Background: Renal cell carcinoma is the most common kidney tumor in adults and accounts for approximately 3% of adult malignancies. An increased incidence of second malignancies has been well documented in a number of different disorders, such as head and neck tumors, and hairy cell leukemia. In addition, treatment associated second malignancies (usually leukemias and lymphomas but also solid tumors) have been described in long term survivors of Hodgkin's lymphoma (HL), Non Hodgkin's lymphoma and in various pediatric tumors.
Background The combination of thalidomide/dexamethasone (TD) induces remission in approximately 70% of previously untreated patients with low or intermediate tumor mass. TD appeared superior to previous programs because of the high response rate and reasonable survival and its low frequency of serious complications. The aim of our study was to assess the efficacy of thalidomide plus dexamethasone as first line therapy and the incidence of deep vein thrombosis. Material and methods Patients with newly diagnosed and symptomatic MM (untreated patients) were evaluated. We enrolled all patients who fulfilled entire criteria for multiple myeloma between January 1998 and December 2005. Patients were divided into 2 groups: thalidomide plus dexamethasone (TD) and VAD group. The present study is a prospective, descriptive, longitudinal and observational one. Thalidomide was prescribed in an oral dose of 100 mg qhs and increased by 50 mg every 7 days to a maximum dose of 300 mg, depending on side effects. Dexamethasone was given in an oral dose of 20 mg/m2 each morning after breakfast on days 1–4, 9–12 and 17–20, followed by 10 days without therapy prior to the next cycle. Treatment with the combination was continued for at least 6 months or until the earliest occurance of maximum plateau of myeloma protein reduction, autologous transplant-supported intensification or other treatments. VAD was given as an Out-patient regimen including: vincristine (0.4mg/day, continuous IV), doxorubicin (9mg/m2/day, continuous IV) and dexamethasone (40 mg/day PO) with a median of 6 courses. Citrate plasma was used to investigate coagulation and anticoagulation parameters. Results Sixty newly diagnosed multiple myeloma patients were included in the study, 35 (58%) male and 25 (42%) female, aged 45–85 (mean 63). Underlying diagnosis was IgG MM in 44 (73.3%), IgA in 12 (20%) and light chain disease in 4 (6.7%). Clinical characteristics were similar for both groups. According to Durie Salmon criteria patients were grouped into: IA (n6, 10%), IB (n3, 5%), IIA (n12, 20%), IIB (n6, 10%), IIIA (n19, 31.6%) and IIIB (n14, 23.4%). The frequency of response (CR, NCR/VGPR and PR) in the group of thalidomide and dexamethasone was 73% being higher than VAD (53%)p0.005. CR was observed in 5 patients treated with thalidomide/dexamethasone (16%). Thrombosis complications DVT was observed in 7 patients. DVT occurred in 4 patients treated with TD and 3 with VAD. From the last 40 patients, 5 presented APC-R and 3 of them developed DVT. A significant shorter time to DVT was observed in patients exposed to VAD chemotherapy (first 2 cycles p 0.007). Patients developing APC-R were tested for Factor V Leiden mutation resulting negative. After patients developed any response criteria were retested for acquired activated protein C resistance, all of them went back to normal. Finally we conclude TD is an effective, less toxic therapy in comparison with VAD as first line therapy and in order to reduce incidence of DVT effective prophylactic anticoagulation should be implemented in all controlled trials, at least during the first few cycles of treatment.
