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Biomedical subjects

F Patrone

Publications and source records attributed to F Patrone.

At least 37 records · Page 2Linked to original sources
PubMed1997

High frequency of trisomy 8 in acute promyelocytic leukemia: a fluorescence in situ hybridization study.

Correct diagnosis of acute promyelocytic leukemia (APL) requires proof of the translocation (15;17)(q24;q11), which appears to be absolutely specific for this particular type of myeloid disorder. We studied the karyotypes of 29 consecutive APL patients at diagnosis: in 5 of them banding techniques failed to detect the t(15;17). In these seemingly cytogenetically negative cases, fluorescence in situ hybridization (FISH) with a chromosome 17 painting probe detected a high percentage of mitoses with 3 hybridization signals: one derived from the intact chromosome 17, and 2 from the rearranged chromosomes 15 and 17. Trisomy 8 (+8) as a secondary chromosomal abnormality was observed in 8 cases (27.5%), confirming that the t(15;17) favors the acquisition of an extra chromosome 8. One of these 8 cases showed a marker that was interpreted by FISH analysis as der(8) with duplication of a segment of the long arm carrying the c-MYC allele. Clinical features of patients with t(15;17) and +8 were no different from patients with t(15;17) alone. The usefulness of FISH to standard banding techniques in the detection of specific structural and/or numerical chromosomal abnormalities is confirmed in this report.

Adult↗
PubMed1997

High-dose mitoxantrone with peripheral blood progenitor cell rescue: toxicity, pharmacokinetics and implications for dosage and schedule.

The optimal use of mitoxantrone (NOV) in the high-dose range requires elucidation of its maximum tolerated dose with peripheral blood progenitor cell (PBPC) support and the time interval needed between drug administration and PBPC reinfusion in order to avoid graft toxicity. The aims of this study were: (1) to verify the feasibility and haematological toxicity of escalating NOV up to 90 mg m(-2) with PBPC support; and (2) to verify the safeness of a short (96 h) interval between NOV administration and PBPC reinfusion. Three cohorts of ten patients with breast cancer (BC) or non-Hodgkin's lymphoma (NHL) received escalating doses of NOV, 60, 75 and 90 mg m(-2) plus melphalan (L-PAM), 140-180 mg m(-2), with PBPC rescue 96 h after NOV. Haematological toxicity was evaluated daily (WHO criteria). NOV plasma pharmacokinetics was also evaluated, as well as NOV cytotoxicity against PBPCs. Haematological recovery was rapid and complete at each NOV dose level without statistically significant differences, and there were no major toxicities. NOV plasma concentrations at the time of PBPC reinfusion were below the toxicity threshold against haemopoietic progenitors. It is concluded that, when adequately supported with PBPCs, NOV can be escalated up to 90 mg m(-2) with acceptable haematological toxicity. PBPCs can be safely reinfused as early as 96 h after NOV administration.

Antineoplastic Agents↗
PubMed1997

Standard-dose recombinant human granulocyte colony-stimulating factor (rhG-CSF) allows safe and repeated administration of high-dose cyclophosphamide, etoposide, and cisplatin (CEP).

High-dose chemotherapy often requires hematopoietic progenitor cell reinfusion, but drugs with extramedullary dose-limiting toxicity may be administered in the high-dose range by simple growth factor support. In this study, we evaluated the feasibility and toxicity of a three-drug high-dose regimen supported by recombinant human granulocyte colony-stimulating factor (rhG-CSF). Ten patients with histologically proven malignancy were enrolled. Eight had breast cancer, one non-Hodgkin's lymphoma, and one a mediastinal tumor of unknown origin. The regimen included cyclophosphamide (C) 5 g/m2, etoposide (E) 1.5 g/m2, and cisplatin (P) 150 mg/m2 (CEP), administered in a 3-day schedule followed by rhG-CSF, 300 micrograms once a day, beginning from day +5 (36 h after the end of chemotherapy). The cycle was repeated as clinically needed up to three times. After the first course, hematologic recovery was rapid and complete without documented infections, and no relevant extramyeloid toxicities were observed. Eight of 10 patients received a second course with comparably low toxicity, and three of them received a third course. We concluded that CEP therapy can be administered safely and even repeatedly, by simple growth factor support, in good performance status cancer patients.

