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Objective: At diagnosis, chronic myeloid leukemia (CML) is genetically characterized by the presence of the classical reciporocal translocation t(9 ; 22)(q34 ; q11.2), resulting in a BCR/ABL1 gene fusion on the derivate chromosome 22 called the Philadelphia (Ph) chromosome and occur usualy as the sole abnormality. In 5–10% of patients, a complex translocation leads to the formation of a variant Ph chromosome and involves not only chromosome 9 and 22, but also a third or more chromosomes. Cryptic BCR/ABL1 rearrangments can be found in cases with complex karyotype in wich the t(9 ; 22) is not detected by conventional cytogenetic analyses. Additional chromosomal abnormalities (ACAs) in Ph-positive cells may appear in 5% of cases and are strongly associated with disease progression. Methods: We cytogenetically investigated a group of 573 CML patients from 1988–2013 years. The CML group consisted of 306 males (median age 47) and 267 females (median age 51) (1, 2/1). Results: Complex variant translocation was demostrated in 49 patients (8%), six with criptic BCR/ABL1 fusion gene. Chromosome bands involved in structural rearrangments include 1q23, 2q37, 3q27, 3p21, 6p23, 6q23, 9p21, 9q34, 10q11, 10q12, 11p15, 11q13, 11q23, 12p13, 13p11, 14p11, 14q11, 15p11, 15q26, 16p13, 17q21, 18p12, 19p13, 21q22, 22q10 and Xp11. ACAs in Ph-positive are non-random (7, 5%), with the most common being +8, +Ph, i(17q), +19, +21, +17, -Y, and -7. Three patients were with clonal Robertson translocarion, one with t(8 ; 21). Konstitutional chromosome abnormalities were 45, X, 47, XXX, and translocation t(2 ; 8)(p11.2 ; p11). Conclusion: These results coincidence with those reported in literature.

A Philadelphia-negative Chronic Myeloid Leukemia with a BCR/ABL Fusion Gene...

Mediastinal (thymic) large B-cell lymphoma (Med- DLBCL) is a subtype of diffuse large B-cell lymphomas (DLBCL) with a typical radiological appearance of bulky anterior mediastinal mass, often with areas of necrosis. We report a case of Med-DLBCL with unusual radiological findings and clinical development. Computed tomography (CT) obtained at presentation revealed a huge anterior mediastinal tumor with an axial diameter of 180 mm. Nineteen days after the first cycle of chemotherapy, chest radiography and CT revealed large areas of tumor necrosis and pneumomediastinum with air-fluid levels. To our knowledge, air-fluid levels inside Med-DLBCL have not been previously described. This finding, in combination with necrotic sputum, may indicate communication between the tracheobronchial tree and the tumor.

Malignant cells express multiple antigens that can be recognized by the immune system and can be targeted by antigen specific immunotherapies including vaccines, antibodies and T cells. To identify genes that are over-expressed in B-cell malignancies PCR subtracted cDNA libraries in conjunction with microarray screening were used. Ten subtracted libraries (lymphoma n=6, CLL n=2, myeloma n=2) were constructed to enrich for B-cell neoplasm or lymphatic tissue specific cDNA sequences. cDNA pools from lymphomas, B-CLL and multiple myeloma (MM) were subtracted against cDNA pools of related normal hematopoietic tissues or normal non-hematopietic tissues. Subtracted libraries showed enrichment for both B-cell neoplasm and lymphatic tissue specific genes compared to an unsubtracted library. 14, 000 clones were sequenced and analyzed by comparison to sequences in 3 electronic databases: GenBank, huEST and GenSeq. At the time of analysis, 1380 (10%) clones had no significant similarities to known genes and 12, 120 (90%) matched known genes. These 14, 000 cDNA fragments were then analyzed using DNA microarray technology. Genes over-expressed in B-cell malignancies were identified using pairs of fluorescence-labeled cDNA probes synthesized from lymphomas, CLL or MM (n=50) and normal tissue poly A+ RNAs (n=50). Over 1.4 Million hybridization signals were analyzed. Expression patterns of 65 overexpressed genes were confirmed and characterized further by Real Time PCR using a panel of 170 cDNAs comprising of lymphomas, CLL, MM, normal tissues and MACS sorted hematopoietic subpopulations. Expression profiles were compared to known therapeutic antibody targets, CD20, CD52 and CD45. Based on their mRNA expression profile a group of cDNA fragments (Ly1448, Ly1456 and Ly1464) was identified demonstrating expression in normal tissues similar to CD20 but displaying broader coverage in B-cell malignancies. These cDNA fragments are expressed in the majority of B-cell lymphomas, B-CLL and multiple myeloma patient samples and were thus termed Pan B-cell neoplasm markers. So far, potential full length open reading frames of 2 of the 3 cDNA fragments have been identified, encoding for proteins with a predicted transmembrane region. Further characterization of these genes is in progress.

