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Biomedical subjects

Giovanni Martinelli

Publications and source records attributed to Giovanni Martinelli.

100 records · Page 6Linked to original sources
PubMed2002

Cryptic translocation of PML/RARA on 17q. A rare event in acute promyelocytic leukemia.

Cryptic translocations in acute promyelocytic leukemia are rare. Usually the gene fusion PML/RARA is located on chromosome 15. Combined cytogenetic, fluorescence in situ hybridization (FISH), and molecular (polymerase chain reaction [PCR]) analysis were employed for the diagnosis and precise localization of the fusion gene. Conventional cytogenetics showed a normal karyotype; PCR showed a typical PML/RARA rearrangement in exon 1. FISH analysis revealed that a submicroscopic part of chromosome 15 had been inserted into 17q. This case adds further information on alternative ways of rearrangement of the PML/RARA genes, possibly correlated with all-trans retinoic acid resistance.

Adult↗
PubMed2002

CXCR4 neutralization, a novel therapeutic approach for non-Hodgkin's lymphoma.

The chemokine stromal cell-derived factor-1 (CXCL12/SDF-1) and its monogamous receptor CXCR4 are involved in trafficking of B cells and hematopoietic progenitors. CXCR4 expression was found in the large majority of non-Hodgkin's lymphoma (NHL) cell lines and primary cells, and CXCR4 neutralization by monoclonal antibodies had profound in vitro effects on NHL cells including inhibition of transendothelial/stromal migration, enhanced apoptosis, decreased proliferation, and inhibition of pseudopodia formation. In a nonobese diabetes/severe combined immunodeficiency (NOD/SCID) mouse model of human high-grade NHL, CXCR4 neutralization had an impressive efficacy. In a first tumor-challenge trial, CXCR4 neutralization of Namalwa cells injected i.p. delayed tumor growth and reduced tumor weight. In a second tumor-challenge trial, NOD/SCID mice received Namalwa cells i.v. All of the controls died of neoplasia within day 36, whereas 83% of mice injected with cells incubated with anti-CXCR4 were still alive and disease-free >150 days after transplant. The crucial role of CXCR4 in tumor cell extravasation was confirmed by the finding that CXCR4 neutralization before i.v. injection of Namalwa cells in NOD/SCID mice increased the number of cancer cells circulating 24 h after injection. In additional preclinical trials, the therapeutic effect of anti-CXCR4 antibodies was evaluated in mice bearing Namalwa cells injected 3 days before. Tumor growth was abrogated in the majority of treated mice and significantly delayed in the remaining group. Taken together, these data support clinical studies on CXCR4 neutralization in NHL patients by monoclonal antibodies or CXCR4 antagonists.

Animals↗
PubMed2002

A randomized study of interferon-alpha versus interferon-alpha and low-dose arabinosyl cytosine in chronic myeloid leukemia.

Interferon-alpha (IFN-alpha) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-alpha has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome-positive CML patients who were assigned at random to treatment with IFN-alpha 2a alone or in combination with LDAC. The scheduled dose of IFN-alpha 2a was 5(6) IU/m(2)/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-alpha-plus-LDAC arm versus 55% in the IFN-alpha arm; P =.11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P =.003), and overall survival (5-year survival, 68% versus 65%; P =.77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-alpha versus IFN-alpha plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

Adult↗
PubMed2002

Real-time quantitation of minimal residual disease in inv(16)-positive acute myeloid leukemia may indicate risk for clinical relapse and may identify patients in a curable state.

