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R Foà

Publications and source records attributed to R Foà.

At least 37 records · Page 2Linked to original sources
PubMed1999

Interleukin-12 is synthesized by mesangial cells and stimulates platelet-activating factor synthesis, cytoskeletal reorganization, and cell shape change.

Preliminary studies indicate the involvement of interleukin (IL)-12 in experimental renal pathology. In the present study, we evaluated whether cultured glomerular mesangial cells are able to produce IL-12 and whether IL-12 may regulate some of their functions, including the cytoskeletal reorganization, the change in cell shape, and the production of platelet-activating factor (PAF). The results obtained indicate that pro-inflammatory stimuli, such as tumor necrosis factor-alpha and bacterial polysaccharides, induce the expression of IL-12 mRNA and the synthesis of the protein by cultured mesangial cells. Moreover, cultured mesangial cells were shown to bind IL-12 and to express the human low-affinity IL-12 beta1-chain receptor. When challenged with IL-12, mesangial cells produced PAF in a dose- and time-dependent manner and superoxide anions. No production of tumor necrosis factor-alpha and IL-8 was observed. Moreover, we demonstrate that IL-12 induced a delayed and sustained shape change of mesangial cells that reached its maximum between 90 and 120 minutes of incubation. The changes in cell shape occurred concomitantly with cytoskeletal rearrangements and may be consistent with cell contraction. As IL-12-dependent shape change of mesangial cells was concomitant with the synthesis of PAF, which is known to promote mesangial cell contraction, we investigated the role of PAF using two chemically different PAF receptor antagonists. Both antagonists inhibited almost completely the cell shape change induced by IL-12, whereas they were ineffective on angiotensin-II-induced cell shape change. In conclusion, our results suggest that mesangial cells can either produce IL-12 or be stimulated by this cytokine to synthesize PAF and to undergo shape changes compatible with cell contraction.

Angiotensin II↗
PubMed1999

Interleukin-2 gene transfer into human transitional cell carcinoma of the urinary bladder.

Transitional cell carcinoma of the bladder is one of the human cancers most responsive to immunotherapy, and local interleukin-2 (IL-2) production appears to be an important requirement for immunotherapy to be effective. In this study, we engineered two human bladder cancer cell lines (RT112 and EJ) to constitutively release human IL-2 by retroviral vector-mediated gene transfer. Following infection and selection, stable and consistent production of biologically active IL-2 was demonstrated at both the mRNA and the protein level. Morphology, in vitro growth rate and proliferation, as well as other cytokine gene mRNA or membrane adhesion receptor expression, were not altered in IL-2 transduced cells as compared to their parental or control vector-infected counterparts. Moreover, IL-2 engineered cells lost their tumorigenicity into nu/nu mice and the mechanism of rejection appeared to involve multiple host effector cell populations, among which a prominent role was played by neutrophils and radiosensitive cells. These findings may offer support to the development of an IL-2-based gene therapy approach to human bladder cancer.

Animals↗
PubMed1998

Platelet-activating factor synthesized by IL-12-stimulated polymorphonuclear neutrophils and NK cells mediates chemotaxis.

IL-12 is chemotactic for NK cells and polymorphonuclear neutrophils (PMN), but not for monocytes. In the present study, we evaluated whether the chemotactic effect of IL-12 is a direct phenomenon or is dependent on the generation of secondary mediators. The results obtained indicate that IL-12 induces a dose- and time-dependent synthesis of platelet-activating factor (PAF) from PMN and NK cells and of reactive oxygen radicals (ROS) from PMN. Monocytes and CD56-negative PBMC cells did not synthesize PAF or ROS after challenge with IL-12. The production of ROS by PMN was significantly inhibited by two chemically different PAF receptor antagonists (WEB 2170 and CV 3988), suggesting an autocrine stimulation of PMN by PAF newly synthesized after the challenge with IL-12. Moreover, the IL-12-induced chemotaxis of PMN and NK cells was significantly reduced by both WEB 2170 and CV 3988, suggesting that synthesized PAF mediates the chemotactic effect of IL-12. Preincubation with superoxide dismutase, which blocks the formation of superoxide anions, also reduced the chemotactic effect of IL-12 on PMN, but not on NK cells, suggesting that superoxide anion generation is relevant only for the IL-12-induced chemotaxis of PMN. In conclusion, the results of the present study indicate that IL-12-induced PAF synthesis plays a critical role in triggering the events involved in the motogenic response of PMN and NK to IL-12.

