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Biomedical subjects

M F Martelli

Publications and source records attributed to M F Martelli.

At least 73 records · Page 4Linked to original sources
PubMed1996

14q+ chromosome marker in a T-cell-rich B-cell lymphoma.

Cytogenetic, in situ hybridization, and molecular studies were performed in a case of T-cell-rich B-cell lymphoma. Demonstration of Ig gene rearrangements for both heavy and light chains confirmed the B-lineage restriction of the neoplastic cell population. Moreover, as expected in B-cell malignancies, all abnormal karyotypes showed a 14q+ chromosome marker involving 14q32. The origin of the extra material on the derivative 14q+, as defined by chromosome painting with a library for chromosome 11, and Southern blotting for c-myc and bcl-2 rearrangements, remains unknown.

Blotting, Southern↗
PubMed1996

Anti-CD30 (BER=H2) immunotoxins containing the type-1 ribosome-inactivating proteins momordin and PAP-S (pokeweed antiviral protein from seeds) display powerful antitumour activity against CD30+ tumour cells in vitro and in SCID mice.

The anti-CD30 immunotoxin (IT) Ber-H2/saporin is effective in patients with refractory Hodgkin's disease. However, responses are short and partial, one of the main reasons being the inability to repeat IT doses because of formation of human antibodies against the murine antibody and/or the toxin. To overcome this problem, we constructed two new anti-CD30 ITs by covalently linking the mouse monoclonal antibody Ber-H2 to the type 1 ribosome-inactivating proteins (RIPs) momordin (MOM) and pokeweed antiviral protein from seeds (PAP-S), which do not cross-react with each other or with saporin. Both ITs inhibited protein synthesis by Hodgkin's disease and anaplastic large-cell lymphoma (ALCL)-derived CD30+ target cell lines with a very high efficiency (IC50 ranging from < 5 x 10(-13) M to 2.75 x 10(-11) M, as RIP). In a SCID mouse model of xenografted CD30+ human ALCL, a 3d treatment with non-toxin doses of Ber-H2/MOM (50%LD50), started 24 h after transplantation, prevented tumour development in about 40% of the animals and significantly delayed tumour growth rate in the others. Main toxicity signs in mice and rabbits were dose-related increase of serum transaminases (AST and ALT) and creatine phosphokinase (CPK). LD50 (as RIP) in Swiss mice was 7 mg/kg for Ber-H2/MOM and 0.45 mg/kg for Ber-H2/PAP-S. Sequential administration of two anti-CD30 ITs (Ber-H2/MOM and Ber-H2/saporin) was well tolerated and did not result in formation of antibodies cross-reacting and with the two plant toxins. The results presented in this paper suggest that in the future, sequential administration of anti-CD30 humanized antibodies linked to antigenically distinct type 1 RIPs (saporin, MOM, PAP-S) should be feasible.

Animals↗
PubMed1996

High-dose chemotherapy followed by autologous bone marrow transplantation versus dexamethasone, cisplatin, and cytarabine in aggressive non-Hodgkin's lymphoma with partial response to front-line chemotherapy: a prospective randomized italian multicenter study.

