B. Cuesta

Cytogenetic analysis of 280 patients with multiple myeloma and related disorders: Primary breakpoints and clinical correlations

Cytogenetic analysis of unstimulated short‐term bone marrow cell cultures was performed on 280 patients with multiple myeloma and related disorders. In 65% of the cases, an additional short term B‐cell stimulated culture was also examined. Chromosomally abnormal clones were found in 31% of the patients, 15% in Waldenström macroglobulinemia, 25% in monoclonal gammopathies, 33% in multiple myeloma, and 50% in plasma cell leukemia. Three primary chromosomal breakpoints were recurrently involved: 14q32, 16q22, and 22q11. Structural rearrangements of chromosome I were the most frequent (26% of the abnormal cases), but always as a secondary change. Rearrangements of band 14q32 were found in 22% of the abnormal cases. Among the multiple myeloma patients who showed an abnormal karyotype, 33 (46%) were hyperdiploid, most frequently with 52–56 chromosomes, 29 patients (40%) were pseudodiploid, and the remaining 12 cases (14%) were hypodiploid. A highly significant relation was observed between the presence of an abnormal karyotype and the following clinical parameters: stage III (P = 0.0001), bone marrow plasma cell infiltration greater than 30% (P = 0.0001), presence of bone lesions (P = 0.0009), and β2‐microglobulin levels greater than 4 mg/L (P = 0.0001). Genes Chromosom. Cancer 18:84–93, 1997.

Measurement of prethrombotic markers in the assessment of acquired hypercoagulable states.

Hypercoagulable states can be detected by measuring activation peptides, enzyme-inhibitor complexes, and fibrin/fibrinogen degradation products, which are markers of hemostatic activation. A series of these prethrombotic markers has been evaluated in the elderly, pregnancy, diabetes and acute myocardial infarction patients (n=30 in each group) as well as in hematologic malignancies (n=42). The parameters assayed were: prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III complexes (TAT), fibrinopeptide A (FPA), plasmin-alpha2 antiplasmin complexes (PAP) and D-Dimer. Results were compared with those obtained in a group of 30 healthy subjects. We found a significant increase of F1+2, TAT and FPA in elderly (p<0.05), acute myocardial infarction (AMI) (p<0.01), hematologic malignancies (p<0.01), and pregnancy (p<0.0001), indicating a marked clotting activation. Diabetic patients under strict metabolic control only presented a moderate increase of TAT (p<0.05), suggesting a slight activation. We also observed a highly significant elevation of PAP and D-Dimer in elderly (p<0.001), AMI (p<0.0001), and malignancy (p<0.0001), indicating an activation of the fibrinolytic system. The combination of selected fibrinolytic and coagulation measurements is useful for the detection of a hypercoagulable state in conditions characterized by a risk of thrombosis.

Clotting activation and impairment of fibrinolysis in malignancy

Different coagulation and fibrinolysis parameters were investigated in 149 patients with metastatic and non-metastatic tumours and results were compared with those obtained in a healthy population. Results showed a significant increase of thrombin-antithrombin complexes, fibrinopeptide A (FPA) and fibrin monomers in the group of patients (p less than 0.001). There was also a significant prolongation of euglobulin lysis time (p less than 0.005) and an increase of plasminogen activator inhibitor activity (p less than 0.0001), fibrinogen degradation products (p less than 0.001), and D-dimer (p less than 0.05) in the group of patients as compared to controls; FPA levels were also increased in patients with metastases (p less than 0.005). This study demonstrates clotting activation, at the level of fibrinogen to fibrin conversion, and impairment of fibrinolysis in patients with malignancy.

Parvovirus B19 acute infection and a reactivation of cytomegalovirus and herpesvirus 6 in a chronic myeloid leukemia patient during treatment with dasatinib (BMS-354825).

T lymphocyte activation is controlled by the T cell antigen receptor (TCR) in combination with additional signals triggered by accessory molecules present on the surface of the antigen-presenting cells (APC). Several studies have reported that treatment with imatinib can induce inhibition of the T-cell mediated immune response [1,2]. Imatinib inhibits T cell receptor-mediated T cell proliferation and activation in a dose-dependent manner and reduces tyrosine phosphorylation of ZAP-70 and LAT in response to activation through TCR [1]. Studies conducted in a mouse model indicate that imatinib treatment also leads to a selective inhibition of memory CTLs without affecting primary T or B cells responses [2]. Recent reports describing the development of severe viral infections such as varicella-zoster [3] and fatal hepatitis B virus reactivation in patients with CML treated with imatinib along with in vitro data suggest that the potential for immune suppression and viral reactivation in patients treated with abl and src kinase inhibitors should be considered [4]. We describe the development of a cytomegalovirus and herpes 6 virus associated with treatment with dasatinib (BMS354825) in a patient with diagnosis of CML. A 53-year-old woman was diagnosed with CML in November 2003. Treatment with imatinib was initiated at doses of 400 mg/day and further increased to 800 mg/day due to the persistence of BCR-ABL chromosome after 1 year. Treatment with imatinib was discontinued 2 years after diagnosis (September 2005) due to the development of grade III/IV cutaneous and gastrointestinal complications. In March 2006 treatment with dasatinib (BMS354825) was started at doses of 140 mg/day. One month after initiation of treatment with dasatinib, the patient was admitted to the hospital with atypical pneumonia (bilateral infiltrates in chest radiography, fever, dry cough, dyspnea and pleuritic pain). Despite extensive work-up, only three positive citomegalovirus cells were identified by the rapid viral culture (shell vial method) from peripheral blood. The patient was treated with antiviral (Ganciclovir) and antibiotic therapy (TeicoplaninMeropenem) with good response and was discharged after 15 days. In May 2006, the patient presented with a generalized cutaneous rash with positive serological test for parvovirus B19 (IgG titer 512 and IgM titer 40) and herpesvirus 6 (IgG titer 80). This pattern is compatible with an acute infection from parvovirus B19 because detectable low levels of B19 specific IgM can be found within 7 – 10 days of the exposure. We excluded the possibility to herpesvirus 6 infection because the patient had low levels of specific herpesvirus 6 IgG and a percentage of healthy adults are IgM positive at any time, making