Chemotaxis, Leukocyte↗
PubMed1998

Evaluation of marrow and blood haemopoietic progenitors in chronic lymphocytic leukaemia before and after chemotherapy.

We have evaluated the number and differentiation pattern of CD34+ cells, as well as the CFU-GM, BFU-E and CFU-GEMM progenitors from the blood (PB) and marrow (BM) of 53 chronic lymphocytic leukaemia (CLL) patients. Twenty-four patients were untreated and 29 were studied at 2 months from the last course of fludarabine or chlorambucil; 6 patients, studied after fludarabine therapy, were further evaluated after mobilization with cyclophosphamide and G-CSF. PB of untreated patients showed a median number of CD34+ cells, CFU-GM, BFU-E and CFU-GEMM/10(5) seeded cells and per litre of PB similar to those of normal controls. No differences were also found in the number of clonogenic progenitors/10(5) cells in patients studied before and after therapy, while significantly fewer BFU-E/l of PB were found after fludarabine. The number of circulating CD34+ cells/l of PB was significantly lower in patients treated with fludarabine or chlorambucil compared to untreated patients. BM growth was significantly reduced in untreated CLL patients compared to healthy donors. Treatment with fludarabine or chlorambucil restored BM progenitors at levels similar to those of normal controls; this effect did not occur for CFU-GM in patients treated with fludarabine. Three-colour fluorescence analysis demonstrated a differentiation pattern of CD34+ cells, with a greater expression of CD13 and CD33 after treatment with fludarabine compared to untreated patients and normal controls. In 4 patients previously treated with fludarabine who underwent a successful cyclophosphamide and G-CSF mobilization therapy, 4x10(6) CD34+ cells/kg were collected. These 4 patients showed a notable increase of CD34+ cells and of clonogenic cells in the PB, but a marked decrease of BM progenitor cells. The 2 patients who failed CD34+ cell mobilization had a reduced CFU-GM growth both in the PB and in the BM. Taken together, these studies indicate that residual haemopoietic progenitors are present in untreated CLL patients and that stem cell mobilization and collection can be carried out following fludarabine treatment.

Adult↗
PubMed1996

Microsatellite instability is associated with the histological features of the tumor in nonfamilial colorectal cancer.

Replication errors (RERs) at microsatellite loci were examined in 46 specimens of nonfamilial colorectal cancer. Somatic microsatellite alterations in at least two genetic loci, D11S904, D13S175, D2S123, and D10S197, consistent with a RER(+) phenotype were found in four cases (8.7%). Six additional cases (13%) showed alterations at a single locus. Mucinous differentiation was observed in 3 of 4 (75%) adenocarcinomas with a RER(+) phenotype and only in 19% (8 of 42) of RER(-) adenocarcinomas (P < 0.05). A distinct cap of inflammatory cells at the advancing edge of the tumor and Crohn's-like reaction in peritumoral stroma were histologically identified in 50 and 25% of RER(+) and in 5 and 0% of RER(-) tumors, respectively (P < 0.05). Also, the plexiform pattern of growth of carcinoma turned out to be significantly associated with the RER(+) phenotype (P < 0.05). Mucinous differentiation and stromal inflammatory reactions are frequent features of hereditary nonpolyposis colorectal cancer in which germ-line mutations of mismatch repair genes cause genetic instability. Our results indicate that a link exists between such histological features and somatic genetic instability consistent with a RER(+) phenotype also in nonfamilial colorectal cancer.

Adenocarcinoma↗
PubMed1994

Serum levels of tumour necrosis factor-alpha in patients with B-cell chronic lymphocytic leukaemia.