BACKGROUND: The randomized trials that evaluate the timing and intensity of initial chemotherapy for chronic lymphocytic leukemia (CLL) have, in general, been too small to provide separately reliable results. We compared the effects on survival of the following: a) immediate versus deferred chemotherapy for early-stage CLL and b) combination chemotherapy (e.g., cyclophosphamide and vincristine plus prednisone/prednisolone [COP] or COP plus doxorubicin [CHOP]) versus single-agent chlorambucil as first-line treatment for more advanced disease. METHODS: All relevant randomized trials, whether published or not, were sought for a collaborative meta-analysis involving centralized review of the data for each patient. RESULTS: There were 2048 patients with early disease in six trials of immediate versus deferred chemotherapy (chlorambucil or chlorambucil plus prednisone/prednisolone). The 10-year survival was slightly worse (but not statistically significantly so) with immediate chemotherapy (44% versus 47% survival; difference = -3%; 95% confidence interval [CI] = -10% to 4%). There were another 2022 patients in 10 trials of combination chemotherapy versus chlorambucil, with or without prednisone/prednisolone. The 5-year survival was 48% in both cases (difference = 0%; 95% CI = -6% to 5%). A subgroup of six of these 10 trials involved an anthracycline-containing regimen but again overall survival appeared no better than with chlorambucil (anthracycline-based regimen: 325 deaths among 627 patients; chlorambucil: 306 deaths among 636 patients; death rate ratio = 1.07; 95% CI = 0.91-1.25; not statistically significant). CONCLUSIONS: In terms of survival, these trials support a conservative treatment strategy for CLL, i.e., no chemotherapy for most patients with early-stage disease, and single-agent chlorambucil as the first line of treatment for most patients with advanced disease, with no evidence of benefit from early inclusion of an anthracycline. This strategy will, however, need to be reconsidered as mature results become available from trials of other agents. Lijec Vjesn 1997 Nov-Dec;119(11-12):328-30 [Case report of a female patient with autoimmune hemolytic anemia and cold agglutinin antibodies]. [Article in Serbo-Croatian (Roman)] Konja, Josip; Jakovljevic, G.; Jaksic, Branimir; Grgicevic, Damir; Car, M.; Glavas, B.: We report a case of acute transient cold agglutinin disease, the etiology of which we could not determine with the available methods. Cold autoagglutinins had anti I specificity, high titers of the autoantibody (> 1:1,000) and the thermal range was relative wide. Our patient had severe haemolysis and immunosuppressive therapy with methylprednisolone and cyclophosphamide was administered. It is a question how much these immunosuppresive agents influenced the recovery, and in what extent it was a self limited disease with spontaneous recovery.

We conducted a prospective, multicenter pilot study of remission induction therapy in patients with poor prognosis MDS and AML evolving from a preceding phase of MDS. Fifty evaluable patients from 15 institutions were treated with one or two remission-induction courses consisting of i.v. idarubicin 12 mg/m2/day on days 1, 2, and 3 combined with a continuous i.v. infusion of cytarabine of 200 mg/m2/day on days 1 to 7. Of the 27 complete remitters (54%), 23 received a consolidation course which was identical to the remission-induction course except for the idarubicin 12 mg/m2 which was given on day 1 only. Fifteen patients received maintenance therapy consisting of six courses of cytarabine 10 mg/m2, s.c. twice daily, for 14 days. Two complete remitters were allografted and five patients received an ABMT. The median survival of all 50 treated patients was 14 months. The median duration of disease-free survival was 11 months with two patients in CR more than 2 years after entering CR. Twenty-four of the 27 remitters have relapsed. Four patients died during remission- induction therapy, but no patient died as a result of persisting hypoplasia. No fatal complications occurred during the consolidation and maintenance courses. Age and stage of disease had no significant impact on CR rate nor on remission duration. The CR rate was significantly (P = 0.03) higher in patients with only normal metaphases compared to patients with cytogenetic abnormalities. The DFS at 2 years was 33 vs 8%, respectively, for patients without or with cytogenetic abnormalities (P = 0.02). This study shows that patients below the age of 60 years with poor risk features are candidates for treatment with combination chemotherapy. A complete remission rate of more than 50% may be expected. Maintaining remission after remission-induction chemotherapy is a difficult issue. Patients not eligible for allogeneic BMT may be treated with intensive post-remission chemotherapy or autologous BMT.