TLS should be looked for during the first cycle of bortezomib treatment and suitable precautions should be considered.
Adult↗
Interactive web-based guidelines for chronic myeloid leukaemia.
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Humans↗
Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS).
The aim of this study was to evaluate the role of markers of bone remodelling, and osteoclast activation/function in patients with monoclonal gammopathy of undetermined significance (MGUS). We have measured serum levels of soluble RANKL (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1alpha (MIP-1alpha), markers of bone resorption [N-telopeptide of collagen type-I (NTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)] and bone formation [bone-alkaline phosphatase (bALP)] in 40 MGUS patients. These parameters were compared with those of 42 newly diagnosed myeloma patients, and 45 healthy, gender- and age-matched controls. MGUS patients had elevated levels of NTX, sRANKL, and sRANKL/OPG ratio compared with controls (P < 0.0001). Furthermore, TRACP-5b, MIP-1alpha and NTX were decreased in patients with MGUS compared with myeloma patients (P < 0.001), while OPG and bALP were increased (P < 0.001). Serum levels of MIP-1alpha, as well as TRACP-5b, and sRANKL/OPG ratio were reduced, while bALP was increased in MGUS patients, even when compared with myeloma patients who had stage I/II disease. These results demonstrate that increased osteoclastogenesis leading to increased bone resorption is present in MGUS but seems to be compensated for by normal bone formation, which is absent in MM. Furthermore MIP-1alpha, bALP, and sRANKL/OPG may be useful tools for distinguishing between cases of MGUS and early myeloma.
Adult↗
Bisphosphonate treatment for multiple myeloma.
Patients with multiple myeloma often experience skeletal-related complications including pathological fractures, hypercalcemia, spinal cord compression, pain requiring surgery or radiotherapy. Myeloma bone disease is characterized by the presence of lytic lesions due to increased osteoclastic activity, which is not accompanied by a comparable increase in bone formation. Targeting osteoclastic bone resorption therefore represents an important approach to treating patients with myeloma-related bone disease. Bisphosphonates are potent inhibitors of osteoclast activity and function. Recent large, placebo-controlled clinical trials have shown the efficacy of bisphosphonates in reducing skeletal complications in multiple myeloma and suggest that these agents may also alter the overall course of the disease. In this review, we summarize the data covering the effect of different types of bisphosphonates on myeloma bone disease, their mode of action and the future implications of their use.
Clinical Trials as Topic↗
Tartrate-resistant acid phosphatase isoform 5b: a novel serum marker for monitoring bone disease in multiple myeloma.
Tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), a new marker reflecting osteoclast activity, and osteoprotegerin (OPG) were measured in 121 patients with multiple myeloma (MM) at diagnosis, and in 63 of them during pamidronate administration, to define their correlation with the extent of bone disease and disease activity in MM. Radiographic evaluation of the skeleton, measurement of other markers of bone remodelling, including N-terminal cross-linking telopeptide of type-I collagen (NTX), bone alkaline phosphatase and osteocalcin and of markers of disease activity (beta2-microglobulin, paraprotein, interleukin-6 (IL-6), were also performed. Levels of TRACP-5b were increased (p <.0001), while OPG was decreased in MM patients compared to controls (p <.01). TRACP-5b levels were associated with the radiographically assessed severity of bone disease (p <.0001) as well as with levels of NTX, IL-6 and beta2-microglobulin (p <.001, for each biochemical parameter, respectively). The combination of pamidronate with VAD-chemotherapy produced a reduction in TRACP-5b, NTX, IL-6, paraprotein and beta2-microglobulin levels from the 2nd month of treatment, with no effect on bone formation and OPG. A strong correlation was observed between changes in TRACP-5b and changes in NTX, IL-6 and beta2-microglobulin, while TRACP-5b predicted the disease progression in 5 patients. These findings suggest that TRACP-5b is increased in MM, reflects the extent of myeloma bone disease and may have a predictive value. TRACP-5b has also proved to be very useful for monitoring antimyeloma treatment, which had no effect on OPG levels.
Acid Phosphatase↗
Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index.
Interaction between receptor activator of nuclear factor kappaB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRP), and beta2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We generated a prognostic index based on these factors that divided our patients into 3 risk groups. The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively. Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.
Adult↗