Serum levels of tumour necrosis factor-alpha (TNF-alpha) have been evaluated in the peripheral blood of 91 patients with B-cell chronic lymphocytic leukaemia (B-CLL), and have been correlated with the clinical stage (according to Rai's staging system) and relevant haematological and immunological data. Increased values were detected, compared to 36 normal age-matched controls (36 pg/ml +/- 5 versus 0.11 pg/ml +/- 0.08; P < 0.05). An increase of TNF-alpha serum levels was observed in all stages including stage 0, with a progressive increase in relation to the stage of the disease. A significant relationship between serum TNF-alpha levels and the number of circulating monocytes (P < 0.002) and an inverse correlation with the level of the haemoglobin (P < 0.001) was established, as defined by the Pearson's correlation test. In contrast, no correlation was observed between TNF-alpha serum levels and the other parameters taken into account, including the white blood cell and platelet counts, the absolute number of peripheral blood (PB) lymphocytes, CD5+ B lymphocytes, CD57+ lymphocytes, serum levels of lactic dehydrogenase, total serum immunoglobulins and the serum levels of IgG, IgA and IgM. These data suggest that, in addition to the B-CLL neoplastic cells, the PB monocytes may be involved in the release of TNF-alpha.

Aged↗
PubMed1994

Long-term results of alpha interferon as initial therapy and splenectomy as consolidation therapy in patients with hairy cell leukemia. Final report from the Italian Cooperative Group for HCL.

PURPOSE: In 1987 the Italian Cooperative Group for the Study of hairy cell leukemia (HCL) started a prospective trial with the following three major aims: 1) to confirm the effectiveness of alpha-IFN as first-line treatment; 2) to assess the usefulness of splenectomy as consolidation treatment in patients achieving a satisfactory partial remission (PR) with alpha-IFN, and 3) to explore whether splenectomy in patients achieving complete remission (CR) with alpha-IFN can reduce the risk of relapse after discontinuation of the drug. PATIENTS AND METHODS: One-hundred seventy-seven patients with histologically-confirmed HCL were registered in the HCL88-A trial between December 1987 and January 1992. Inclusion criteria included no previous treatment and age less than 66 years. All patients received total doses of 3 MU of alpha-IFN daily for 12 months except for those who achieved early CR and would stop treatment after 6 or 9 months. Patients could be treated with different alpha-IFNs. At the time of the present analysis, 166 patients (93.8%) were fully evaluable. RESULTS: Treatment of HCL patients with alpha-IFN at the onset of the disease resulted in 28 CR (16.9%), 103 PR (62.0%), and 27 Minor Remissions (MR) (16.3%). Patients treated with different alpha-IFNs achieved similar results: the overall response rate (CR + PR + MR) was 92.7%, 97.2%, and 95.3% for patients treated with r-alpha-2a, r-alpha 2b, and alpha-N1, respectively. The presence of a leukemic phase and a poor performance status were associated with a statistically significant lower response rate. Patients who were randomly assigned and underwent splenectomy after achieving a PR had a better but not significant 4-year progression-free survival than cases randomized for observation (53% vs. 22%, p = 0.116). Overall, 5 patients died after study entry, with an actuarial 5-year survival rate of 96% for the entire group of 166 patients. After a mean follow-up time of 38 months, only one second malignancy has been recorded. CONCLUSIONS: Initial therapy with alpha-IFN, regardless of the type of alpha-IFN used, induces satisfactory responses in the majority of patients with HCL, but in most instances discontinuation of treatment results in recurrence of disease. In most cases alpha-IFN improves the performance status of patients and favors a satisfactory bone marrow recovery and thus could still play a role in the initial management of the disease. Although splenectomy following alpha-IFN could prolong the progression free survival, its use should be restricted to selected cases.

Adult↗
PubMed1994

Immunoglobulin light chain restriction and clonal rearrangement in nodular paragranuloma.

