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Biomedical subjects

G Martinelli

Publications and source records attributed to G Martinelli.

At least 19 recordsLinked to original sources
PubMed2000

Endostatin, an antiangiogenic drug, induces tumor stabilization after chemotherapy or anti-CD20 therapy in a NOD/SCID mouse model of human high-grade non-Hodgkin lymphoma.

Both chemotherapy and chimeric anti-CD20 monoclonal antibodies are effective agents against B-cell non-Hodgkin lymphoma (NHL). However, patients achieving remission are at risk of relapse. To evaluate the effect of the antiangiogenic drug endostatin used alone and after the administration of cyclophosphamide (CTX) or the anti-CD20 antibody rituximab, we generated a new model of human NHL by transplanting Namalwa cells intraperitoneally into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. First, we determined the most effective treatment schedule for the drugs assessed. When administered alone, CTX (3 courses of 75 mg/kg of body weight given intraperitoneally), rituximab (3 courses of 25 mg/kg given intraperitoneally), and endostatin (5 courses of 50 microg given subcutaneously) delayed tumor growth, and CTX was the most effective in controlling bulky disease. When given after chemotherapy or immunotherapy, endostatin effectively induced tumor stabilization. When mice given CTX or rituximab on days 3, 5, and 7 after transplantation were randomly assigned to receive endostatin or phosphate-buffered saline on days 15 to 19, tumor growth was prevented in endostatin-treated mice as long as the drug was administered. Furthermore, administration of endostatin on days 25 to 29 after tumor regrowth still induced significant tumor regression, whereas CTX and rituximab were not effective. The specific antiangiogenic action of endostatin was confirmed by in vitro and in vivo studies indicating that the drug inhibited proliferation and induced apoptosis of endothelial (but not of NHL) cells. In conclusion, sequential administration of chemotherapy and endostatin seems promising for treating bulky NHL, and the less toxic sequential administration of rituximab and endostatin is promising for treating limited disease. (

Angiogenesis Inhibitors↗
PubMed2000

Molecular monitoring of minimal residual disease in patients in long-term complete remission after allogeneic stem cell transplantation for multiple myeloma.

In the present study, we used a polymerase chain reaction-based (PCR-based) strategy to retrospectively analyze the presence of residual myeloma cells in serial posttransplant bone marrow samples obtained from 13 patients in remission after allogeneic hemopoietic stem cell transplantation (allo SCT). For this purpose, patient-specific primers were generated from complementarity determining regions 2 and 3 of the rearranged IgH gene. The level of sensitivity of the PCR-based assay ranged from 1 in 10(5) to 1 in 10(6) normal marrow cells. Following transplantation, 9 of 12 patients who attained stringently defined complete remission (CR) remained persistently PCR(-) for a median of 36 months, and 4 of the patients remained PCR(-) up to the latest analysis, which was performed at 48, 72, 72, and 120 months, respectively, after allo SCT. None of the patients in the PCR(-) subgroup experienced a disease relapse, and only 1 of 4 PCR(+) patients experienced a relapse. It is concluded that allo SCT has the potential ability to induce sustained serological and molecular CR in selected patients with multiple myeloma.

Adult↗
PubMed2000

Human myeloid and lymphoid malignancies in the non-obese diabetic/severe combined immunodeficiency mouse model: frequency of apoptotic cells in solid tumors and efficiency and speed of engraftment correlate with vascular endothelial growth factor production.

