Antonino Carbone

Rearrangements of bcl-6, bcl-2, c-myc and 6q deletion in B-diffuse large-cell lymphoma: Clinical relevance in 71 patients

BACKGROUNDnB-diffuse large-cell lymphomas (DLCL) have been associated with some molecular lesions, but the role of such lesions as prognostic markers is still controversial. This report concerns an investigation of the frequency and clinical correlation of bcl-6, bcl-2, c-myc rearrangements and 6(q) deletions in B-DLCL.nnnPATIENTS AND METHODSnThe presence of these genetic lesions was analyzed in samples of lymph nodes or bone marrow collected at diagnosis in 71 patients with B-DLCL, all treated with an anthracycline-containing chemotherapy regimen.nnnRESULTSnRearrangement of bcl-6 was found in 11 patients (15%), rearranged bcl-2 in 12 (17%), 6(q) deletions in 10 patients (14%) and c-myc rearrangement in four (6%). Patients with rearranged bcl-6 tended to have a more aggressive disease than patients with germ-line bcl-6 (intermediate-high/high risk according to IPI criteria: 73% vs. 43%), but there were no differences in three-year survival rates (62% vs. 42%) between the two groups. The numbers of involved extranodal sites were similar in patients with rearranged and those with germ-line bcl-6. Patients with bcl-2 rearrangement appeared to have a less aggressive disease than those with germ-line bcl-2 (low/ low-intermediate risk 75% vs. 47%) and a slightly better three-year survival rate (70% vs. 41%) but again the difference was not significant. Both groups with or without 6(q) deletion had similar clinical characteristics and outcomes. The four patients with c-myc rearrangement had aggressive disease and did poorly.nnnCONCLUSIONSnThe analysis of molecular lesions in B-DLCL may be useful for a better diagnostic definition; however, in this study we were unable to show that the evaluated genetic lesions had a significant impact on clinical outcome.

Molecular heterogeneity of B-lineage diffuse large cell lymphoma

B‐lineage diffuse large cell lymphoma (B‐DLCL) arising de novo is characterized by a marked degree of clinical heterogeneity. To determine whether or not the clinical heterogeneity of de novo B‐DLCL is reflected by heterogeneity in the molecular features of these tumors, we investigated the pattern of distribution of several genetic lesions in 70 cases of de novo B‐DLCL at diagnosis. The panel of genetic lesions tested comprised the molecular alterations most frequently detected in B‐DLCL, including rearrangements of BCL2, BCL6, and MYC as well as deletions of 6q and mutations of TP53. One or more genetic lesions were detected in 39/70 cases of B‐DLCL. Isolated structural alterations of BCL2, BCL6, 6q or TP53 were detected in 8/70, 10/70, 11/70, and 3/70 cases, respectively. No isolated MYC lesions were detected. Six cases carried different combinations of two genetic lesions, including lesions of BCL2 + BCL6 (1 case), BCL2 + MYC (1 case), BCL2 + 6q (2 cases), or BCL6 + 6q (2 cases). One case had accumulated three genetic lesions, namely a rearrangement of BCL2 and BCL6 and a mutation of TP53. Overall, these data show that multiple distinct patterns of genetic lesions may associate with de novo B‐DLCL, indicating that the molecular pathogenesis of this group of lymphomas is characterized by a high degree of molecular heterogeneity. Genes Chromosom Cancer 16:21–30 (1996).

Point mutations of the BCL‐6 gene in Burkitt's lymphoma

BCL‐6 codes for a transcription factor implicated in chromosomal translocations of diffuse large cell lymphomas. Recent evidence indicates that BCL‐6 may also be altered by mutations of its 5′ non‐coding regions. In this study we have investigated the distribution of BCL‐6 5′ mutations among 35 Burkitts lymphoma cases representative of the epidemiologic variants of the disease. Mutations were detected in 6/21 (28.6%) sporadic Burkitts lymphomas and 7/14 (50%) endemic Burkitts lymphomas. These data expand the spectrum of B‐cell non‐Hodgkins lymphomas associated with BCL‐6 5′ mutations and have implications for the pathogenesis, histogenesis and clinical monitoring of Burkitts lymphoma.

Human herpesvirus type-8 (HHV-8) in haematopoietic neoplasia.

Human herpesvirus type-8 (HHV-8) is a lymphotropic herpesvirus originally identified in Kaposis sarcoma. Among lymphoproliferative disorders, HHV-8 infection is restricted to body-cavity-based lymphoma (BCBL) and multicentric Castlemans disease (MCD). BCBL are B-cell lymphomas growing in liquid phase in the body cavities and most frequently associated with AIDS. BCBL express indeterminate phenotypes, in all cases are associated with HHV-8 infection, and frequently carry Epstein-Barr virus genomes in the absence of c-MYC rearrangements or other genetic lesions characteristic of B-cell lymphomas. The clinical outcome of BCBL is poor with a median survival of only few months. MCD is an atypical lymphoproliferative disorder which displays marked vascular hyperplasia and is commonly associated with Kaposis sarcoma. HHV-8 infection occurs in 100% of AIDS-related MCD and in approximately 40% of AIDS-unrelated cases. Overall, the consistency of HHV-8 infection in BCBL and MCD, its selectivity throughout the spectrum of lymphoproliferative disorders and the high copy number of HHV-8 DNA sequences in infected cells suggest that the virus plays a pathogenetic role in these disorders.