B-cell clonality was demonstrated in a typical nodular paragranuloma case (NP) by both immunoglobulin (Ig) surface analysis and Ig genes rearrangement studies. On frozen sections, immunostaining for Ig light chain expression revealed a clear-cut predominance of Ig lambda-expressing cells, recognizable as both small lymphocytes and lympho-histiocytic (L&H) cells. Accordingly, molecular analysis of the Ig genes showed a monoclonal rearrangement of the lambda chain gene, although no specific pattern of heavy chain gene rearrangement could be detected by JH analysis. The C lambda rearranged band was identified with two different restriction enzymes, excluding the hypothesis of a genomic polymorphism. Furthermore, the C kappa gene was almost completely deleted, indicating that the developmental hierarchy of Ig genes rearrangement has been respected. The molecular pattern of the C lambda hybridizing band was consistent with monoallelic rearrangement of almost the entire DNA sample, indicating that clonal proliferation was not limited to L&H cells, but also involved surrounding lymphocytes. This finding is in keeping with the immunohistochemical evidence of a lambda light chain restriction on both L&H cells and small lymphocytes, pointing to a close relationship between these two cell types. Our results as a whole suggest that L&H cells and B lymphocytes share a common origin and may both be involved in clonal proliferation in NP.

Antigens, CD↗
PubMed1994

Molecular evaluation of clonal remission in hairy cell leukemia patients treated with 2-chlorodeoxyadenosine.

Several reports have documented complete and long-lasting remissions in hairy cell leukemia (HCL) patients after a single one-week course of 0.1 mg/kg/d of 2-Chlorodeoxyadenosine (2-CdA) administered by intravenous infusion. In these studies the evaluation of the clinical response was based on physical examination, blood cell counts, as well as cytochemical and immunological detection of residual leukemic cells. Since HCL is a chronic lymphoproliferative disorder characterized by the expansion of monoclonal B cells, analysis of the configuration of the immunoglobulin gene regions represents a valuable tool towards a more accurate monitoring of treatment response. We hereby describe the molecular assessment of the neoplastic clone in six HCL patients treated with 2-CdA; in five of them a disappearance of the rearranged bands could be documented in bone marrow cells aspirated between 2 and 21 months after a single course of continuous infusion 2-CdA. The last HCL case analyzed, revealed molecular persistence of the neoplastic clone. In all cases but one, the molecular evaluation was in agreement with the definition of clinical response based on conventional analysis. This study demonstrates that HCL patients treated with 2-CdA show a high incidence of molecularly-defined complete remissions, the likelihood of which is much greater than for patients treated with Interferon alpha.

Bone Marrow↗
PubMed1994

In vitro susceptibility of acute leukemia cells to the cytotoxic activity of allogeneic and autologous lymphokine activated killer (LAK) effectors: correlation with the rate and duration of complete remission and with survival.

Acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) blasts were studied for their sensitivity to the lytic activity of normal allogeneic interleukin 2 (IL-2) activated killer (LAK) cells, and of autologous LAK effectors generated at the time of complete remission (CR). In 12 of 23 ALL cases (52%), the blasts were susceptible to normal LAK cells (> 15% lysis) and ten of them achieved a CR. Of the remaining 11 LAK-resistant cases, seven obtained a CR. No correlation was found between susceptibility to LAK activity, cytomorphology, immunophenotype, CR duration and survival. Eighteen of the 26 AMLs tested (70%) were susceptible to normal LAK cells, and nine of the 13 cases studied (70%) were also lysed by autologous LAK effectors generated at CR. No clearcut correlation was observed between blast sensitivity to normal LAK cells and morphologic cytotype, though a higher incidence of resistant cases was observed in the M4 subgroup. All AMLs susceptible to normal LAK cells but one achieved a CR, while this occurred only in three of the eight resistant cases (p = 0.004). The median survival and event-free survival duration in the resistant patients were significantly shorter (p = 0.03 and p = 0.02, respectively) compared to those of the susceptible patients. In ten ALL and in six AML, which at presentation displayed less than 10% circulating blasts, the susceptibility of the leukemic population to normal and autologous LAK effectors could be tested, both at diagnosis and at remission. All cases but one were resistant to autologous LAK cells generated at diagnosis, while at CR, seven cases (four ALL and three AML) became susceptible to autologous LAK cells (p = 0.01). The remaining nine were resistant to both allogeneic and autologous LAK effectors. Taken together, these findings suggest that in AML, but not in ALL, the LAK cell compartment may play a role in the clinical course and overall outcome of the disease.