The inv(16) cytogenetic subtype of acute myeloid leukemia (AML) has a relatively good prognosis. Many patients achieve complete remission (CR). The prognostic uncertainty of negative qualitative reverse transcription-polymerase chain reaction (RT-PCR) assays suggests the need to identify prognostically significant critical thresholds by real-time RT-PCR. A reliable and sensitive (10(-5)) real-time RT-PCR assay was set up for the evaluation of relevant CBFbeta-MYH11/ABL transcript ratios and was applied to the 21 patients with inv(16) AML routinely referred for cytogenetic and molecular monitoring in Seràgnoli Institute (Bologna, Italy) since 1990. Among the 18 patients who underwent ablative chemotherapy, all achieved CR with a 3-year disease-free survival probability of 63% (95% CI, 40%-87%) and no recorded events after 26 months. Five patients had relapses; 2 died of disease and 3 entered second CR. Analysis of the 125 bone marrow (or peripheral blood) samples studied by real-time RT-PCR showed that transcript ratios of samples taken during CR at any time before a relapse were always greater than 0.12%, whereas those of samples taken during first or second CR from patients who did not subsequently have relapses were always less than 0.25%. This suggests that transcript ratios greater than 0.25% may correspond to high risk for relapse, whereas ratios below 0.12% might indicate the patient is in a curable state. If confirmed, such thresholds could open the way to a new phase in post-CR therapeutic decision making for patients with inv(16) AML.

Adolescent↗
PubMed2002

In vitro and in vivo hematopoietic potential of human stem cells residing in muscle tissue.

OBJECTIVE: We studied the in vitro and in vivo hematopoietic potential of human stem cells residing in muscle tissue collected from adults with head and neck cancer. MATERIALS AND METHODS: Adherent muscle cells were cultured in F12 medium with 10% fetal bovine serum and transplanted into immunodeficient mice. RESULTS: On day 12 we obtained a median of 500,000 adherent cells per gram muscle sample. Thy-1, endoglin, HER2/neu, and P1H12 were expressed in the majority of cells. CD34, VEGFR2, c-kit, VCAM-1, and CXCR4 were expressed in 0.5-1.5%, 1-5%, 1-15%, 9-15%, and 30% of cells, respectively. Immunodeficient mice transplanted with fresh muscle cells or less than 500,000 cultured cells showed little or no human engraftment. In mice transplanted with more than 500,000 cultured cells, up to 14% human CD45(+) hematopoietic cells (including myeloid and lymphoid subsets) were detected by flow cytometry. Engraftment was confirmed by polymerase chain reaction, Southern blotting, and DNA sequencing. Liver, muscle, and spleen evaluated for human DNA were positive in the majority of mice showing hematopoietic engraftment in the bone marrow. In vivo hematopoietic engraftment potential was maintained in cultured CD45(-) muscle cells transduced with the green fluorescence protein gene. CONCLUSIONS: Human stem cells residing in muscle tissue can generate multilineage hematopoiesis in immunodeficient mice. Surprisingly, this hematopoietic potential increased in cultured versus fresh cells from muscle tissue.

Adult↗
PubMed2002

Novel types of bcr-abl transcript with breakpoints in BCR exon 8 found in Philadelphia positive patients with typical chronic myeloid leukemia retain the sequence encoding for the DBL- and CDC24 homology domains but not the pleckstrin homology one.

BACKGROUND AND OBJECTIVES: We previously described a novel type of the chimeric bcr-abl mRNA transcript in a patient with a Philadelphia chromosome positive chronic myeloid leukemia. A similar bcr-abl transcript has also been described by others. DESIGN AND METHODS: Sequence analysis of the fusion region showed a join between part of exon e8 of the bcr gene and an intronic sequence of abl intron 1b spliced on exon a2 of the abl gene, giving rise to an in-frame e8-int-a2 bcr-abl transcript, translated into a 197.5 kDa BCR-ABL protein of 1804 amino acid residues, which we named p200 BCR-ABL. RESULTS: In this work, employing protein comparison analysis (pFAM) we show that these novel bcr-abl transcripts retain the DBL homology (DH) domain and the recently recognized CDC24 homology domain, but not the pleckstrin homology (PH) domain of the bcr gene. INTERPRETATION AND CONCLUSIONS: This observation, along with the myeloid immunophenotype of the tumor and, at least in one case, the patient's correspondingly good response to alpha-interferon therapy, suggests that p200 BCR-ABL is more similar to p210 BCR-ABL, in which the DH, CDC24 and PH domains are all maintained, than to p185, in which these domains are all lost.

