G. Pizzolo | Università di Verona (original) (raw)

Papers by G. Pizzolo

Blood, 2002

for the GIMEMA Group Little is known about the prognostic role of multidrug resistance (MDR) in a... more for the GIMEMA Group Little is known about the prognostic role of multidrug resistance (MDR) in adults with newly diagnosed acute lymphoblastic leukemia (ALL). In the context of the GIMEMA ALL0496 protocol, we evaluated the impact of MDR1 (protein expression and function) on the achievement of complete remission (CR) and clinical outcome. Flow cytometric analysis of MDR1 expression (D) and function (rhodamine-123 efflux) was obtained in 203 and 158 patients, respectively. MDR1 expression was detected in 44 (21.7%) of 203 patients, and function was found in 23 (14.6%) of 158 (14.6%) patients. Expression of the multidrug resistance-associated protein 1 (MRP1) and lung-resistance protein (LRP) evaluated in 43 samples was found in 13 and 26 patients, respectively. Among the 200 patients evaluable for the clinical correlation study, 125 (79.6%) of 157 without MDR1 expression achieved CR compared with 23 (53.5%) of 43 with MDR1 expression (P ‫؍‬ .001). At univariate analysis, MDR1 expression was significantly associated with CR when considered as a dichotomized (P ‫؍‬ .001) or continuous (P ‫؍‬ .01) variable. At multivariate analysis, dichotomized evaluation of MDR1 expression independently predicted CR (P ‫؍‬ .004) with age (P ‫؍‬ .03) and CD34 (P ‫؍‬ .03); as a continuous variable, MDR1 expression (P ‫؍‬ .03) was the only significant factor other than CD34 (P ‫؍‬ .01). MDR1 function failed to predict achievement of CR or of MRP1 and LRP expression. MDR1 expression did not correlate with CR duration, nor did it predict for survival duration. These results demonstrate that MDR1 expression in de novo adult ALL is an independent predictor of CR achievement.

Blood, 1997

The recently cloned cytokine interleukin-15 (IL-15) shares several functional activities with IL-... more The recently cloned cytokine interleukin-15 (IL-15) shares several functional activities with IL-2 in different cell systems. Although IL-15 does not show sequence homology with IL-2, it uses components of the IL-2 receptor (IL-2R) for binding and signal transduction, namely, p75 (β) and the p64 (γ) chains of IL-2R. To evaluate whether IL-15 is involved in the activation of granular lymphocytes (GL) in patients with lymphoproliferative disease of granular lymphocytes (LDGL), we evaluated the ability of IL-15 to stimulate GL proliferation, cytotoxic function, and the role of IL-2R β and γ molecules on relevant cells. Our results show that IL-15 stimulates cell proliferation and cytotoxic activity of GL in LDGL patients. Reverse-transcriptase polymerase chain reaction (RT-PCR) and phenotypic analyses using the anti–IL-2R γ-chain–specific TUGh4 monoclonal antibody (MoAb) indicate that both CD3+ and CD3− GL express the p64 IL-2R, a result previously unknown. IL-15 activity was inhibited...

Laboratory investigation; a journal of technical methods and pathology, 1998

Evidence has recently been provided to support a role for genomic imprinting in the regulation of... more Evidence has recently been provided to support a role for genomic imprinting in the regulation of embryonic implantation and development and placental growth, as well as in the pathogenesis of proliferative trophoblastic diseases. The cyclin-dependent kinase inhibitor p57KIP2 has recently been recognized as a maternally imprinted gene. We investigated p57KIP2 expression in first-trimester normal placentas from interrupted pregnancy, spontaneous abortions, and different types of proliferative trophoblastic diseases using single- and double-marker immunohistochemical techniques. In normal placenta, nuclear p57KIP2 expression was observed at high frequency (up to 100%) in extravillous trophoblast, cytotrophoblast, and implantation-site interstitial trophoblast, but was absent in syncytiotrophoblast. p57KIP2 was also expressed in the stromal cells of maternal decidua, which was one of the few adult tissues retaining p57KIP2 expression (most other adult tissues investigated were negative...