Adolescent↗
PubMed1993

Persistent polyclonal lymphocytosis in human immunodeficiency virus-1-infected patients.

In this study we describe the clinical, morphologic, immunologic, and genetic features of a chronic peripheral blood lymphocytosis associated with posttraumatic splenectomy in patients with human immunodeficiency virus-1 (HIV-1) infection. Among a series of 2,365 consecutive HIV-1 seropositive cases investigated, eight patients were selected for the presence of more than 4,000 lymphocytes/mm3. All cases were characterized by a lymphocytosis with cytoplasmic azurophilic granules; in three patients the hematologic picture was superimposable with that of lymphoproliferative disease of granular lymphocytes. Phenotypic analysis of lymphocytes showed a prevalent CD3+CD8+ pattern. In vitro evaluations, including the response to mitogens and interleukin-2 and the cytotoxic assays, showed an unimpaired lymphocyte function in the majority of our patients, even in those with advanced stages of the syndrome. The analysis of the configuration of the T-cell receptor (TCR) beta and gamma genes showed a polyclonal pattern of rearrangement. At the mean follow-up time of 45 +/- 8 months, one patient died of overdose when the clinical conditions were stable; all the other patients are alive, although disease progression was documented in two. Our results indicate that a chronic polyclonal lymphocytosis may be associated with HIV-1 infection; this finding seems to be restricted to patients who have undergone splenectomy. The demonstration of a still uncompromised immune system together with a silent clinical course in the patients under study also suggest that splenectomy per se does not favor an aggressive clinical behavior of HIV-1 infection.

CD4-CD8 Ratio↗
PubMed1993

Immunophenotype of acute lymphoblastic leukemia cells: the experience of the Italian Cooperative Group (Gimema).

The immunophenotype of 304 adult lymphoblastic leukemias (> 18 years) diagnosed on the basis of the FAB criteria was determined at the time of diagnosis using a panel of monoclonal antibodies. The series comprised cases diagnosed and immunophenotyped in 43 Italian centers (GIMEMA Cooperative Group) between April 1988 and June 1991. The immunophenotypic characterization consisted of two consecutive steps. The initial screening was based on the reactivity for TdT, HLA-Dr, CD7, CD10, CD13, CD19, CD24, CD33 and CD41. According to the results obtained, the second level of investigation assessed the positivity for intra cytoplasmic (Cy) Ig, CD1a, CD2, CD3, CD4, CD5, CD8 and CD20. Based on the hierarchical expression of the different B- and T-cell related antigens, each case was assigned to a given differentiation stage. B-lineage ALL were classified in five subgroups (B0-B4) and T-lineage ALL in four subgroups (T0-T3). Cases in which the blasts were lymphoid according to the FAB criteria, but expressed myeloid antigens in association with B- and T-lymphoid markers were defined as hybrid leukemias. As expected, CD10+ cases (B2-B3) were the most frequent within the B-lineage ALL (83.2% of cases). CyIg+ (B3) accounted for about 20% of CD10+ ALL. Twenty eight cases (13.4%) were at a pre-cALL stage (B0-B1) and of these, 8 (3.8% of the total series) were positive only for TdT and HLA-Dr (B0). Intermediate and mature thymic phenotypes (T2-T3) were predominant within the T-ALL (67.2%) groups. Five cases, were positive only for TdT and CD7 (CD5+), and classified as T0. 9.2% of cases fulfilled the definition of hybrid leukemia, largely in view of the co-expression of B-lymphoid and myeloid markers.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed1993

Cytogenetic rearrangement of C-MYC oncogene occurs prior to infection with Epstein-Barr virus in the monoclonal malignant B cells from an AIDS patient.

