Biomedical subjects

Athanasios Anagnostopoulos

Publications and source records attributed to Athanasios Anagnostopoulos.

At least 19 recordsLinked to original sources

PubMed2006

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↗

PubMed2006

Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acid.

Osteonecrosis of the jaw (ONJ) has been associated with the use of pamidronate and zoledronic acid. ONJ was assessed prospectively since July 2003 in 202 patients with multiple myeloma (MM) who received bisphosphonates since April 1995. Fifteen patients (7.4%) developed ONJ. The median time of exposure to bisphosphonates was 39 months for patients with ONJ compared to 28 months (p=0.048) for patients with no ONJ. The cumulative hazard of developing ONJ was significantly higher in patients treated with zoledronic acid alone than in those treated with pamidronate alone/pamidronate+zoledronic acid/zoledronic acid+ibandronate sequentially (1% at 1 year and 15% at 4 years vs. 0% and 5%, p=0.003). In conclusion, the risk of ONJ is increased with time of exposure and probably with the use of zoledronic acid.

Adult↗

PubMed2006

Update on treatment recommendations from the Third International Workshop on Waldenstrom's macroglobulinemia.

Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells into bone marrow and the presence of an IgM monoclonal gammopathy. As part of the Third International Workshop on WM, held October 7 to 10, 2004 in Paris, France, a consensus panel charged with providing treatment recommendations for WM updated its recommendations on both frontline and salvage therapies. The panel considered encouraging results from recent studies that addressed the use of extended-dose rituximab as well as other treatment options: therapy with either nucleoside analogs and alkylator agents, rituximab in combination with nucleoside analogs, nucleoside analogs plus alkylator agents, or combination chemotherapies, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or cyclophosphamide and dexamethasone. The panel determined that these were reasonable treatment options for WM patients and such therapeutic approaches were likely to yield results that are at least as good as if not better than the currently recommended use of single-agent alkylator, nucleoside analog, or standard-dose rituximab therapy. Such approaches were deemed to be reasonable treatment for WM patients in both the upfront and salvage settings, though randomized studies addressing the efficacy and toxicity of such novel approaches over previously established standard of care options are needed.

Alkylating Agents↗

PubMed2006

Autologous or allogeneic stem cell transplantation in patients with Waldenstrom's macroglobulinemia.

The role of hematopoietic stem cell transplantation (SCT) in Waldenstrom's macroglobulinemia (WM) has not been extensively studied. To determine the potential for long-term disease control using SCT in WM, we performed a retrospective review of 36 patients with WM who received autologous (n = 10) or allogeneic (n = 26) SCT and were reported to the Center for International Blood and Marrow Transplant Research between 1986 and 2002. The following outcomes were described: nonrelapse mortality (NRM), relapse, progression-free survival (PFS), and overall survival (OS). Median age at the time of SCT was 51 years (range, 30-76 years), and median time from initial treatment to SCT was 29 months (range, 2-198 months). A total of 78% of the patients had 2 or more previous chemotherapy regimens, and 52% had disease resistant to salvage chemotherapy. In the allogeneic SCT group, 58% of the patients received myeloablative conditioning regimens containing total body irradiation (TBI), and of the allograft recipients, 19% received nonmyeloablative/reduced-intensity conditioning. After a median follow-up of 65 months, 15 of the 36 patients (42%) are alive. Primary disease accounted for 29% of the deaths in the allogeneic SCT group and 25% of the deaths in the autologous SCT group. The relapse rate at 3 years was 29% (95% confidence interval [CI], 14%-48%) in the allogeneic group and 24% (95% CI, 4%-54%) in the autologous group. PFS at 3 years was 31% (95% CI, 14%-50%) in the allogeneic group and 65% (95% CI, 32%-91%) in the autologous group; OS was 46% (95% CI, 27%-65%) in the allogeneic group and 70% (95% CI, 40%-93%) in the autologous group. NRM at 3 years was 40% (95% CI, 23%-59%) in the allogeneic group and 11% (95% CI, 0-36%) in the autologous group. Autologous SCT is a safe and feasible treatment option for patients with WM, especially for those who present with adverse prognostic factors. Allogeneic SCT carries a much higher (40%) risk of NRM and should not be considered outside the context of a clinical trial.