Leukemia, 1998

On the basis of a previous experience suggesting that daunorubicin dose in induction was an indep... more On the basis of a previous experience suggesting that daunorubicin dose in induction was an independent prognostic factor in adult ALL, we designed a chemotherapeutic regimen (ALLVR589) characterized by high doses of daunorubicin (270 mg/m 2) in induction and by high-dose Ara-C in postremission. The protocol was otherwise conventional: induction and post-remission therapy were followed by chemo-radio prophylaxis of the central nervous system (CNS) and periodical reinductions over a 3-year maintenance period. Sixty consecutive patients (male 42, female 18, median age 34 years, range 14-71; B-lineage, 35; T-lineage, 25; PhЈ and bcr/abl positive, 7) recruited between 1989 and 1996, were evaluated for treatment outcome. Complete remissions were 56 (93%), one patient had refractory disease, early deaths were five (8%); 19/56 (34%) patients relapsed, five of whom were PhЈ+. Median time to relapse was 11 months (range 3-47); 68% of relapses occurred within 12 months from CR. No CNS relapses were observed. After a median follow-up of 44 months (1-100), 33/60 (55%) patients remain event-free; 23/60 (38%) are off-therapy in continuous CR (median follow-up from diagnosis: 63 months; range 38-100). These results suggest that increasing DNM dosage in induction is one of the possible approaches to improve the outcome of adult ALL by decreasing the relapse occurrence.

Clinical and Experimental Immunology, 1996

SUMMARY There is evidence that both cellular and humoral components of the immune response are re... more SUMMARY There is evidence that both cellular and humoral components of the immune response are required for viral clearance to occur in chronic hepatitis B. Recent studies demonstrated that CD30 molecule, a member of the tumour necrosis factor superfamily of membrane cytokine receptors, is expressed on, and released as a soluble molecule (sCD30) by activated T cells producing T helper 2 (Th2) cytokines, which modulate antibody responses. To better characterize the immunoregulatory mechanisms in chronic hepatitis B virus (HBV) infection, sCD30 values were evaluated by an ELISA in 90 hepatitis B surface (HBsAg)-positive patients with chronic hepatitis, selected on the basis of active viral replication and biochemical activity. At presentation abnormal levels (>20 U/ml) of sCD30 were detected in 57 (63%) out of 90 patients with chronic hepatitis B, and median value was significantly higher in this group of patients compared with that of healthy HBsAg carriers (26.7 versus 10.5 U/ml,...

Cancer Immunology Immunotherapy, 1989

Experiments herein reported were designed to clarify the degree of sensitivity of hairy cells to ... more Experiments herein reported were designed to clarify the degree of sensitivity of hairy cells to lysis in vitro. The cytotoxic capacity of peripheral blood lymphocytes from hairy cell leukemia patients against autologous and/or allogenic hairy cells was tested both at resting conditions and after in vitro stimulation. While effectors activated by interferon «, lectins, or interleukin-2 were unable to induce a lysis of hairy cells, in some cases we were successful in eliciting a definite lysis of these cells by triggering the effector cells with anti-CD3 monoclonal antibodies. Our results favour the interpretation that hairy cells are relatively, but not completely resistant to in vitro lysis. Furthermore, the evidence that anti-CD3 antibodies increase the efficacy of the cytotoxic machinery might support the use of these molecules in designing new immunotherapeutic approaches against tumor targets.

Annals of Allergy, Asthma & Immunology, 1999

Patients completely asymptomatic with extremely high levels of IgE have rarely been reported. One... more Patients completely asymptomatic with extremely high levels of IgE have rarely been reported. One such case, in which the immunophenotype pattern of lymphocyte subsets and their cytokine profile were investigated, is described here. To assess whether the cytokine production was consistent with a T helper 2-type immune response, as suggested by theories regarding the functional polarization of helper and cytotoxic T cells in hyper-IgE conditions. An asymptomatic 79-year-old man presented with persistent high levels of serum IgE and sporadic hypereosinophilia without any evidence of an underlying pathologic condition. We investigated the immunophenotype of circulating lymphocytes, the expression/release of CD30 (a member of the tumor necrosis factor receptor family preferentially associated with T helper 2-type immune responses) and the intracellular patterns of interferon-gamma (IFN-gamma), Interleukin-2 (IL-2), IL-4, IL-5, and IL-10 production by T cell subsets, as evaluated by single-cell flow-cytometric analysis. The majority of lymphocytes displayed the membrane immunophenotype of NK cells. Both CD4+ and CD8+ T cells were reduced and expressed the "memory" (CD4+/CD45RO+) and the "naive" (CD8+/CD45RA+) phenotypes, respectively. Among CD4+ T cells, CD30 expression was increased in the resting condition and was further inducible following stimulation with mitogenic anti-CD3. Interleukin-4, IL-2, and IL-10 production by CD4+ T cells was increased, whereas IFN-gamma was reduced as compared with normals. The data suggest that a polarization of CD4+ T cells towards a T helper 0/2-type cytokine pattern occurred in this patient in spite of CD4+ cell reduction and NK cell expansion.