Two cell lines were originated from the peripheral blood (PB-LAM) and bone-marrow (BM-LAM) of a patient with Burkitt-type acute lymphoblastic leukemia and AIDS. 26 and 7 clones were isolated from PB-LAM and BM-LAM respectively by limiting dilution. All of these had surface IgM lambda and the CD10 marker with low to absent CD23, CD30, CD39 and surface adhesion molecules. Furthermore, they shared the same chromosomal abnormalities (trisomy 7 and t(8;14) translocation) and the same rearrangements of immunoglobulin L and H chain and of c-myc gene loci. These features are those most frequently found in Burkitt's lymphoma (BL) cells and were different from those of the parental cell lines, which, besides cells identical to those of the malignant clones, also contained normal lymphoblastoid cells. Therefore, the cloning procedure used selected for the growth of cells with malignant features. EBV latent antigens were detected in all clones by Western blotting and their pattern of expression resembled that usually observed in BL cells. All the clones were positive for the EBV genome by Southern blotting and had monomorphic EBV-fused termini as determined by using cDNA probes specific for sequences at either end of the viral genome. However, the clones derived from PB-LAM had EBV fused termini of a different size from that of the clones derived from BM-LAM. The presence of different EBV-fused termini in otherwise monoclonal malignant cells indicate that EBV infection was possibly a late event in lymphomagenesis following rearrangement of the c-myc and the Ig gene loci.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Mixed acute leukemia with genotypic lineage switch: a case report.

Morphologically well classifiable leukemias can reveal a mixed phenotype. A case of acute myeloid leukemia (CD13, CD33, CD14, CD11b) which at presentation showed a co-expression of B-lymphoid markers (CD19, CD10, CD20), at the time of the first relapse revealed a morphologic, phenotypic and genotypic switch of the blasts to a purely lymphoid form. Analysis of the immunoglobulin (Ig) H chain locus and of the T-cell receptor (TCR) genes showed at diagnosis a germline configuration of the IgH, TCR beta and tau genes, and a deletion of the TCR delta gene at the second chromosome. At relapse, monoclonal rearrangements of the IgH, TCR tau, and TCR delta were detected. At a subsequent relapse, the blasts re-expressed myeloid morphologic features and myeloid-associated antigens, while they retained the same rearranged configuration of the IgH and TCR beta and delta genes. The TCR delta gene configuration, which links each phase of the disease, may represent an early pathogenetic event and makes the emergence of a second malignancy unlikely. Each phenotypic change occurred after anti-myeloid and anti-lymphoid oriented chemotherapy. The close correlation between the progressive acquisition of different phenotypes and the switch at the genomic level represent the peculiar features of this unusual case.

Adult↗
PubMed1992

Autologous bone marrow transplantation followed by interleukin-2 in children with advanced leukemia: a pilot study.

In an attempt to prolong disease-free survival in children with acute leukemia, we tested the feasibility of interleukin-2 (IL-2) administration after an autologous bone marrow transplantation (ABMT). We report the clinical and biological data obtained in three children with acute myelocytic leukemia (AML) in second complete remission (CR) and in seven children with acute lymphocytic leukemia (ALL) in second or subsequent CR, who received IL-2 at a median interval of 78 days (range 38-125) from ABMT. Patients were treated with 1-2 cycles of IL-2 given by continuous infusion over a 5-day period using a daily escalating protocol, from 100 micrograms/m2 per day to the maximum tolerated dose, followed after 3 weeks by low-dose IL-2 for 5 days monthly over a 6-h infusion on an out-patient basis. Side effects greater than grade 2 (WHO system), consisting of thrombocytopenia, fever, cutaneous rash, nausea and vomiting, diarrhoea were common during the high-dose IL-2 cycles, but resolved 24-48 h after stopping IL-2. Only one patient developed liver toxicity (grade 3, WHO) on day +3 of the first cycle which prompted us to stop the administration of IL-2. An increase in lymphocytes and eosinophils was also observed. IL-2 treatment was followed by a normalization of NK function and by the generation of a high proportion of endogenous LAK cells. All seven ALL patients relapsed at a median of 5 months (range 1-23). Two AML patients relapsed at 1 and 11 months, while the other is still in continuous CR at 23 months after IL-2 treatment. Our IL-2 schedule for treatment of leukemia in children after ABMT is thus feasible but its efficacy requires further investigation.

Adolescent↗