Adjuvants, Immunologic↗
PubMed1995

Fluorescence in situ hybridization provides evidence for two-step rearrangement in a masked Ph chromosome formation.

A chronic myelogenous leukemia (CML) patient with a masked Ph chromosome due to the translocation (9;10;22)(q34;q24;q11) is reported. Banding analysis showed a 9q+ chromosome typical of standard t(9;22)(q34;q11), and fluorescence in situ hybridization studies confirmed the involvement of a chromosome 10 in the masked Ph formation and also the presence of 3' ABL-DNA sequences in the der(22). This complex rearrangement could be explained by two consecutive translocations: the first, a standard t(9;22) (q34;q11), the second, a translocation between a chromosome 10 and the der(22) with a breakpoint in sequences derived from chromosome 9 telomeric to the ABL gene. By reverse transcription polymerase chain reaction (RT-PCR), we studied the BCR/ABL transcript junction: a chimeric m-RNA b3-a2, indicating a breakpoint within the major breakpoint cluster region, was found.

Adult↗
PubMed1995

Four-step high-dose sequential chemotherapy with double hematopoietic progenitor-cell rescue for metastatic breast cancer.

PURPOSE: High-dose chemotherapy produces high complete remission (CR) rates and some survival advantage in patients with metastatic breast cancer (BC). A current issue is the possibility that these patients may have an even better prognosis with multiple high-dose treatments. In this study, we evaluated the feasibility of a four-step, high-dose sequential chemotherapy (HDSC) with double autologous hematopoietic progenitor-cell rescue. We also tested the hypothesis that peripheral-blood progenitor cells (PBPCs) harvested following a single recruitment with cyclophosphamide (CY) and granulocyte-macrophage colony-stimulating factor (GM-CSF) allow the safe administration of the whole HDSC with closely timed repeated courses of several non-cross-resistant agents. PATIENTS AND METHODS: The treatment plan included CY 7 g/m2, followed by GM-CSF 5 to 7 micrograms/kg/d administered by continuous intravenous (i.v.) infusion on days 2 to 14; PBPCs with or without bone marrow (BM) harvest; mitoxantrone (NOV) 60, 75, or 90 mg/m2 plus melphalan (L-PAM) 140 to 180 mg/m2 with hematopoietic rescue; methotrexate (MTX) 8 g/m2 plus vincristine (VCR) 1.4 mg/m2; and etoposide (VP-16) 1.5 g/m2 plus carboplatin (PP) 1.5 g/m2 with hematopoietic rescue. RESULTS: All 15 patients enrolled completed the entire treatment and there were no toxic deaths. Hematologic reconstitution was good at each step. The median number of days with an absolute neutrophil count (ANC) less than 100/microL and platelet count less than 20,000/microL were 8 and 3, respectively, after NOV plus L-PAM, and 7 and 4, respectively, after VP-16 plus PP. The main non-hematologic toxicity was mucositis, while organ toxicity was mild and reversible. CONCLUSION: This regimen is feasible, with acceptable toxicity. GM-CSF and PBPCs have a pivotal role, as they hasten hematologic reconstitution, abate toxicity, and allow rapid recycling.

Adult↗
PubMed1995

Cytogenetic clonality in chronic myelomonocytic leukemia studied with fluorescence in situ hybridization.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS) subtype, characterized by monocytosis, dysgranulocytosis and a low number of blast cells in the peripheral blood (PB). The clonal nature of MDS has been demonstrated by various techniques: the stem cell involved initially is capable of myeloid and lymphoid differentiation. Fluorescent in situ hybridization (FISH) is a technique which can be utilized without any pretreatment on whole interphase cells. In this study leukocytes of PB Wright-stained smears from four CMML patients with trisomy 8 (three cases) and 9 (one case) have been analyzed by FISH. Utilizing a probe for the centromere of chromosome 8 and for the heterochromatic region of chromosome 9, we observed the cells involved by trisomy. In each of the four cases neutrophils, eosinophils, basophils and monocytes may show trisomy 8 or 9, whereas lymphocytes resulted disomic. The comparison between leukocytes morphology and genotype suggests that the supernumerary chromosome does not influence cellular differentiation and maturation. We conclude that FISH analysis of PB leukocytes of patients with CMML is informative when studying the clonality of the disease. Chromosomal abnormalities seem to involve a hematopoietic cell committed to myeloid but not lymphoid differentiation. Trisomies 8 and 9 seem to confer some proliferative advantage without influencing the morphologic characteristics of leukocytes. Other causes will be investigated to explain dysmorphisms of neutrophils and monocytes typical of this disease.