To elucidate the mechanisms of a-interferon's (a-INF) therapeutic effect on clinical and lab... more To elucidate the mechanisms of a-interferon's (a-INF) therapeutic effect on clinical and laboratory findings in hairy cell leukemia. we sequentially monitored different immunologic parameters in three patients treated with recombinant a-INF. The most evident effect of this treat- ment on the immune system was the recovery of natural killer (NK) cell in vitro activity of peripheral blood lympho- H AIRY CELL LEUKEMIA (HCL) is a malignant B cell disorder usually characterized by isolated spleno- megaly and peripheral pancytopenia associated with the presence in the blood of mononuclear hairy cells that infil- trate the spleen and bone marrow."2 Although splenectomy has been the treatment of choice in this disease for a number of years, a large number of patients fail to respond to this approach.2 The use of different therapeutic strategies based on chemotherapeutic agents has been unsatisfactory.3 A highly effective treatment of these patients has been recently offered by a-i...

Leukemia Research, 1987

To further define the mechanisms responsible for the alpha-interferon (alpha-IFN) efficacy in the... more To further define the mechanisms responsible for the alpha-interferon (alpha-IFN) efficacy in the treatment of hairy cell leukemia (HCL), experiments were carried out to specify the cytotoxic events taking place following this type of therapy. Although an increased natural killer (NK) activity was demonstrable after alpha-IFN treatment, evidence has been provided that hairy cells were not specifically lysed either by fresh autologous/ allogenic NK lymphocytes or by lymphokine activated killer (LAK) cells. This property could not be induced in vitro by alpha-IFN or by interleukin-2 (IL-2). Our data favour the hypothesis that the increase of NK cell activity observed following alpha-IFN therapy has not a direct antineoplastic effect but is likely to be of relevance for a non-specific enhancement of the host immune system. In alpha-IFN treated HCL this latter property may account for the better resistance to infections which usually represents the major cause of mortality in these patients.

OBJECTIVE To measure the levels of serum soluble CD30 (sCD30), a marker of cells producing T help... more OBJECTIVE To measure the levels of serum soluble CD30 (sCD30), a marker of cells producing T helper 2(Th2)-type cytokines, in systemic lupus erythematosus (SLE) and undifferentiated connective tissue disease (UCTD), and to determine its value in assessing disease activity. METHODS Serum levels of sCD30 were measured by ELISA in 21 patients with SLE, in 17 patients with UCTD and in 40 normal donors. Disease activity was evaluated according to the ECLAM scoring system. RESULTS sCD30 values were 53.84 +/- 58.24 U/mL in SLE, 22.65 +/- 9.82 U/mL in UCTD and 5.3 +/- 5.7 in normal controls (p < 0.0005 SLE vs controls; p < 0.05 SLE vs UCTD). sCD30 levels were directly related to the disease activity (p < 0.002). CONCLUSION These data support a relationship between the Th2-type immune response and the pathogenesis of SLE, and suggest that sCD30 can be used as a simple marker for the evaluation of disease activity.

Blood

2601 Background: Tyrosine Kinase Inhibitors (TKI) have been shown to be very effective for the tr... more 2601 Background: Tyrosine Kinase Inhibitors (TKI) have been shown to be very effective for the treatment of Acute Lymphoblastic Leukemia (ALL), with a Complete Hematologic Remission (CHR) rate close to 100%, and a high rate of Complete Cytogenetic and Molecular responses (CCgR and CMR). However, when they are used alone, as single agents, most patients relapse, so that they are currently used in combination with chemotherapy and as a preparation to allogeneic stem cell transplantation (SCT). Since Ph+ ALL is more frequent in the elderly, many patients cannot tolerate intensive chemotherapy and are not eligible for SCT. We have explored if the administration of two TKIs, Nilotinib (NIL) and Imatinib (IM) can improve the results without increasing the toxicity. Aims: To evaluate the response and the outcome of Ph+ ALL patients treated with the sequential administration of NIL and IM, to investigate the type and number of BCR-ABL kinase domain mutations developing during and after the ...