Adult↗

PubMed2006

Macrofocal multiple myeloma in young patients: a distinct entity with favorable prognosis.

There are limited reports of young patients with multiple myeloma (MM) who presented with multiple lytic bone lesions but without intervening infiltration of bone marrow, a pattern consisting of macrofocal MM. In order to clearly define the clinical and laboratory features and outcome of such patients, a retrospective analysis was performed of symptomatic patients with MM <or=40 years of age at diagnosis who received primary treatment over a 20-year period. Ten of 51 patients fulfilled the criteria of macrofocal MM. When compared to patients with typical MM, patients with macrofocal pattern were less anemic, none had hypercalcemia, renal impairment, elevated serum LDH or stage 3 according to the International Staging System (ISS). Patients with macrofocal MM usually had preserved the uninvolved immunoglobulins. An objective response to primary treatment was noted in 55% of patients with macrofocal MM and in 50% of patients without this pattern. The median survival of patients with typical MM was 57 months and is projected to exceed 8 years in patients with macrofocal MM (p = 0.087). With macrofocal MM despite multiple lytic bone lesions, patients have features of low tumor burden and improved survival when compared with young patients with typical MM.

Adult↗

PubMed2006

Rituximab therapy in monoclonal IgM-related neuropathies.

Monoclonal IgM-related neuropathies constitute a heterogeneous group of disorders, which are generally poorly responsive to treatment. Rituximab, a chimeric monoclonal antibody against the CD20 molecule, has been used with success in patients with neuropathy and monoclonal IgM with anti-MAG or anti-GM1 ganglioside activity. Based on this observation, four patients were treated with IgM-related neuropathy with rituximab. Between January 1999 - December 2000, four patients with IgM-related neuropathy (one with chronic inflammatory demyelinating polyneuropathy (CIDP) and three with sensorimotor demyelinating neuropathy) were treated with rituximab. Rituximab was administered at a standard dose of 375 mg m(-2) iv weekly for a consecutive 4 weeks; 3 months later, four additional weekly courses were administered to patients who did not experience deterioration of their neuropathy symptoms. Neurological evaluation was performed before each rituximab infusion and at 1 week and 2 months after last infusion and every 6 months the following years; including motor (MRC in six muscle groups, 9-hole peg test, 10 m walk, hand grip strength), sensory neuropathy (vibration threshold and sensory subjective score) assessment. Neurophysiological parameters were also assessed (MNCV, SNCV, CMAP, SNAP). Strength improved in three of four patients; including the patient with CIDP. This patient developed a significant worsening of her weakness 3 weeks after the initiation of rituximab. This phenomenon coincided with a serum monoclonal IgM flare and resolved spontaneously 1 week later. Her improvement is ongoing for more than 5 years. Considering neurophysiological parameters, two patients showed a slight improved regarding conduction velocities and CMAP (10%) and the patient with IgM flare had a transient worsening of conduction velocities followed by improvement. In conclusion, rituximab is a safe and well-tolerated treatment which may be effective in some patients with IgM-related neuropathy.

Adult↗

PubMed2006

Abnormal bone remodelling and increased levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) in Waldenström macroglobulinaemia.

Serum levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) and bone remodelling markers were evaluated in 38 patients with Waldenström macroglobulinaemia (WM) and correlated with clinical and laboratory variables. MIP-1alpha was elevated in WM; untreated patients had higher MIP-1alpha levels than patients in remission or with active disease after treatment. MIP-1alpha correlated with increased bone resorption, beta2-microglobulin and splenomegaly. Receptor activator of nuclear factor-kappaB ligand serum levels were elevated in WM patients; the subsequent increased bone resorption was balanced by a comparable elevation of osteoprotegerin production and bone formation. These findings may explain the absence of lytic lesions in WM patients and suggest a potential role of MIP-1alpha in WM.