Aged↗
PubMed1994

Trisomy 8 detection in Ph+ CML patients using conventional cytogenetic and interphase fluorescence in situ hybridization techniques.

We examined bone marrow (BM) cells from 6 Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) patients in advanced phase of the disease using conventional cytogenetic techniques and fluorescence in situ hybridization (FISH) for detection of an extra chromosome 8. All patients showed mosaicism for trisomy 8 as a secondary chromosome abnormality. For FISH, we used the D8Z5 probe specific for the centromeric region of chromosome 8 and analyzed 300 interphase nuclei and a variable number of mitoses for each patient. The percentages of metaphases carrying trisomy 8 were similar with both techniques, whereas the percentage of interphase nuclei showing three hybridization spots indicative of trisomy 8 was significantly lower than that in metaphases. This finding suggests that cells with a supernumerary chromosome 8 may have a cell cycle time shorter than that of disomic cells.

Aged↗
PubMed1994

Variant Philadelphia chromosome translocations are frequently associated with additional structural abnormalities.

This work contains a cytogenetic analysis of 507 consecutive CML patients examined at diagnosis before any therapeutic treatment. Philadelphia chromosome translocations different from the standard t(9;22)(q34;q11) were observed in 28 patients (5.5%). Structural chromosomal abnormalities apparently unrelated to the Ph were found in six patients carrying variant Ph (6 of 28 = 21.4%) and in three patients carrying standard Ph translocations (3 of 472 = 0.6%). This finding confirms that structural abnormalities other than Ph are a rare event at diagnosis but that they occur with significantly different frequencies between the variant and standard Ph translocations, indicating that causes favoring the variant Ph formation may promote additional non-lethal DNA breakpoints.

Cells, Cultured↗
PubMed1993

Subcutaneous recombinant human erythropoietin for the treatment of anemia in myelodysplastic syndromes.

Recombinant human erythropoietin (rhEPO) was administered subcutaneously to 13 anemic (Hb < 10 g/dl) patients with myelodysplasia (MDS). rhEPO was given 3 times a week at doses of 75-250 U/kg body weight, over a maximum period of 24 weeks. Five patients (38%) showed a response to rhEPO treatment. rhEPO was well tolerated and without relevant side effects throughout the study. All responding patients had low but detectable pretreatment circulating erythroid progenitor cells (BFU-E) and the response to rhEPO was associated with a significant increase in BFU-E (p < 0.01); concentrations of serum transferrin receptor (TfR) also consistently rose in all responding patients. Baseline erythropoietin (EPO) concentrations did not significantly differ between responders and nonresponders, although 4 out of the 5 responders had relatively low levels of EPO. In conclusion, subcutaneous rhEPO administration appears to be an effective treatment of anemia in a substantial subset of patients with MDS. Relatively low baseline EPO concentrations, detectable pretreatment circulating BFU-E and an early increase in the serum concentrations of TfR seem to be criteria for predicting response to rhEPO in patients with MDS.

Aged↗
PubMed1992

Influence of ST 789 on human neutrophil function in vitro.

We report the results of our in vitro experiments on the effects of an L-Arg terminal synthetic hypoxanthine derivative (ST 789) on human neutrophil function. To verify the hypothesis that the reported immunomodulatory effects of ST 789 in vivo are accounted for, at least in part, by effects on phagocytic cells, we experimented in parallel also with methisoprinol, a well known stimulator of neutrophil chemotaxis, structurally related to ST 789. Our results demonstrate that ST 789 is able to improve the true chemotactic response of human neutrophils without interfering with other phagocytic functions, following a pattern largely shared by methisoprinol. Accordingly, ST 789 may be able, when used in vivo, to prime neutrophils for timely and efficient migration to inflammatory sites, and it could be considered for therapeutic use in patients with impaired inflammatory response or severe infections.

Adjuvants, Immunologic↗
PubMed1991

Tumor cell lysis by activated human neutrophils: analysis of neutrophil-delivered oxidative attack and role of leukocyte function-associated antigen 1.

