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Biomedical subjects

M Ladetto

Publications and source records attributed to M Ladetto.

28 records · Page 2Linked to original sources
PubMed1997

Molecular monitoring of minimal residual disease in follicular and mantle cell non-Hodgkin's lymphomas treated with high-dose chemotherapy and peripheral blood progenitor cell autografting.

Minimal residual disease (MRD) was evaluated in 30 patients with follicular or mantle cell non-Hodgkin's lymphoma (NHL) undergoing an intensive treatment with high-dose sequential (HDS) chemotherapy and peripheral blood progenitor cell (PBPC) autografting. To minimize the potential tumor cell contamination, PBPC harvests were scheduled at the end of HDS pretransplant phase. All patients had advanced-stage disease and most of them presented with bone marrow (BM) involvement. A tumor marker could be generated in 90% of patients using bcl-2 or lg heavy-chain genes. MRD was analyzed on PBPC, BM harvests, and after autografting by polymerase chain reaction (PCR). All evaluable follicular and 6 of 9 mantle cell patients achieved clinical complete remission. PCR negativity of PBPC and/or BM harvests was documented in 68% of follicular and 12% of mantle cell lymphomas. Molecular remission of PBPC and/or BM harvests was achieved in 9 of 15 patients with overt marrow involvement and in all patients with only molecular marrow infiltration at onset. Molecular follow-up was conducted on 14 patients: all 7 evaluable patients who received at least one PCR-negative graft maintained the negative status at a median follow-up of 24 months and none of them relapsed so far. Thus, the results show that (1) a molecular marker to monitor MRD can be obtained in most follicular and mantle cell NHL patients, (2) the HDS regimen may provide PCR-negative PBPC and/or BM harvests even from patients with BM disease, and (3) autograft with at least one PCR-negative harvest is associated with a durable clinical and molecular remission.

Adult↗
PubMed1997

Analysis of the immunoglobulin heavy-chain gene rearrangement providing molecular evidence of second lymphoma in a patient in apparent relapse after autotransplantation.

Development of a second lymphoma after autotransplantation is an unusual event. Its real incidence, however, could be underestimated, since histologic and immunophenotyping techniques are often unable to distinguish it from a relapse. We report a lymphoma patient in apparent relapse after 42 months of molecular remission achieved by autotransplantation. Sequencing analysis of the immunoglobulin heavy-chain genes showed that the rearrangement of variable, diversity and joining segments had changed between diagnosis and relapse and suggested that a second lymphoma had developed.

Adult↗
PubMed1997

A novel nested-PCR strategy for the detection of rearranged immunoglobulin heavy-chain genes in B cell tumors.

Several methods have been developed for the detection of minimal residual disease (MRD) in B cell tumors. Chromosomal translocations or the rearrangement of the immunoglobulin heavy chain (IgH) and T cell receptor genes are generally employed. We report a novel PCR method to detect MRD using IgH genes. IgH rearranged variable region (VDJ) were amplified from tumor specimens using consensus primers for variable and joining region genes. Complementarity-determining regions (CDR) were identified and used to generate tumor-specific primers. Two-round amplifications using primers derived from CDRs and joining or constant regions were performed for MRD detection. IgH nested-PCR approach was tested on a panel of 75 B cell tumors including acute lymphoblastic and chronic lymphocytic leukemias, non-Hodgkin's lymphomas and multiple myelomas. A VDJ sequence was obtained in 62 out of 75 cases (83%). Sensitivity using DNA or cDNA templates was 10(-5) and (-6), respectively. This method is specific and sensitive and provides a simple, non-radioactive approach for the evaluation of MRD in B cell tumors.

Burkitt Lymphoma↗
PubMed1996

Clinical and molecular remission after allogeneic blood cell transplantation in a patient with mantle-cell lymphoma.

Mantle-cell lymphoma (MCL) is a B-cell tumour with a usually poor prognosis, characterized by the proliferation of small cleaved lymphocytes with a diffuse growth pattern. We report a polymerase chain reaction-based analysis of minimal residual disease in a patient who achieved complete remission after allogeneic blood cell transplantation (BCT). Rearrangement of the immunoglobulin heavy-chain genes was used to generate a lymphoma-specific molecular marker. Lymphoma cells were not detectable in a bone marrow sample collected 12 months after BCT. Our findings suggest that allogeneic BCT may offer a curative approach to MCL.

Adult↗
PubMed1995

High-dose sequential chemoradiotherapy in multiple myeloma: residual tumor cells are detectable in bone marrow and peripheral blood cell harvests and after autografting.