Recent studies have suggested that non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice transplanted with human hematological malignancies show higher levels of engraftment compared with other strains. We used this model to compare xenotransplantability of human leukemia and lymphoma cell lines and to investigate angiogenesis in hematopoietic malignancies. Ten of 12 evaluated cell lines were able to engraft NOD/SCID mice within 120 days. A strong correlation was observed between the amount of vascular endothelial growth factor (VEGF) produced in vitro by cultured cells and the efficiency of tumor engraftment (r = 0.808; P = 0.001), and an inverse correlation was found between VEGF production and the time of tumor engraftment (r = -0.792; P = 0.006) and between VEGF production and the frequency of apoptotic/dead cells in solid tumors (r = -0.892; P = 0.007). Moreover, VEGF production correlated with the frequency of endothelial (CD31+/CD34+) cells in solid tumors (r = 0.897; P = 0.001). Taken together with in vitro data presented here and indicating that the VEGF antagonist Flt-1/Fc chimera inhibits leukemia and lymphoma cell proliferation, our findings support a role for tumor-derived VEGF in leukemia and lymphoma progression. Furthermore, the present study confirms previous observations indicating that VEGF expression may play a crucial role in xenotransplantability of human solid malignancies in SCID mice. The NOD/SCID model is promising for future evaluations of antiangiogenic drugs, alone or in combination with established chemo- or immunotherapy regimens.

Acute Disease↗
PubMed2000

Engraftment, clinical, and molecular follow-up of patients with multiple myeloma who were reinfused with highly purified CD34+ cells to support single or tandem high-dose chemotherapy.

Eighty-two patients with advanced multiple myeloma (MM) were enrolled in 2 sequential clinical studies of 1 or 2 courses of myeloablative therapy with stem cell support. Conditioning regimens consisted of high-dose melphalan (MEL) with or without total body irradiation (TX1 = 35) and MEL as the first preparative regimen, followed within 6 months by busulfan and melphalan (TX2 = 47). On the basis of adequate stem cell harvest, 31 patients (TX1 = 13; TX2 = 18) were transplanted with highly purified CD34+ cells. Positively selected stem cells did not adversely affect hematopoietic reconstitution compared with unmanipulated peripheral blood stem cell. Overall, the complete remission (CR) rate of evaluative patients was 13.8% and 41% for single and double autotransplant, respectively (P =.04). Moreover, 3 patients undergoing TX2 achieved molecular remission and 2 remain PCR-negative after 36 and 24 months from autograft. The median event-free survival (EFS) durations for TX1 and TX2 were 17 and 35 months, respectively (P =.03). Actuarial 3-year overall survival for patients treated with 1 or 2 transplants are 76% and 92%, respectively (P = NS). On multivariate analysis, superior EFS was associated with low beta2 microglobulin (beta2-M) level at diagnosis and TX2, whereas overall survival was correlated with beta2-M. Positive selection of CD34+ cells did not influence the achievement of clinical or molecular CR, as well as remission duration or survival of MM patients. Thus, whereas multiple cycles of high-dose therapy may be beneficial for patients with myeloma, the clinical impact of tumor cell purging remains highly questionable.

Adolescent↗
PubMed2000

Resection of solid tumors reverses T cell defects and restores protective immunity.

We have previously reported that CTL were demonstrable early after inoculation of CMS5 fibrosarcoma cells, but that they disappeared within 3 wk. These mice were unable to reject a challenge with CMS5 tumor cells. Other studies demonstrated cell surface phenotype and signaling abnormalities of cells within the spleen. Since we assumed that such an environment would make it more difficult to elicit antitumor immune responses via immunotherapy, we asked whether resection of the tumor could reverse these abnormalities. Although early after tumor cell inoculation tumor resection leads to the development of immunity, the effect at late time points has not been studied critically. To test this, mice were inoculated s.c. with CMS5 cells and after 28 days the tumors were resected. We observed a gradual normalization of the cellular phenotype of the spleen. In particular, there was a decrease in the number of Mac1+/Gr1(high) cells and an increase in the number of CD3+ cells in the spleen within 24-48 h of tumor resection. By day 10, these values were normal. Levels of p56lck increased as well. The functional implications of these changes were illustrated by the reduced growth rate or the complete rejection of a challenge of tumor cells in the resected mice. Both CD4+ and CD8+ cells were involved in the restoration of tumor immunity. Our results suggested that tumor resection not only led to the reversal of immune suppression, but also unmasked a population of primed T cells able to mediate protective immunity.