The lysis of tumor cells, and other nucleated mammalian cells, by neutrophilic polymorphonuclear leukocytes (PMNs) triggered by phorbol myristate acetate (PMA) represents a widely used model system to dissect the PMN cytolytic armamentarium, potentially responsible for the cell damage at tissue sites of PMN activation. Although oxidants are generally considered to be instrumental in the target lysis by PMNs, the mediators actually involved remain a matter of controversy. Moreover, other factors potentially crucial to the lysis have not been clearly identified. In order to reexamine the determinants of the cytolytic process, we studied the events underlying the PMA-triggered PMN-delivered attack against two different targets, selected on the basis of preliminary experiments (B lymphoblastoid Daudi cells and erythroleukemic K 562 cells). The results suggest that the lysis is promoted by hypochlorous acid (HOCl) or a compound with characteristics very similar to HOCl itself. No evidence was obtained for the intervention or contribution of hydrogen peroxide (H2O2), hydroxyl (OH.) radicals, and the major HOCl-derived chloramines. PMNs appeared to use 35% of the generated H2O2 to produce HOCl, while the remainder appears to be consumed by PMNs themselves and target cells as well. Moreover, PMNs and target cells coaggregated at an early step of the cytolytic reaction, through a process efficiently prevented by a monoclonal antibody (MoAb J-90) directed against leukocyte function-associated antigen-1 (LFA-1). The inhibition of the PMN-target aggregation by the MoAb J-90 resulted in the impairment of the lysis, despite a normal generation of HOCl. Thus, the data demonstrate that the PMA-triggered lysis of tumor target cells by PMNs requires at least two events, occurring simultaneously: the LFA-1-mediated effector-target adherence and the PMN production of HOCl. The intervention of the LFA-1-mediated PMN-target adherence in the PMA-triggered lysis is likely to allow PMNs to focus HOCl on the target cell surface and suggests that the process requires a sort of molecule to molecule recognition at the effector-target surface level.

Antibodies, Monoclonal↗
PubMed1991

Suppression of lymphokine-activated killer (LAK) cell function by neutrophil polymorphonuclear leukocytes.

Peripheral blood neutrophil polymorphonuclear leukocytes (PMN) from healthy donors were found to inhibit the cytolytic efficiency of interleukin 2 (IL-2)-activated lymphocytes (LAK cells) in a dose-dependent manner. The inhibitory activity of PMN was not merely due to PMN acting as cold alternative targets, PMN ingestion of the label released by target cells or cell overcrowding in test wells. Heat-treated (50 degrees C, 30 min) lysates from PMN maintained their ability to inhibit LAK cell cytotoxicity, whereas PMN supernatants were completely ineffective. Oxidant scavengers (catalase, superoxide, dismutase) did not affect the PMN-mediated inhibition of LAK cell function. The results suggest that PMN contain heat-stable factor(s) able to suppress LAK cytotoxicity and potentially capable of limiting the therapeutic efficacy of IL-2 and/or LAK cells.

Catalase↗
PubMed1990

Cytoprotection against neutrophil derived hypochlorous acid: a potential mechanism for the therapeutic action of 5-aminosalicylic acid in ulcerative colitis.

The aim of the present study was to investigate the effects of 5-aminosalicyclic acid (5-ASA) on the cell injury mediated by activated neutrophils. We used a system constituted of neutrophils, triggered with phorbol myristate acetate, and 51Cr-labelled Daudi cells as targets. The results show that 5-ASA is capable of efficiently preventing neutrophil-mediated lysis. 5-ASA was up to 10-fold more effective than taurine, which acts as an hypochlorous acid scavenger. Moreover, 5-ASA was found to compete with taurine for the neutrophil derived hypochlorous acid. The results are consistent with the conclusion that 5-ASA is capable of limiting the neutrophil mediated cell damage by scavenging the generated hypochlorous acid. This may represent a potential mechanism for the therapeutic action of 5-ASA in ulcerative colitis.

Aminosalicylic Acids↗
PubMed1990

Inactivation of neutrophil-derived hypochlorous acid by nimesulide: a potential mechanism for the tissue protection during inflammation.