PURPOSE: To evaluate, in a prospective multicentric study, the efficacy of a conventional salvage chemotherapy (dexamethasone, cisplatin, and cytarabine [DHAP]) versus high-dose chemotherapy (carmustine, etoposide, cytarabine, and cyclophosphamide [BEAC]) followed by autologous bone marrow transplantation (ABMT) in patients with aggressive non-Hodgkin's lymphoma (NHL) in clinical partial response (PR) after two thirds of a conventional front-line therapy. PATIENTS AND METHODS: From August 1988 to August 1991, 286 patients with aggressive NHL were randomized in seven Italian institutions to receive fluorouracil, methotrexate, cytarabine, cyclophosphamide, doxorubicin, vincristine, and prednisone (F-MACHOP) or methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) as front-line therapy. Of the 286 patients enrolled onto the trial, 77 (27%) were considered in PR after two thirds of the front-line therapy, and 49 of 77 (64%) were randomized: 27 to receive DHAP chemotherapy and 22 to receive BEAC followed by ABMT. RESULTS: The response after second-line treatment was as follows: in the DHAP group, four patients (15%) achieved a complete remission (CR), 12 (44%) remained in stable PR, and 11 (41%) showed progressive disease; in the ABMT group, three patients (14%) obtained a CR, 18 (82%) obtained a stable PR, and one (4%) progressed, with an overall response (CR + stable PR) of 59% and 96% (P < .001) in the DHAP and ABMT groups, respectively. The overall survival was 59% versus 73% and the progression-free survival (PFS) was 52% versus 73% in the DHAP and ABMT groups, respectively (P, not significant). The toxicity was mild, particularly in the ABMT group, and no treatment-related deaths occurred in either group. CONCLUSION: Because of the small number of patients randomized, we were unable to determine whether ABMT or a standard salvage regimen (DHAP) is superior for PR patients. However, we confirmed that myeloablative treatment is a safe and well-tolerated procedure in this category of patients and this may enable us to evaluate its role as part of a front-line treatment in poor-risk NHL patients.

Adolescent↗
PubMed1996

Anaplastic large-cell lymphoma: clinical and prognostic evaluation of 90 adult patients.

PURPOSE: During the last few years, the application of CD30 monoclonal antibodies has led to the identification of a new lymphoma entity, termed anaplastic large cell lymphoma (ALCL). This tumor includes four distinct histologic subtypes, among which the Hodgkin's-like/Hodgkin's-related one (ALCL-HL) shares morphologic and phenotypic features with Hodgkin's disease (HD). PATIENTS AND METHODS: From September 1988 to October 1993, 90 ALCL patients were treated with third-generation chemotherapy regimens (either vincristine, cyclophosphamide, fluorouracil, cytarabine, doxorubicin, methotrexate with leucovorin, and prednisone [F-MACHOP] or methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B]) during the course of an Italian multicentric randomized trial on high-grade non-Hodgkin's lymphomas (HG-NHL). In particular, 47 patients had ALCL of the common type (ALCL-CT) and 43 ALCL-HL. Null phenotype was the most common (39.8%), while T-cell, B-cell, and hybrid forms accounted for 35.5%, 22.2%, and 2.5%, respectively. RESULTS: Complete remission (CR) was achieved in 66 of 90 (73.5%) patients (33 of 47 [70%] with ALCL-CT and 33 of 43 [77%] with ALCL-HL). The majority of the patients in CR (56.5%) were alive and well at a median follow-up time of 38 months; no significant differences were observed between the two histologic groups, with the rate of complete responders being 49% and 65% in ALCL-CT and ALCL-HL, respectively. The probability of relapse-free survival (RFS), projected at 63 months, was 67% for ALCL-CT and 82% for ALCL-HL. The risk of lower CR and RFS rates was associated with the presence of bulky disease, advanced stage, and B symptoms. CONCLUSION: The data of the present study confirm that ALCL responds to third-generation chemotherapy regimens similarly to other aggressive malignant lymphomas in terms of both CR and RFS rates.

Adolescent↗
PubMed1996

Monoclonal antibodies PG-B6a and PG-B6p recognize, respectively, a highly conserved and a formol-resistant epitope on the human BCL-6 protein amino-terminal region.