Adoptive Transfer↗
PubMed2000

Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy.

OBJECTIVES: We investigated the role of cardiac troponin I (cTnI) in patients with aggressive malignancies treated with high-dose chemotherapy (HDC). BACKGROUND: High dose chemotherapy is potentially limited by cardiac toxicity. Considering the fact that cardiac dysfunction may become clinically evident weeks or months after HDC, the availability of an early marker of myocardial injury, able to predict late ventricular impairment, is a current need. METHODS: We measured, in 204 patients (45+/-10 years) affected by cancer resistant to conventional treatment, the cTnI plasma concentration after every single cycle of HDC. According to the cTnI value (< or = or >0.4 ng/ml), patients were divided into a troponin positive (cTnI+, n = 65) and a troponin negative (cTnI-, n = 139) group. All patients underwent echocardiographic examination during the following seven months. RESULTS: In the cTnI- group, left ventricular ejection fraction (LVEF) progressively decreased after HDC, reaching a maximal reduction after three months; however, myocardial depression was transient and no longer detectable at later follow-up. By contrast, in the cTnI+ group LVEF reduction was more marked and still evident at the end of the follow-up. In cTnI+ patients, a close relationship between the short-term cTnI increment and the greatest LVEF reduction was found (r = -0.87, p<0.0001). CONCLUSIONS: The elevation of cTnI in patients undergoing HDC for aggressive malignancies accurately predicts the development of future LVEF depression. In this setting, cTnI can be considered a sensitive and reliable marker of acute minor myocardial damage with relevant clinical and prognostic implications.

Adult↗
PubMed2000

Docetaxel (Taxotere)-cisplatin (TC): an effective drug combination in gastric carcinoma. Swiss Group for Clinical Cancer Research (SAKK), and the European Institute of Oncology (EIO).

PURPOSE: A multi-centric trial was performed to explore the clinical activity, in terms of response and toxicity (primary objectives), duration of response and survival (secondary objectives), of docetaxel with cisplatin in advanced gastric cancer (AGC). PATIENTS AND METHODS: Patients with measurable unresectable and/or metastatic gastric carcinoma, performance status < or = 1, normal hematological, hepatic and renal functions and not pretreated for advanced disease by chemotherapy received up to eight cycles of TC (docetaxel 85 mg/m2 dl, cisplatin 75 mg/m2 dl) q3w. Dose escalation to 100 mg/m2 was performed in five patients and was discontinued for excessive toxicity. RESULTS: Forty-eight patients were accrued. A median of 5 cycles/patient was given. We observed 2 complete and 25 partial responses for an overall intent to treat response rate of 56% (95% CI: 41%-71%). Twelve patients had stable disease for > or = 9 weeks (3 cycles). The median time to progression and overall survival were 6.6 and 9 months, respectively. Grade > or = 3 toxicities were neutropenia 81%, anemia 32%, thrombocytopenia 4%, alopecia 36%, fatigue 9%, mucositis 9%, diarrhea 6%, nausea/vomiting 4%, neurologic 2%, and one anaphylaxis precluding treatment administration. We recorded nine episodes of non-fatal febrile neutropenia in eight patients, two of them with docetaxel at 100 mg/m2. There were no direct treatment-related deaths. CONCLUSIONS: TC is active in AGC with a high response rate in a multicentric trial. Despite its hematotoxicity, this regimen is well tolerated and can be recycled as originally planned in 78% of the cases. These results may serve as basis for further developments of docetaxel containing regimens in this disease.

Adenocarcinoma↗
PubMed2000

Evaluation of acute toxicities associated with autologous peripheral blood progenitor cell reinfusion in patients undergoing high-dose chemotherapy.