The anti-inflammatory drug nimesulide was found to effectively reduce the availability of hypochlorous acid, the most potent chlorinated oxidant generated by the myeloperoxidase system of activated neutrophils. Such an effect was observed at concentrations achievable in vivo after the oral administration of the drug. Higher concentrations of nimesulide were also found to limit both the oxygen consumption and the superoxide anion/hydrogen peroxide production by neutrophils. Taken together, the results suggest that nimesulide is endowed with a high potential to efficiently control the harmful effects of oxidants produced by neutrophils at inflammatory tissue sites.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1989

Platelets as scavengers of neutrophil-derived oxidants: a possible defence mechanism at sites of vascular injury.

Platelets (PLTs) were found to inhibit the chemiluminescence (CL) response of neutrophils (neutrophilic polymorphonuclear leukocytes, PMNs) activated with phorbol myristate acetate. The inhibition of the PMN CL response could be efficiently prevented by pulsing PLTs with carmustine (BCNU) to block their glutathione cycle. In ancillary experiments, the CL response of PMNs was inhibited by catalase (H2O2-scavenger), -azide (myeloperoxidase-MPO-inhibitor), taurine (hypochlorous acid-HOCl-scavenger) and chloride ion omission. These data suggest that the PMN CL response requires the HOCl production by the following pathway: H2O2 + Cl--MPO----H+ HOCl + H2O. Therefore, the BCNU-preventable PLT-induced inhibition of CL may reflect the consumption of PMN-derived H2O2 by the PLT glutathione cycle with a consequent impairment of the HOCl production. Consistent with such a possibility, PLTs lowered the H2O2 and HOCl recovery from PMNs via a BCNU-inhibitable process. Based on these results, we suggest that PLTs have the capacity of limiting the oxidant production by PMNs. This PLT capacity may represent a natural device for the protection of vascular structures from PMN-mediated oxidative stresses.

Blood Platelets↗
PubMed1989

Platelets as inhibitory cells in neutrophil-mediated cytolysis.

Neutrophilic polymorphonuclear leukocytes (PMNs), triggered by opsonized zymosan (OPZ), lysed chicken red blood cells as measured by a chromium 51 release method. The lysis was prevented by scavengers of hypochlorous acid. When platelets were added to the cytolytic system, a dose-dependent inhibition of the lysis was observed. Moreover, platelets lowered the HOCl recovery from OPZ-triggered PMNs. A positive linear relationship was found between the extent of the lysis mediated by and the amount of HOCl recovered from PMNs. Finally, both the inhibition of the lysis and the reduction of the HOCl recovery induced by platelets were prevented by pulsing platelets with carmustine (BCNU) to block their glutathione cycle. These results suggest that platelets act by consuming via their glutathione cycle significant amounts of PMN-derived hydrogen peroxide, with a consequent impairment of the PMN HOCl production and, in turn, lytic efficiency. Consistent with such a conclusion, platelets were found to consume PMN-derived H2O2 via a BCNU-inhibitable process. Further, the platelet inhibitory activity could be abolished by the addition of an appropriate extra-flux of enzymatically generated H2O2. No evidence for a platelet-induced inhibition of OPZ-PMN interaction, PMN myeloperoxidase release, and H2O2 production was obtained. The present study provides direct evidence for a platelet-dependent mechanism capable of controlling the PMN production of highly reactive oxidants and, in turn, the PMN cytolytic activity.

Acute-Phase Reaction↗
PubMed1989

Effector-target co-aggregation as a crucial step in the neutrophil-mediated tumour cell lysis.

The Daudi cell lysis by human neutrophils, incubated with phorbol myristate acetate (PMA), was inhibited by amino acids (taurine, methionine), consistent with the involvement of hypoclorous acid (HOCl) in the lytic process. Also, the lysis was inhibited by a monoclonal antibody (mAb J-90) directed against the leukocyte function-associated antigen-1 (LFA-1). The inhibition of the target cell lysis by mAb J-90 is not due to a HOCl-scavenging mechanism, as suggested by the use of control mAb Dako M-1 (anti CD-15). As detected by the microscopic examination of samples from test tubes and measured by monitoring the light transmission from the cell suspensions, neutrophils and Daudi cells were found to co-aggregate during the lytic reaction. Co-aggregation was efficiently inhibited by the mAb J-90. The results suggest that tumour cell lysis by PMA-triggered human neutrophils involves at least two events: production of HOCl and LFA-1-mediated effector-target adhesion.

Antibodies, Monoclonal↗