The human BCL-6 gene, which is rearranged in approximately 30% of diffuse large B cell lymphomas, encodes a 706-amino-acid nuclear protein of the Kruppel-type zinc finger transcription factors mainly expressed in normal germinal center B cells and related lymphomas. Four monoclonal antibodies (PG-B6, PG-B6a, PG-B6p, and PG-B6m), specifically directed against the human BCL-6 protein, were generated by immunizing BALB/c mice with a recombinant protein corresponding to the BCL-6 amino-terminal region (amino acids 3 to 484). The PG-B6 monoclonal antibody reacted with a BCL-6 epitope sensitive to fixatives and preserved in all mammalian species. PG-B6a (a is for avian) recognized the most evolutionarily conserved BCL-6 epitope (expressed in all animal species including avian). PG-B6p (p is for paraffin) recognized a fixative-resistant epitope of BCL-6 that was detectable on paraffin sections after microwave heating in 1 mmol/L EDTA buffer. PG-B6m (m is for mantle) was the least specific monoclonal antibody as, in addition to BCL-6, it reacted with a yet undefined antigen selectively located in the cytoplasm of mantle and marginal zone B cells. All monoclonal antibodies detected strong nuclear expression of BCL-6 in follicular lymphomas, diffuse large B cell lymphomas, Burkitt's lymphomas, and nodular, lymphocyte-predominance Hodgkin's disease. In diffuse large B cell lymphomas, BCL-6 expression was independent of BCL-6 gene rearrangements and did not correlate with expression of other markers or the proliferation index. BCL-6 was not expressed in B-CLL, hairy cell leukemia, mantle-cell- and marginal-zone-derived lymphomas. Labeling of paraffin sections with PG-B6p proved useful for differentiating proliferation centers in B-CLL (BCl-2+/BCL-6-) from trapped germinal centers in mantle cell lymphomas (BCL-2-/BCL-6+) and for identifying neoplastic cells in cases of nodular, lymphocyte-predominance Hodgkin's disease. Because of their high specificity, wide reactivity in humans and animal species including avians (PG-B6a), and suitability for labeling routine paraffin sections (PG-B6p), the reagents described in this paper should prove valuable in both research and diagnostics.

Amino Acid Sequence↗
PubMed1996

Unusual split chimaerism after mismatched T-depleted BMT.

We report a case of haploidentical T-depleted BMT that engrafted durably after a highly immunosuppressive conditioning regimen. DNA polymorphism analysis showed that granulocytes and monocytes were donor type but T and B lymphocytes were host derived. Host tolerance to donor antigens was documented. The patient suffered from serious recurrent CMV infections until split chimaerism shifted to full donor type 2 years post-BMT. Seven years after BMT the patient remains in complete remission.

Adult↗
PubMed1995

TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13).

A t(5;12)(q33;p13) translocation is a recurrent chromosome abnormality in a subgroup of myeloid malignancies with features of both myeloproliferative disorders and myelodysplastic syndromes (MDSs). The molecular consequence of a t(5;12) is a fusion between the platelet-derived growth factor receptor-B gene on chromosome 5 and a novel ETS-like gene, TEL, on chromosome 12. We report on three patients with a t(5;12)(q33;p13) diagnosed as chronic myelomonocytic leukemia, and one case of a t(10;12)(q24;p13) in a progressive MDS, with eosinophilia and monocytosis. Involvement of the TEL gene in these chromosome translocations was investigated by fluorescence in situ hybridization (FISH) with cosmid probes containing selectively the 5' end or 3' end of TEL. Hybridization of these cosmids to the der(5)/der(10) or a der(12), respectively, demonstrated a rearrangement of TEL in both translocations, showing that the t(10;12) is a variant translocation of the t(5;12). Cloning of the fusion cDNA of one case of t(5;12) showed that the breakpoint occurred at the RNA level at exactly the same position as reported by Golub et al (Cell 77:307, 1994). In addition, the TEL gene on chromosome 12 could be localized between two probes previously mapped to 12p13, namely PRB1 and D12S178, leading to a better definition of the position of TEL in this chromosome region. Moreover, in the case involving chromosome 10, the breakpoint occurred between cKTN206 and cKTN312/LYT-10 at 10q24. Clinicohematological data in these studies as well as the restriction mapping of chromosomal breakpoints strongly suggest that (1) common features in MDSs involving the TEL gene are monocytosis and eosinophilia, (2) chromosomes other than no. 5 may be involved and at least a t(10;12)(q24;p13) variant chromosome translocation does exist in these MDSs, and (3) both standard and variant 12p/TEL translocations may be identified by FISH with appropriate probes.