CD13 Expression in B-Cell Chronic Lymphocytic Leukemia is Associated with the Pattern of Bone Marrow Infiltration

The ectopic expression of the cell surface peptidase CD13 (aminopeptidase N) and of three other myelomonocytic antigens i.e. CD33, CD14 and CD15 was analyzed by flow cytometry in neoplastic lymphocytes from 81 consecutive patients with B-cell chronic lymphocytic leukemia (B-CLL). CD13 and CD14 antigens were detected on lymphocytes from 30% and 60% of patients respectively whilst a smaller percentage of samples was found positive for CD15 (5%) and CD33 (12%). The presence of CD13 and CD33 antigens on neoplastic B cells showed a statistically significant association with the two most important clinicopathologic prognostic factors in B-CLL: the clinical stage (CD13, p < 0.01; CD33, p < 0.05—Rai and Binet staging systems) and the pattern of bone marrow infiltration (CD13, p < 0.001; CD33, p = 0.02). A multiple logistic regression analysis showed that the increased risk of CD13 positive patients (13.7 fold higher than in CD13 negative cases; p = 0.001) of presenting a diffuse pattern of bone marrow infiltratio...

Association of Epstein-Barr Virus with Hodgkin’s Disease

The nature of Hodgkin’s disease (HD) and the origin of its characteristic cells, the Reed-Sternberg (RS) cells, are still obscure in spite of the abundant literature on this disorder. In recent years, the concept that HD is a malignant lymphoma has become widely accepted among pathologists, clinicians, and medical researchers working on this disease. However, the evidence accumulated so far with regard to the standard parameters defining neoplastic proliferation, such as clonality, chromosomal abnormality, and transplantability, is still controversial. A further enigma concerning HD as a neoplastic lymphoproliferative disease is the extremely low percentage of putative neoplastic cells (RS cells and their variants) occurring in the polymorphic histopathological setting that characterizes the disease. In contrast, well-recognized neoplastic lymphoproliferative diseases, the so-called non-Hodgkin’s lymphomas (NHLs), usually show monomorphic histological patterns and are constituted predominantly of monoclonal or, more rarely, oligoclonal cell populations.

The NF-κB inhibitor DHMEQ decreases survival factors, overcomes the protective activity of microenvironment and synergizes with chemotherapy agents in classical Hodgkin lymphoma

The NF-κB inhibitor DHMEQ has shown preclinical activity in classical Hodgkin Lymphoma (cHL). Here we evaluated if DHMEQ could affect microenvironmental interactions and formation and improve the activity of drugs used in relapsed/refractory cHL. We demonstrated that DHMEQ down-regulated the NF-κB target genes IRF4 and CD40, the secretion of IL-6, CCL5, CCL17 and generated ROS. Cytotoxicity, CD30 down-modulation and CD30 shedding by DHMEQ were prevented by ROS scavenger NAC. DHMEQ overcame stimuli from CD40 engagement and fibroblasts and enhanced doxorubicin, cisplatin and gemcitabine activity. Our results suggest that DHMEQ may be a promising agent for future therapeutic strategies in cHL.

Genetic Markers in Sporadic Tumors

Progress in understanding the molecular basis of neoplastic transformation has strengthened the concept that cancer is a genetic disease. This concept, however, lumps together two types of genetic diseases with the same outcome: the first linked to an entirely somatic cell-gene deregulation and the second dealing with a genetic susceptibility. At the somatic cell level, deregulation of cancer genes that control the careful balance between increase in cell number and withdrawal from the cell cycle promotes neoplastic growth by disrupting this balance. This deregulation occurs as a result of circumvention of the apoptotic machinery, promotion of cell division and cell proliferation, loss of cell differentiation pathways, and disruption of cell-cell communication and interaction. Thus, cancer represents the end point of a multistep process involving cancer genes and stimulatory and inhibitory signals provided by and controlled by products of the cancer genes.

Expression of myeloid associated antigens in chronic lymphocytic leukaemia.

I have read with interest the recent article entitled ‘An in vitro direct chemiluminescence assay for assessment of plateletbound antibody in thrombocytopenic patients’ (Kazemi et al. 1991). The authors, without looking at our study (Ozsoylu et al, 1977). stated that ‘the interaction between phagocytes and autologous autosensitized platelets was not measured’. In our study it was looked for in vivo but could not be found (~zsoylu et al, 1977). I would also l i e to bring to the authors attention that by using the method described by Handel & Stossel (1974) we were able to detect antiplatelet antibodies (APA) in all 103 patients with acute idiopathic thrombocytopenic purpura (ITP) and 46 patients with chronic ITP. These antibodies could also be found during remission in all children who had had acute (100 cases) and chronic (32 cases) ITP, although the level was markedly lower than that during the thrombocytopenic period. Moreover, a rise in the APA level was seen during relapse in four chronic and two acute ITP patients. A decrease of APA was also shown by two out of four children who had re-entered remission after relapsed chronic ITP (c)zsoylu et aI, 1991). APA were not found in any of 126 control sera obtained from 67 haematologically normal individuals and 59 thrombocytopenic patients of whom 28 had acute leukaemia. 10 acquired aplastic anaemia, 10 Fanconi’s anaemia and 11 sepsis with thrombocytopenia ((lzsoylu et al. 1991). The persistence of APA during remission in cases of acute and chronic ITP, previously reported by us ((lzsoylu et al, 1976), explains the shorter survival of platelets in these children. Although the results of Kazemi et al (1991) are somewhat supportive of our findings it could be concluded that the method of Handin & Stossel (1974) is more appropriate for the detection of APA in ITP cases in relapse or in remission even though the two methods are very similar in principle.

Management of Non-Hodgkin’s Lymphomas in Elderly Patients: Conclusions of the Second Intercity Meeting, 1987

The occurrence of malignant non-Hodgkin’s lymphomas (NHL) in elderly patients is a clinical condition probably requiring a specific therapeutic approach. This issue is, however, quite controversial, since it has only recently been brought to the attention of medical oncologists and haematologists: the few available studies in the literature provide rather conflicting results.