Adult↗

PubMed2006

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↗

PubMed2006

Update on recommendations for assessing response from the Third International Workshop on Waldenstrom's Macroglobulinemia.

This report by an international consensus panel updates current recommendations for defining clinical response in Waldenstrom's macroglobulinemia (WM). The previously published response criteria incorporated parameters for monoclonal protein reduction and/or improvement of marrow and nodal involvement, and included definitions of complete and partial remissions. The criteria have been updated to include minor response and stable disease categories. In addition, the criteria now recognize that delayed responses after treatment with nucleoside analogues and biologic agents and the time point for assessing response in patients with WM should be considered so as to not miss or miscategorize a response. The new criteria should therefore help in better delineating responses to therapy in patients with WM, particularly with the wide use of nucleoside analogues and biologically based agents for this disease.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Angiogenetic factors and biochemical markers of bone metabolism in POEMS syndrome treated with high-dose therapy and autologous stem cell support.

The cause of the polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes (POEMS) syndrome is currently unknown, but increased levels of vascular endothelial growth factor (VEGF) appear to play a pathogenetic role. Osteosclerotic bone lesions are a characteristic finding in POEMS, but there are no data about the specific role of various molecules that control bone remodeling in patients with POEMS. Serum levels of angiogenic cytokines (VEGF, angiogenin, angiopoietin-2, and basic fibroblast growth factor) along with a series of bone remodeling indices (C-telopeptide of type I collagen, bone-alkaline phosphatase [bALP], osteocalcin [OC], soluble receptor activator of nuclear factor-kappaB ligand [RANKL], osteoprotegerin [OPG], and macrophage inflammatory protein-1alpha) were measured in 2 patients with POEMS before and after high-dose therapy (HDT) with autologous stem cell transplantation and in age- and sex-matched controls. Increased VEGF levels before HDT were reduced significantly after treatment, although levels of the other angiogenetic factors did not differ from that of controls and were less influenced by HDT. Serum RANKL levels were increased before HDT, whereas OPG levels were within the levels of healthy controls, resulting in an abnormal soluble RANKL to OPG ratio. Levels of bone resorption markers (C-telopeptide of type I collagen) were very low or undetectable before HDT, although bALP and OC levels were similar to that of controls. After HDT, soluble RANKL levels decreased, OPG remained rather stable, bone resorption markers increased to levels of normal individuals, bALP levels were rather unchanged, and OC levels increased. Decreasing VEGF levels parallel clinical improvement, and the restoration of normal bone metabolism follows HDT.

Age of Onset↗

PubMed2006

Prognostic value of serum beta2-microglobulin in patients with Waldenstrom's macroglobulinemia requiring treatment.

PURPOSE: Waldenstrom's macroglobulinemia (WM) is a lymphoplasmacytoid lymphoma characterized by a relatively indolent course with median survival ranging from 5 years to 10 years in different series. Several clinical and laboratory variables have been associated with inferior survival, such as advanced age, hyperviscosity, presence of cytopenia, and hypoalbuminemia. Recent data indicate that serum 2-microglobulin (2M) might also be significant. The purpose of our study was to assess possible correlations of 2M with clinical and laboratory variables and to further evaluate its association with cause-specific and overall survival (OS) of patients with WM requiring treatment. PATIENTS AND METHODS: We analyzed 124 patients with WM with an available pretreatment value of 2M. Median age was 70 years (range, 28-89 years), and median survival was 105 months. Multiple clinical and laboratory parameters were evaluated for their possible correlation with OS. RESULTS: Patients with older age, anemia, thrombocytopenia, hypoalbuminemia, and higher creatinine levels had significantly greater serum 2M levels. This variable was associated with impaired cause-specific survival and OS in the whole group of patients and in patients aged </= 70 years. More specifically, OS for all patients according to serum 2M > 4 mg/dL versus </= 4 mg/dL was 79 months versus 115 months (P = 0.01). CONCLUSION: Our data provide further evidence that high 2M levels are an important parameter associated with inferior OS and cause-specific survival of patients with WM requiring treatment. This parameter may be used to stratify patients involved in prospective clinical trials.