Adult↗
PubMed1995

Characterization of a new monoclonal antibody (PG-M3) directed against the aminoterminal portion of the PML gene product: immunocytochemical evidence for high expression of PML proteins on activated macrophages, endothelial cells, and epithelia.

PG-M3 is a new monoclonal antibody (MoAb) specifically directed against a peptide sequence located in the aminoterminal region of the human PML protein. PML gene fuses with the retinoic acid receptor alpha (RAR alpha) gene during the t(15; 17) chromosomal translocation of acute promyelocytic leukemia (APL). The epitope recognized by PG-M3 is species-specific and fixative-resistant and is shared by most PML isoforms and PML/RAR alpha fusion proteins. PML is consistently located within the nucleus, although a minority of cells (about 20%), both in vitro and in vivo, show positivity for PML also in the cytoplasm. The nuclear staining pattern of PG-M3 varies from speckled (cells other than APL) to micropunctate (APL cells). Although two physiologically expressed PML isoforms are detectable by immunocytochemistry only or predominantly in the cytoplasm of transfected cells, the cytoplasmic localization of PML is a property also shared by the PML isoforms that predominantly localize to the nuclei. Immunohistologic analysis of normal human tissues with the PG-M3 MoAb showed variable PML expression, with the highest levels of the protein in postmitotic, differentiated cell types, such as endothelial cells, epithelia, and tissue macrophages, especially activated ones. In keeping with this in vivo finding, PML appears strongly upregulated in the U937 promonocyte cell line after exposure to agents that induce monocyte/macrophage activation (interferon gamma) or maturation (vitamin D3 and transforming growth factor beta 1).

3T3 Cells↗
PubMed1995

Cytogenetic and FISH investigations on tetrasomy 8 in ANLL.

Two patients with "de novo" ANLL and tetrasomy of chromosome 8 at diagnosis are described. A mosaic karyotype with coexistence of normal metaphases was found in both cases. Trisomy 8 was also present in one metaphase of the first patient. Fluorescent in situ hybridization with a centromeric probe from chromosome 8 was applied in the second case, confirming the presence of a minor population with trisomy 8 in interphase nuclei.

Aged↗
PubMed1995

Bone marrow transplantation across HLA barriers by increasing the number of transplanted cells.

Throughout the 1970s, graft-versus-host disease (GVHD) was uniformly lethal in recipients of HLA-mismatched bone marrow. This major obstacle was overcome in 1980 by the introduction of rigorous T-cell depletion prior to transplantation into patients with severe combined immunodeficiency. However, in leukemia patients, the benefit of preventing GVHD was offset by graft rejection or graft failure. In this article, Yair Reisner and Massimo Martelli discuss how this problem may be overcome by intensification of the conditioning protocol in conjunction with a major increase in the dose of transplanted stem cells.

Animals↗
PubMed1995

Mediastinal large B-cell lymphoma: clinical and immunohistological findings in 18 patients treated with different third-generation regimens.

We report on the immunophenotype, clinical findings and response to aggressive chemotherapy of 18 patients with mediastinal large B-cell lymphoma (MLCL). Cases were collected from a series of 286 high-grade non-Hodgkin's lymphomas (HG-NHL) which, in the period September 1988 to August 1991, were enrolled in a prospective multicentre trial designed to compare the MACOP-B and F-MACHOP regimens. Immunostaining on frozen sections revealed a previously unrecognized phenotype, i.e. co-expression of B-cell (CD19, CD20, CD22, Ig-associated dimer) and activation-associated antigens (CD30 and CDw70) in about 60% of MLCL cases; in contrast, the activation-associated antigens CD25 and Ki-27 (unclustered) were consistently negative. This peculiar phenotype may reflect a derivation of the tumour from a subset of thymic activated B cells. Clinically, the patients (median age 31 years; F/M ratio 2.6) presented with bulky mediastinal mass (72%) associated with mediastinal syndrome in > 50% cases; disease was stage IIA in most cases. All 18 patients received aggressive chemotherapy (F-MACHOP 11; MACOP-B 7). Complete response (CR) was achieved in 57.1% of cases treated with MACOP-B. In contrast, the response of the 11 MLCL treated with F-MACHOP was poor (CR 18.2%) as compared to that of the 135 HG-NHL treated with the same regimen during the trial (CR 69.6%). This difference was still statistically significant after adjusting for negative prognostic factors (mediastinal mass > 10 cm plus increased LDH) and suggests that F-MACHOP might not be the most appropriate regimen for this kind of lymphoma.