Background The pathogenesis of thalidomide induced DVT is poorly understood. It has been suggested that effect may involve a direct action of thalidomide on endothelial cells previously damaged by chemotherapy agents. The purpose of the present study was to examine the efficacy of daily low-dose (81 mg orally) in decreasing the incidence of venous thromboembolic events (VTE’s) in patients with multiple myeloma receiving thalidomide plus dexamethasone as primary therapy and the comparison with a control group of MM patients without aspirin. Material and methods Patients with newly diagnosed multiple myeloma treated with thalidomide plus dexamethasone were assigned to receive aspirin at lower doses and were compared with an historical cohort of patients without thromboprophylaxis. We enrolled patients who fulfilled entire criteria for multiple myeloma between January 2003 and May 2006. Thalidomide was prescribed in an oral dose of 100 mg qhs and increased by 50 mg every 7 days to a maximum dose of 200 mg, depending on side effects. Dexamethasone was given in an oral dose of 20 mg/m2 each morning after breakfast on days 1–4, 9–12 and 17–20, followed by 10 days without therapy prior to the next cycle. Treatment combination was continued for at least 6 months or until the earliest occurance of maximum plateau of myeloma protein reduction, autologous transplant-supported intensification or other treatments. Coagulations tests and thrombosis: Citrate plasma was used to investigate coagulation and anticoagulation parameters. The coagulations tests include: prothrombin time, activated partial thromboplastic time (aPTT), fibrinogen, anticardiolipin antibodies, lupus anticoagulant, antithrombin III, protein C and protein S activities, activated protein C (APC) resistance, Factor V Leiden, and D-dimers. Results Sixty multiple myeloma patients treated with thalidomide plus dexamethasone were included. Patients were assigned to receive either aspirin at a dose of 81 mg qd (newly diagnosed, n20) or nothing (newly diagnosed n20, relapsed n10 or refractory n10). DVT was developed in 7 patients (17.5%) in the NARG (Non aspirin group) and only in 1 patient for the ARG (5%, Aspirin receiver group) P0.005. Five patients were confirmed to have acquired activated C protein resistance (NARG 4/ARG1). Known risk factors for DVT, such as central venous catheters (CVC) (present in 16% patients), performance status, and hormonal therapy were not significantly different between these 2 groups of patients (all p values >0.2) None patient has prior history of DVT and neither one was receiving anticoagulation at the time of enrollment. Conclusions Low dose aspirin (81 mg) given daily to patients with newly diagnosed and relapsed/refractory MM treated with thalidomide plus dexamethasone. To fully evaluate the potential synergistic anticancer activity of combinations of chemotherapy and thalidomide, effective prophylactic anticoagulation should be implemented in all controlled trials, at least during the first few cycles of treatment.
The use of high-resolution aCGH allows for whole genome screening for copy number changes even in tumors that rarely produce metaphase spreads. The aim of this study was to characterize the aCGH findings in B-CLL, lung MALT lymphoma, Waldenström’s Macroglobulinemia (WM), Multiple Myeloma (MM) and human myeloma cell lines (HMCLs). This study includes 301 B-cell malignancy samples (19 B-CLL, 19 MALT, 20 WM, 48 HMCLs and 195 MM) and an additional 76 melanoma samples. We found MM to have the highest number of abnormalities per karyotype, with 15.8±7.5 (mean ± SD) and 20.6±17.0 in hyperdiploid (H) and non-hyperdiploid MM (NH), respectively. The remaining diseases have a significantly lower number of abnormalities: 5.5±4.5 in B-CLL, 3.5±1.96 in MALT and 4±3.5 in WM. Aneuploidy and biallelic deletions were rare events in these three diseases. B-CLL has two highly recurrent abnormalities involving 11q22-q23 (29%) and 13q14.3 (33%). A minimal deleted region (MDR) of ∼108Kb was identified at 11q comprising ACAT1, NPAT and ATM. In 13q, a 280Kb MDR was recognized, including TRIM13, KCNRG, mir-15a and mir-16. The subgroup of MALT patients with t(11;18) had very few abnormalities and the majority are a consequence of unbalanced translocations (MALT, BIRC2 and BIRC3 deletions). In the remaining MALT samples, trisomy 3 and 18q gain were the most common abnormalities (31% each). The 6q16.3-q26 deletion was the most common abnormality in WM (45%). In 4 of 9 patients with 6q deletion there was an associated 6p gain. The same observation was found in 2 of 3 patients with 8p loss and concomitant 8q gain. Interestingly, 6p and 8q gain were not identified in patients without 6q and 8p deletions. Deletion of 17p was the most common recurrent abnormality observed in our panel of B-cell cancers, being identified in MM, WM and B-CLL. In B-CLL and WM, small mono and biallelic deletions of the NF-kB negative regulators, TRAF3 and NFKBIA, were identified, suggesting a potential involvement of this pathway in the pathogenesis of these diseases. Hierarchical clustering of the aCGH data in MM identified 3 distinct groups, NH-MM, H-MM and MM with deletions of chromosome 13 and 14. Interestingly, MGUS and SMM were more commonly clustered with H-MM. Several sub-clusters were observed in the H-MM group, the most prominent being made up exclusively of patients from TC class D1. This cluster was characterized by the presence of trisomy 11 and 21. The 11q13 TC group clustered and was highly associated with 11q amplifications due to unbalanced t(11;14). The 6q deletion defined a cluster with WM, MM and Melanoma patient with that abnormality. In the case of B-CLL and MALT, the only identifiable clusters were observed in cases with 13q loss and trisomy 3, respectively. These results highlight both, the common and unique aCGH findings in several B-cell cancers. By hierarchical clustering, MM was significantly divergent from the rest of the B-cell diseases. Due to the limited number of abnormalities in B-CLL/MALT/WM, the clustering of these groups was exclusively based on the common abnormalities. The use of aCGH has refined the MDRs of 11q and 13q in B-CLL. Additionally, the identification of deletions affecting the NF-kB pathway in B-CLL and WM has prompted us to hypothesize on the importance of constitutive NF-κB activation in these diseases.
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