Peripheral blood progenitor cell reinfusion (PBPC) in patients undergoing high-dose chemotherapy (HDC) for poor prognosis malignancies, has been described as causing possible acute gastrointestinal (nausea, vomiting), allergic (oedema, bronchospasm, anaphyl- axis), renal (proteinuria, haematuria) and/or cardiovascular (hypotension, arrhythmia, conduction disturbances, transient ischaemic phenomena) toxicities. To establish the clinical relevance of these observations and the possible relationship with different HDC regimens used, we performed a clinical and instrumental evaluation on 33 patients with advanced breast cancer, non-Hodgkin's lymphoma, Hodgkin's disease, relapsed ovarian cancer, Ewing's sarcoma, extragonadal germinal tumour and small cell lung cancer. They underwent at least one reinfusion each for a total of 51 studied procedures. No patient had a previous history of cardiovascular disease or significant intercurrent illness such as diabetes or liver, renal or neurologic impairment. All patients had totally implanted central venous catheters, through which the transplants had been collected and reinfused without technical consequences. To evaluate cardiovascular function, we continuously monitored 12-lead ECGs, with arterial pressure (AP) measurements every 5 min from the beginning of the procedure to 15 min after the reinfusion ended. We did not observe any significant differences between basal and subsequent steps in AP, heart rate, PQ and QTc time, P wave and QRS complex duration or P wave and QRS electrical axes. No patient showed any ST-T tract pathological abnormality, but one patient developed a transient ectopic atrial rhythm, without any haemodynamic disfunction and with spontaneous reversion to sinus rhythm. No patient complained of symptoms of haemodynamic failure. Gastrointestinal side-effects appeared to be strictly related to speed of reinfusion and to the number of packs reinfused, probably reflecting on the amount of dimethylsulphoxide infused. In one patient a tonic-clonic seizure occurred during a vomiting episode, but no patient developed allergic or renal toxicities. We conclude that PBPC reinfusion, if managed according to the procedure we propose in patients without organic impairment, is a safe procedure not associated either with increased risk of acute arrhythmias or ischaemic or significant systemic acute toxicities. Bone Marrow Transplantation (2000) 25, 173-177.

Adult↗
PubMed2000

Pulmonary toxicity following carmustine-based preparative regimens and autologous peripheral blood progenitor cell transplantation in hematological malignancies.

Sixty-five patients with hematological malignancies (25 multiple myeloma, 18 Hodgkin's disease, 22 non-Hodgkin's lymphomas) who received a carmustine-based regimen followed by autologous PBPC transplantation, were studied retrospectively to evaluate the incidence of post-transplant non-infective pulmonary complications (NIPCs), risk factors predictive of NIPCs, and response to steroids. Carmustine (BCNU) given i.v. at a dose of 600 mg/m2 was combined with etoposide and cyclophosphamide in 40 patients (BCV regimen) and with etoposide and melphalan in 25 patients (BEM regimen). Seventeen of 65 patients (26%) had one episode of NIPCs. The median time to NIPCs was 90 days (52-289). Factors that increased the risk of developing NIPCs on multivariate analysis were female sex (P < 0. 001) and BCV regimen (P < 0.05). All patients with NIPCs received prednisone at a dose of 1 mg/kg body weight for 10 days then tapered by 5 mg every two days; complete response to steroids was achieved in 15 of 17 patients; one unresponsive patient died of interstitial pneumonia. BCNU given at the dose of 600 mg/m2 is well tolerated when associated with melphalan and etoposide. In females and in patients receiving BCNU with cyclophosphamide, a BCNU dose reduction may be advisable. Bone Marrow Transplantation (2000) 25, 309-313.

Adolescent↗
PubMed2000

Quantification of BCR-ABL transcripts in CML patients in cytogenetic remission after interferon-alpha-based therapy.