Adolescent↗
PubMed1995

MACOP-B vs F-MACHOP regimen in the treatment of high-grade non-Hodgkin's lymphomas.

A prospective randomized study on aggressive non-Hodgkin's lymphomas was conducted by investigators at several Italian institutions with the intent of comparing two third-generation conceptually different regimens: the regimen containing methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B), a short-term continuous twelve-week therapy, and F-MACHOP (5-fluorouracil, methotrexate with leucovorin rescue, cytarabine, cyclophosphamide, doxorubicin, vincristine, and prednisone), a monthly intensive cyclic treatment combining prednisone with six active non-cross-resistant cytotoxic drugs. The goals of this study were the response rate, relapse-free survival, and incidence of hematologic and nonhematologic toxicities. Two hundred-eighty-six patients included between 15 and 60 years fulfilled the criteria for entry to the study; 140 patients were treated with MACOP-B and 146 with F-MACHOP. The minimum follow-up was 24 months. Clinical characteristics of all patients were similar and known prognostic factors were equally distributed between the two groups. Complete remission (CR) was achieved by 61% and 67% of the patients treated with MACOP-B and F-MACHOP, respectively; 4% and 6% were primarily resistant, 2% and 5%, respectively, died of causes directly related to therapy. At 50 months, 74% of all CR patients were alive without disease and there were no significant differences in relapse-free survival between the two groups: 75% in the F-MACHOP group and 73% in the MACOP-B group at 50 months. There was a higher incidence of mucositis among patients treated with MACHOP-B than among those given F-MACHOP (11% vs 3.5%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Is there any future for T-cell depleted bone marrow transplantation in chronic myeloid leukaemia?

There is no doubt that the poor reputation of T-cell depleted bone marrow transplant arises from its use in CML patients, where an increase in graft rejection and, above all, in leukaemia relapse has been reported by almost all centres. Evidence suggests that the standard conditioning regimen (once thought to be sufficiently immunosuppressive and myeloablative in unmanipulated transplants) should no longer be considered adequate when the immunological balance has shifted in favour of unopposed host-versus-graft reactivity and the GvL effect is lacking. Since GvHD remains the major problem in BMT, we suggest T-cell depletion should be considered the most effective method for GvHD prophylaxis but the cytoreductive effect of the conditioning regimens and the anti-leukaemia immune reactivity should be enhanced.

Adolescent↗
PubMed1993

Residual clonable host cell detection for predicting engraftment of T cell depleted BMTs.

Rejection of T-depleted BMTs is predominantly mediated by alloreactive host T cells. A low but significant number of radiochemoresistant clonable T cells can be detected following a conventional cytoreductive protocol given prior to T-depleted BMT. Elimination of these cells increases the engraftment rate. We found no clonable T cells at the end of the conditioning regimen in 100 ml of peripheral blood from 47 patients who received an HLA-identical T-depleted BMT. None rejected the graft and none displayed mixed chimerism. In addition, although no clonable T cells were detected in nine patients who received a mismatched BMT, two rejected their graft. However, in three mismatched patients, who for clinical reasons received a modified pre-BMT schedule, the presence of host clonable T cells was associated with immunological rejection. These findings suggest that the detection of clonable T cells should prove a valuable indicator for optimising immunosuppression prior to T-depleted BMT.

Adolescent↗