Adult↗

PubMed2006

Primary treatment with pulsed melphalan, dexamethasone and thalidomide for elderly symptomatic patients with multiple myeloma.

Fifty patients with multiple myeloma >or=75 years of age received primary treatment with melphalan (M) 8 mg/m(2) on days 1-4, dexamethasone (D) 12 mg/m2 on days 1-4 and 17-20 and thalidomide (T) 300 mg at bedtime on days 1-4 and 17-20. This regimen was repeated every 5 weeks for three courses. Patients without evidence of disease progression received nine additional courses of MDT, but without DT on days 17-20, every 5 weeks. Sixty-two percent of patients achieved a partial response and 10% a complete response. The median time to response was 2 months. The median time to progression for all patients was 21.2 months. Deep venous thrombosis and peripheral neuropathy each occurred in 9% of patients.

Aged↗

PubMed2006

Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center, randomized, placebo-controlled trial.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the effect of zoledronic acid (ZA) on thalassemia-induced osteoporosis. DESIGN AND METHODS: We studied 66 thalassemia patients with osteoporosis, who were randomized to receive 4 mg ZA iv, every 6 months (23 patients; group A) or every 3 months (21 patients; group B), or to receive placebo every 3 months (22 patients; group C), for a period of 1 year. Bone mineral density (BMD) of the lumbar spine, femoral neck and wrist was determined before and 12 months after treatment. Pain scores and markers of bone resorption [C-telopeptide of collagen type-I (CTX), 5b-isoform of TRAP], bone formation [bone-alkaline phosphatase (bALP), osteocalcin (OC), C-telopeptide of procollagen type-I (CICP)], and osteoclast stimulators [sRANKL, osteoprotegerin (OPG), osteopontin] were also measured at baseline and before each treatment administration. RESULTS: The values of CTX, bALP, CICP, sRANKL, and OPG were higher in the all patients than in the controls. Patients in group A showed no differences in BMD of all sites at 12 months, while they had reductions in bone pain, bALP, OC and OPG. Conversely patients in group B had a significant increase in their lumbar spine BMD, which was accompanied by dramatic reductions in bone pain, CTX, bALP, CICP, and OC. Patients in group C showed no alteration in BMD of any studied site or in bone pain, while they had an aggravation in bone resorption. INTERPRETATION AND CONCLUSIONS: ZA, at a dose of 4 mg, iv, every 3 months is an effective treatment for increasing BMD and reducing bone resorption in thalassemia-induced osteoporosis.

Bone Density↗

PubMed2005

Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors.

PURPOSE: Osteonecrosis of the jaw (ONJ) has been associated recently with the use of pamidronate and zoledronic acid. We studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates for bone metastases. PATIENTS AND METHODS: ONJ was assessed prospectively since July 2003. The first bisphosphonate treatment among patients with ONJ was administered in 1997. Two hundred fifty-two patients who received bisphosphonates since January 1997 were included in this analysis. RESULTS: Seventeen patients (6.7%) developed ONJ: 11 of 111 (9.9%) with multiple myeloma, two of 70 (2.9%) with breast cancer, three of 46 (6.5%) with prostate cancer, and one of 25 (4%) with other neoplasms (P = .289). The median number of treatment cycles and time of exposure to bisphosphonates were 35 infusions and 39.3 months for patients with ONJ compared with 15 infusions (P < .001) and 19 months (P = .001), respectively, for patients with no ONJ. The incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (P < .001). All but two patients with ONJ had a history of dental procedures within the last year or use of dentures. CONCLUSION: The use of bisphosphonates seems to be associated with the development of ONJ. Length of exposure seems to be the most important risk factor for this complication. The type of bisphosphonate may play a role and previous dental procedures may be a precipitating factor.

Adult↗

PubMed2005

Extent of damage and repair in the p53 tumor-suppressor gene after treatment of myeloma patients with high-dose melphalan and autologous blood stem-cell transplantation is individualized and may predict clinical outcome.