We measured using a competitive quantitative polymerase chain reaction-capillary electrophoresis (PCR-CE)-based assay, the levels of bcr-abl transcripts in 44 patients with chronic myeloid leukemia (CML) after interferon-alpha (IFN-alpha) therapy, who achieved a major (10 patients, MCR group) or complete (34 patients, CCR group) cytogenetic response. All 34 CCR patients had molecular evidence of residual disease detected in bone marrow samples at the time of best karyotypic response. The median number of bcr-abl transcripts of 34 evaluable patients in the CCR group at the time of complete cytogenetic remission was 4/microg RNA (range 3-4600), while the median number of bcr-abl transcripts of 10 patients in the MCR group at the time of best cytogenetic response was 4490/microg RNA (range 600-23 900) (P = 0.000024). In nine CCR and five MCR patients we were able to quantify the amount of bcr-abl transcript both at diagnosis and after interferon therapy: no statistical difference (P = 0.18) was found between the two groups at diagnosis (median bcr-abl transcripts/microg RNA was 30 000 vs. 39 650, respectively). During IFN-alpha therapy, the two groups were evaluable at the time of major karyotypic conversion: at this point, there was a statistical difference of expression of bcr-abl transcript between the CCR group (17 patients) (median 2700; range 76-40 000) and the MCR group (10 patients) (median 4490; range 600-23 900), respectively (P = 0.046). No differences of bcr-abl amount of transcript were found in patients with CCR obtained either by IFN-alpha therapy alone (20 patients) vs. IFN-alpha plus ABMT (13 patients) (P = 0.47). We firstly demonstrated that although the CCR and MCR groups were clinically, cytogenetically and molecularly indistinguishable at diagnosis, the two groups could be recognized successfully during interferon therapy based on the level of bcr-abl transcript.

Adolescent↗
PubMed2000

Alpha-interferon improves survival and remission duration in P-190BCR-ABL positive adult acute lymphoblastic leukemia.

Treatment of P190BCR-ABL+ acute lymphoblastic leukemia (ALL) patients remains problematic: one possibility is to use biologic response modifiers such as alpha-interferon (alpha-IFN), which is known to be active in chronic myeloid leukemia (CML). We used alpha-IFN to treat 10 adult P190BCR-ABL+ ALL patients (eight newly diagnosed; two in first relapse). All received a remission induction chemotherapy (modified L-20 protocol). Patients achieving morphological, immunological and cytogenetic complete remission (CR) were then submitted to a rotational consolidation regimen lasting 6 months. When no HLA-identical donor was available, patients aged <55 years underwent stem cell harvest followed by autologous transplantation; patients aged >/=55 years received standard maintenance treatment for 6 months. In the second year, maintenance treatment (all ages) was based on cycles of alpha-IFN (3 MU three times a week for 6 weeks) alternated with methotrexate/6-mercaptopurine continuously for up to 2 years from first demonstration of CR. Thereafter, patients maintaining CR had the same schedule of alpha-IFN (6 weeks on, 6 off). Eight patients (6/8 first diagnosis, 2/2 relapsed) obtained morphological, immunological and cytogenetic CR with persistent molecular positivity. Two with an HLA-identical donor had allogeneic bone marrow transplantation. Six proceeded with chemotherapy: one experienced early relapse, three were autotransplanted, and two received maintenance. Five patients then received alpha-IFN as scheduled. All five are in continuous morphological and cytogenetic CR, with a longer mean duration of maintained morphological CR (mean 46 months; range: 20-88) than in previous reports of Ph+ ALL patients treated with chemotherapy regimens (excluding allogeneic BMT). alpha-IFN thus appears effective in this poor-risk subset of patients. This well-tolerated IFN-containing maintenance treatment could be considered to reinforce intensified programs based on autologous stem cell transplantation as an alternative to allogeneic transplantation in P190BCR-ABL+ ALL patients (and by extension for Ph+ ALL patients) lacking an HLA-matched donor. Leukemia (2000) 14, 22-27.

Adult↗
PubMed2000

Inhibition of angiogenesis and induction of endothelial and tumor cell apoptosis by green tea in animal models of human high-grade non-Hodgkin's lymphoma.