Amino Acid Motifs↗
PubMed2002

Novel mutation and RNA splice variant of fibroblast growth factor receptor 3 in multiple myeloma patients at diagnosis.

BACKGROUND AND OBJECTIVES: The karyotypically silent t(4;14)(p16.3;q32) translocation can be found in approximately 15-20% of multiple myeloma (MM) patients and results in the ectopic expression of fibroblast growth factor receptor 3 (FGFR3) from der4. Point mutations in specific FGFR3 domains can be found in the translocated allele, and have been recently proven to be oncogenic. These mutations produce a constitutively activated receptor, which shows dimerization and autophosphorylation even in the absence of ligand. We investigated the presence of FGFR3 expression and activating mutations in a series of newly diagnosed MM patients. DESIGN AND METHODS: We validated a new sensitive and specific Taqman real-time reverse-transcription polymerase-chain-reaction (RT-PCR) set up to evaluate FGFR3 mRNA expression, and applied it to 78 newly diagnosed patients; in positive cases, FGFR3 mRNA transcripts were sequenced. Fluorescence in situ hybridization (FISH) was done in 32 cases with sufficient material. RESULTS: Real-time RT-PCR revealed FGFR3 mRNA expression in 10/78 (13%) patients. In two cases, sequence analysis revealed novel FGFR3 mutations. In a patient with FISH evidence of the t(4;14), a CGC to TGC transition was detected in codon 248. In a patient without the t(4;14), three additional, abnormal-sized transcripts were detected, corresponding to truncated transcripts originating from cryptic splice donor sites located within exon 7. INTERPRETATION AND CONCLUSIONS: We describe a novel FGFR3 mutation (with a demonstrated deregulatory mechanism), as well as a case of alternative splicing in the absence of t(4;14), detected in newly diagnosed MM patients overexpressing FGFR3. This implies that FGFR3 mutation can occur at an early stage of myelomagenesis and even in the absence of the t(4;14).

Alternative Splicing↗
PubMedDate not supplied

Intrathecal chemotherapy in carcinomatous meningitis from breast cancer.

UNLABELLED: Meningeal metastases occur in 2-3% of patients with breast cancer, leading to neurological morbidity and increased mortality. The criteria for treatment choice are controversial and intrathecal chemotherapy (ITC) has no documented role in the management of this disorder. We therefore evaluated the efficacy of an ITC regimen for patients presenting with carcinomatous meningitis from breast cancer. PATIENTS AND METHODS: Patients with meningeal carcinomatosis with or without concomitant parenchymal brain metastasis, were treated with repeated courses of intrathecal chemotherapy according to the following alternated weekly schedule: Day 1: Thiotepa 10 mg, methotrexate 15 mg, hydrocortisone 30 mg; Day 5: cytarabine (Ara-C) 70 mg, methotrexate 15 mg, hydrocortisone 30 mg. Folinic acid 15 mg was given orally, every six hours after methotrexate on days 2-3 and 6-7. RESULTS: Thirteen consecutive patients were treated. The median age was 45 (range 30-67) years. Eleven patients had performance status (PS) 2-3. Nine patients had other metastatic sites; synchronous parenchymal brain metastasis were present in 5 patients. Concomitant systemic chemotherapy was administered in 5 patients and external whole brain radiotherapy in 7 patients. With 12 evaluable patients we observed no responses or improvement in symptoms. Side-effects were minimal. CONCLUSION: In our series of patients, ITC failed to provide objective response or relief in clinical symptoms. Despite evidence reported in the literature indicating symptomatic improvement after ITC in a number of patients with leptomeningeal metastasis, the results of our study confirm the controversial role of ITC. New drugs and new modalities of treatment should be studied in order to efficiently control meningeal involvement of breast cancer.

Adult↗