Based on preliminary encouraging results in terms of response rate and survival, high-dose chemoradiotherapy has gained considerable interest in the treatment of patients with multiple myeloma (MM). We have evaluated the presence of residual myeloma cells in 15 of 18 patients enrolled in a high-dose sequential (HDS) chemoradiotherapy program followed by autografting. Our analysis has been performed both on bone marrow (BM) and peripheral blood (PB) cell harvests and after autografting. As it has been recently shown that B cells clonally related to malignant plasma cells are detectable in MM patients, we have developed a polymerase chain reaction (PCR)-based strategy to detect both residual B cells and plasma cells using clone-specific sequences derived from the rearrangement of Ig heavy chain (IgH) genes. The complementarity-determining regions (CDR) of IgH genes have been used to generate tumor-specific primers and probes. The constant (C) region usage defined the differentiation stage of residual myeloma cells. We report that plasma cells were detectable in PB and BM cell harvests and after transplantation in all assessable patients, irrespective of disease status. B cells were detectable in a consistent proportion of BM and PB samples at diagnosis, but only in one case at the time of PB and BM cell harvests. These cells became sometimes detectable after transplantation. Whether residual myeloma cells are clonogenic and contribute to relapse is currently unknown, and further investigations are required.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

N- and K-ras oncogenes in plasma cell dyscrasias.

N- and K-ras oncogene mutations represent the most frequent molecular lesions in plasma cell dyscrasias. They are not randomly distributed since they are detectable in multiple myeloma (MM) (9-31%) and plasma cell leukemia (PCL) (30%), and not in monoclonal gammopathy of undetermined significance (MGUS) and solitary plasmacytoma (SP). Codons 12, 13 and 61 of N- and K-ras genes have been found mutated. Mutations affecting codon 61 of N-ras gene are the most frequent finding. A heterogeneous pattern of mutations is described with a prevalence of purine-pyrimidine transversions. Ras gene mutations have been predominantly detected in myelomas characterized by an advanced stage disease, and adverse prognostic parameters. These findings suggest that ras mutations represent a late molecular lesion and may be implicated in tumor progression rather than tumor initiation.

DNA Mutational Analysis↗
PubMed1994

Inactivation of tumor suppressor genes, p53 and Rb1, in plasma cell dyscrasias.

The role of loss or inactivation of the retinoblastoma (Rb1) and p53 tumor suppressor genes in the pathogenesis of various human malignancies has been well established, yet little is known regarding plasma cell dyscrasias. In the present study, the loss of Rb1 protein expression, and the presence of Rb1 gene rearrangements as well as the presence of p53 somatic mutations (exons 5 through 9) were investigated in a panel of plasma cell dyscrasias, including 15 monoclonal gammopathies of undetermined significance (MGUS), 63 multiple myelomas (MM), and 18 plasma cell leukemias (PCL). In the same panel of cases, we established the frequency of ras oncogene mutations, the main genetic lesion associated with MM. We report that loss of Rb1 protein and p53 mutations are detectable in 34.7 and 9.8% of MM and PCL primary cases; no lesion was found in MGUS. In advanced stage MM, and PCL cases, Rb1 and p53 inactivation, as well as ras mutations were detected. Our findings show that Rb1 and p53 inactivation are associated with aggressive plasma cell dyscrasias, suggesting a role for these lesions in tumor progression rather than initiation.

Base Sequence↗
PubMed1993

Mutational activation of N- and K-ras oncogenes in plasma cell dyscrasias.

The frequency of N- and K-ras oncogene mutations was investigated in plasma cell dyscrasias. Genomic DNAs from 128 patients were selected for this study: 30 monoclonal gammopathies of undetermined significance, 8 solitary plasmacytomas, 77 multiple myelomas (MM), and 13 plasma cell leukemias (PCL). A two-step experimental approach was devised. All samples were screened for mutations by single-strand conformation polymorphism analysis. DNA fragments displaying an altered electrophoretic mobility were further studied by direct sequencing to confirm and characterize the nature of the mutations. Ras mutations are not randomly distributed because they are detectable only in MM (9%) and PCL (30.7%). N-ras codons 12, 13, and 61 and K-ras codon 12 were found to be mutated, but N-ras codon 61 mutation was the most frequent finding (63.6%). In conclusion, ras mutations were found in PCL, and in a subset of MM characterized by advanced-stage disease and adverse prognostic parameters. Furthermore, based on our findings, it is possible to speculate that ras mutations represent a late molecular lesion in the process of multistep carcinogenesis.

Base Sequence↗
PubMedDate not supplied

Long-term molecular remission after conventional chemotherapy in a patient with Philadelphia-negative acute lymphoblastic leukemia.

Adult Philadelphia (Ph1) negative acute lymphoblastic leukemia (ALL) is usually treated with conventional chemotherapy regimens. Long-term disease-free survival is often achieved. The rearrangement of immunoglobulin heavy-chain genes has been used to evaluate minimal residual disease. A novel nested-polymerase chain reaction (PCR) approach was used here to study a patient in long-term complete remission (CR) after the BFM regimen. No evidence of tumor cell contamination was found in bone marrow cells collected after 93 months of CR. This finding supports the hypothesis that conventional chemotherapy can induce long-term molecular remission and cure in Ph1 negative ALL.

Acute Disease↗