Long-term survival in primary plasma cell leukemia after therapy with VAD, autologous blood stem cell transplantation and interferon-alpha.

Primary plasma cell leukemia (PCL) is a rare form of plasma cell neoplasm with a poor prognosis. Conventional melphalan-based treatments have been most disappointing. We report the case of a 62-year-old man with a primary form of PCL treated with VAD combination achieving an objective response, and who received high-dose melphalan and autologous peripheral blood stem cell (PBSC) transplantation followed by interferon-α. During the remission time, lasting for 3 years, an infiltration by large granular lymphocytes (LGL) was noted in peripheral blood. However, when the number of LGL declined, a bone marrow relapse was observed. The treatment for PCL and the possible role of these LGL on tumor cell control after autologous PBSC transplantation are discussed.

Fibrinolytic response in malignancy

Fibrinolytic response was investigated in 71 patients with different malignancies and compared with findings in 30 healthy persons. Euglobulin lysis time, fibrinolytic activity on fibrin plate, tissue plasminogen activator (t-PA) activity and antigen before and after venous occlusion and the fast-acting inhibitor to t-PA (PA-inhibitor) were performed. Fifteen patients (21%) showed low fibrinolytic activity on fibrin plate after venous occlusion (low responders), whereas all control subjects showed a positive response (p < 0.03). t-PA activity was significantly lower in patients (p < 0.003) and t-PA antigen showed no significant differences between patients and controls in post-occlusion samples. PA-inhibitor was significantly higher in patients (p < 0.0002). We conclude that defective fibrinolysis in malignancy, resulting of highly increased PA-inhibitor levels in combination with low t-PA activity, and may have pathogenetic implications.

Role of sialic acid in acquired dysfibrinogenemia associated with liver cirrhosis

SummaryThe possible existence of acquired dysfibrinogenemia was investigated in blood samples from 30 patients with liver cirrhosis, 15 newborns and 30 healthy control subjects. Alterations of thrombin time were found in newborns and in 14 cirrhotic patients; glucide fraction levels were measured in these subjects and an increase in sialic acid content was observed. Its functional role was studied by comparing thrombin time and electrophoretic mobility of purified and desialylated forms of fibrinogen. We observed a thrombin time normalization, which was initially prolonged upon the removal of the sialic acid. The anodic electrophoretic mobility underwent changes due to the removal of sialic acid.

Incidence of Non-Hodgkin's Lymphoma in Patients Treated for Hodgkin's Disease

The purpose of this study was to evaluate the incidence of non-Hodgkins lymphoma (NHL) as a second tumor in patients treated for Hodgkins disease (HD), as well as to establish the role of different variables in its appearance. Between January 1973 and June 1988, 101 patients with HD were treated according to the stage, with chemotherapy and/or radiotherapy. Complete remission was obtained in 87 patients. Five patients developed secondary NHL between the 77th and 124th month of complete remission. The median follow up was 73 months (range 3-227 months). The incidence of second NHL in our series was, 0%, 4.6% (CI 0-11%) and 17% (CI 4-32%) at 5, 10 and 15 years respectively. Coxs stepwise regression analysis performed with all initial and treatment covariates (sex, age, splenectomy, histology, stage and treatment modality) showed that the only statistically significant variable was the treatment received (p < 0.01). Cumulative incidence of NHL at 15 years, ranged from 0% for patients treated with radiotherapy or chemotherapy alone to 39.6% for those who received combined therapy (p = 0.002). We can conclude that the use of chemotherapy plus radiotherapy for treatment of HD increases the risk for the development of second NHL.

Complex karyotype including 14q+ marker in a case of Waldenström's macroglobulinemia

We describe a case of Waldenströms macroglobulinemia with a complex karyotype including a 14q+ marker. Secondary changes affected chromosomes 2, 4, 6, 7, 8, and 17. The cytogenetic significance of the changes and their prognostic value, as compared with those described in previous reports, are discussed.

Congenital dysfibrinogenemias. A review

SummaryInherited qualitative abnormalities of fibrinogen have been documented in 144 families. These dysfibrinogenemias have been inherited as autosomal dominant traits and usually are clinically silent, but in some cases are associated with bleeding, thrombosis, or defective wound healing. Dysfibrinogenemias may be associated with defects in any of the three basic steps in the thrombin-fibrinogen reaction, i.e., cleavage of the fibrinopeptides by thrombin, polymerization, and fibrin cross-linking. Biochemical studies of several abnormal fibrinogens have demonstrated that the functional defects are the result of single amino acid substitutions. Most of the reported cases may be distinguished by functional criteria and by the physicochemical behavior and biochemical nature of the abnormal protein.