PURPOSE: To quantitate the individual levels of melphalan-induced DNA damage formation and repair in vivo and to search for possible correlations with clinical outcome in patients with multiple myeloma (MM). PATIENTS AND METHODS: The formation and subsequent repair of DNA damage (monoadducts and interstrand cross-links) in the p53 tumor-suppressor gene, the proto-oncogene N-ras, and the housekeeping gene beta-actin during the first 24 hours after treatment with high-dose melphalan (HDM; 200 mg/m2) supported by autologous blood stem-cell transplantation (ABSCT) was measured in blood leukocytes of 26 patients with MM. The peak DNA adduct levels, the total amount of adducts over time, and the rate of adducts repair in each gene were correlated with response and time to progression after HDM. RESULTS: The levels of gene-specific DNA damage formation and the individual repairing capacity varied up to 16-fold among patients, indicating that the melphalan-induced biologic effect in vivo is highly individualized. A significantly greater DNA damage and a slower rate of repair in p53 for all end points under study were found in patients who achieved tumor reduction compared with nonresponding patients. Furthermore, longer progression-free survival correlated with increased peak monoadduct levels in the p53 gene (P = .032). CONCLUSION: Increased DNA damage and slower repairing capacity in the p53 gene from blood leukocytes after HDM correlate with improved outcome of patients with MM who undergo ABSCT. These results suggest that quantitation of such biologic end points may identify patients who are more likely to benefit from this procedure.

Actins↗

PubMed2005

Diagnosis and management of Waldenstrom's macroglobulinemia.

PURPOSE: To review the diagnostic criteria, prognostic factors, response criteria, and treatment options of patients with Waldenstrom's macroglobulinemia (WM). METHODS: A review of published reports was facilitated by the use of a MEDLINE computer search and by manual search of the Index Medicus. RESULTS: WM should be regarded as a distinct clinicopathologic entity and confined to those patients with lymphoplasmacytoid lymphoma who have demonstrable serum immunoglobulin M monoclonal protein. Treatment decisions should rely on specific clinical and laboratory criteria. Initiation of therapy should not be based on serum monoclonal protein levels per se. The three main choices for systemic primary treatment of symptomatic patients with WM include alkylating agents (chlorambucil), nucleoside analogs (fludarabine and cladribine), and the monoclonal antibody rituximab. There are no data from prospective randomized studies to recommend the use of one first-line agent over another, although consideration of a patient's candidacy for autologous stem-cell transplantation (ASCT) should be taken into account to avoid stem cell-damaging agents. There are preliminary data to suggest that combinations of nucleoside analogs and alkylating agents with or without rituximab may improve response rates at the expense of higher toxicity. CONCLUSION: WM is a distinct low-grade lymphoproliferative disorder. When therapy is indicated, alkylating agents, nucleoside analogs, and rituximab are reasonable choices. Several factors, including the presence of cytopenias, need for rapid disease control, candidacy for ASCT, age, and comorbidities, should be taken into consideration when choosing the most appropriate primary treatment.

Alkylating Agents↗

PubMed2005

Waldenström's macroglobulinemia.

The diagnosis of Waldenström's macroglobulinemia (WM) requires evidence of bone-marrow infiltration by lymphoplasmacytoid lymphoma and detection of serum monoclonal protein of IgM type. The normal counterpart of the WM malignant cell is believed to be a postgerminal-center B cell. The clinical manifestations and laboratory abnormalities associated with WM are related to direct tumor infiltration and to the amount and specific properties of IgM. Asymptomatic patients should be followed without treatment. When treatment is indicated, the three main choices for systemic frontline treatment are chlorambucil, the nucleoside analogues fludarabine or cladribine and the monoclonal antibody rituximab. There is evidence that high-dose therapy with autologous stem-cell transplantation is effective even in patients with advanced and resistant disease. Patient's age, hemoglobin and serum beta2-microglobulin before treatment are important prognostic variables which correlate with survival.

Antineoplastic Agents↗

PubMed2005

Multiple myeloma in elderly patients: prognostic factors and outcome.

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.

Age Factors↗