Recent reports suggest that green tea consumption may prevent or delay the growth of human cancer, possibly by impairing tumor invasion and/or by an anti-angiogenic effect. In NOD/SCID mice transplanted intraperitoneally with human non-Hodgkin's lymphoma (NHL) cell lines, Namalwa, RAP1-EIO and HS-Sultan, green tea prevented 50% of Namalwa tumors (P = 0.0017 by log-rank) and significantly inhibited RAP1-EIO and HS-Sultan tumor growth. Notably, treatment with the chemotherapy drug cyclophosphamide at the maximum tolerable dose was unable to prevent Namalwa tumor occurrence. In the three models evaluated, the frequency of apoptotic endothelial and tumor cells was significantly increased in mice given green tea compared to controls. These results support further trials in NHL to evaluate whether green tea, alone or in combination with chemotherapy, may delay or prevent disease progression.

Animals↗
PubMed2000

Second chronic phase before transplantation is crucial for improving survival of blastic phase chronic myeloid leukaemia.

Because successful outcome after transplantation seems to depend in acute myeloid leukaemia (AML) and in chronic phase chronic myeloid leukaemia (CML) on disease status at the time of transplantation, we investigated whether FLAN (fludarabine, cytosine arabinoside, mitoxantrone) induction before allogeneic stem cell transplantation (allo-SCT) may be useful in blastic phase (BP)-CML. Twenty patients with BP-CML were studied: 10 patients received FLAN induction chemotherapy before proceeding to early allo-SCT, whereas 10 patients were submitted to bone marrow transplantation (BMT) without remission induction. Eight out of 10 (80%) patients achieved second chronic phase after one course of therapy with FLAN and seven patients (six in second chronic phase and one with partial response) were then submitted to allo-SCT. Of the six patients transplanted in the second chronic phase, all achieved molecular remission, four are still in second chronic phase, with intervals ranging from 10 to 54 months, whereas one patient died from infection having relapsed 14 months after SCT and one died of transplant-related complications in the second chronic phase. Mean durations of second chronic phase and survival after allo-SCT were both significantly longer than in the group of 10 BP-CML patients submitted to allo-SCT without FLAN remission induction treatment [22.4 (range 1-61) vs. 3.5 months (range 1-10) with FLAN and 22.7 (range 2-61) vs. 6.4 (range 1-16) months without FLAN]. We conclude that FLAN induction therapy followed by early allo-SCT appears to be effective in the treatment of BP-CML and could provide a curative possibility for BP-CML patients.

Adult↗
PubMed2000

Idarubicinol myelotoxicity: a comparison of in vitro data with clinical outcome in patients treated with high-dose idarubicin.

We evaluated in vitro the toxicity of idarubicin and its active metabolite idarubicinol on haematopoietic progenitors, using human umbilical cord blood and peripheral blood progenitors to obtain dose-response curves. We treated 16 patients with poor prognosis lymphoma in a phase I-II trial of high-dose idarubicin and melphalan and investigated if idarubicinol persisting in patients' plasma at the time of transplantation (day 0), on day +1 and +2 could result in an inhibition of infused progenitors. Colony inhibition was correlated with pharmacokinetic data and with the time of patients' engraftment. Plasma samples obtained before idarubicin treatment demonstrated a colony-stimulating effect, increasing the cloning efficiency by 72%. The inhibitory activity on colony forming unit granulocyte-macrophage (CFU-GM) of patients' plasma collected on the day of transplantation was lower than expected from dose-response curves (21% measured vs 70% expected). The time to patients' WBC and PLT recovery correlated with the amount of CD34+ cells reinfused and, to a lesser extent, with the colony-inhibiting effect of patients' plasma. The correlation between idarubicinol concentration and CFU-GM inhibition was not significant. These data suggest that plasma drug concentration on the day of stem cell reinfusion may overestimate the toxicity of residual anthracyclines to the transplanted cells.

Adult↗