Morphological. immunologic. and functional properties of peripheral blood cells from two patients... more Morphological. immunologic. and functional properties of peripheral blood cells from two patients with chronic proliferations of granular lymphocytes are described. Cells from both patients showed a heterogeneous pattern from both a morphological and immunologic standpoint. indicat- ing a polyclonal. rather than a monoclonal. expansion of these cells. In fact. both large and small-to-medium-sized

Blood, 1990

Natural killer (NK) cell activity is severely impaired in untreated patients with hairy cell leuk... more Natural killer (NK) cell activity is severely impaired in untreated patients with hairy cell leukemia (HCL). In an attempt to investigate whether this impairment is related to a defect at the target cell binding and/or at the post target cell binding level, we evaluated the peripheral blood mononuclear cells (PBMC) of HCL patients for their ability to: (1) bind and kill K-562 NK-sensitive targets at the single cell binding level; (2) release the NK cytotoxic factor (NKCF) under different in vitro stimuli, including K-562 and phytohemoagglutinin; and (3) kill K-562 targets in a lectin-dependent cellular cytoxicity (LDCC) assay. This study demonstrates that untreated HCL patients' PBMC show a low ability to form conjugates with K-562 targets at the single cell binding level (5.7% +/- 1.0%) with respect to patients studied after treatment (9.3% +/- 1.3%) and controls (15.0% +/- 4.0%); P less than .05 and P less than .001, respectively. A decreased ability to kill the bound target w...

British journal of cancer, Jan 26, 2004

The optimal treatment of primary mediastinal large B-cell lymphoma (PMLBCL) is still undefined. I... more The optimal treatment of primary mediastinal large B-cell lymphoma (PMLBCL) is still undefined. In the absence of randomised studies, we retrospectively analysed: (a) the effectiveness of two chemotherapy regimens (CHOP vs MACOP-B/VACOP-B) in complete remission (CR) achievement and event-free survival (EFS) and (b) the role of mediastinal involved-field radiotherapy (IF-RT) as consolidation. From 1982 to 1999, 138 consecutive patients affected by PMLBCL were treated in 13 Italian institutions with CHOP (43) or MACOP-B/VACOP-B (95). The two groups of patients were similar as regard to age, gender, presence of bulky mediastinal mass, pleural effusion, stage and international prognostic indexes category of risk. Overall, 75.5% of patients in CR received IF-RT as consolidation. Complete remission was 51.1% in the CHOP group and 80% in MACOP-B/VACOP-B (P<0.001). Relapse occurred in 22.7% of CHOP- and in 9.2% of MACOP-B/VACOP-B-treated patients (n.s.). Event-free patients were 39.5% in...

Blood, Jan 15, 1998

Preliminary reports suggested a prognostic significance for serum levels of soluble CD30 (sCD30) ... more Preliminary reports suggested a prognostic significance for serum levels of soluble CD30 (sCD30) in patients with Hodgkin's disease (HD). In this study, we investigated the prognostic impact of sCD30 concentration at diagnosis in relation to the other recognized prognostic parameters in 303 patients with HD observed in three different institutions between 1984 and 1996. sCD30 levels were correlated with stage, presence of B symptoms, and tumor burden. High sCD30 levels entailed a higher risk of poor outcome, and the event-free survival (EFS) probability at 5 years for patients with sCD30 levels >/=100 and less than 100 U/mL was 59.9% (95% confidence interval [CI], 40.6% to 65.9%) and 87.5% (95% CI, 81.5% to 91.6%), respectively (P < .001). On the basis of the results of univariate analysis of 14 pretreatment characteristics, we included five prognostic factors (high sCD30 serum level, stage III-IV, B symptoms, low hemoglobin level, and age >/=50 years) into a multivaria...

Journal of leukocyte biology, 1997

CD30 is a member of the tumor necrosis factor (TNF) receptor family, originally described as a ma... more CD30 is a member of the tumor necrosis factor (TNF) receptor family, originally described as a marker for Hodgkin and Reed-Sternberg cells in Hodgkin's disease, which has been found to be preferentially expressed by T cells producing Th2-type cytokines. The presence of CD30 expression was assessed by both immunohistochemistry and reverse transcriptase-polymerase chain reaction in the target organs of patients with Th1- or Th2-dominated disorders. CD30 expression was found in neither the gut of patients with Crohn's disease nor in the gastric antrum of Helicobacter pylori-infected patients, where there was high interferon-gamma (IFN-gamma) expression. In contrast, high CD30 expression in the apparent absence of IFN-gamma expression was observed in the skin of patients with systemic sclerosis or chronic graft versus host disease (GVHD), which can be considered Th2-dominated disorders. Moreover, high levels of soluble CD30 were found in the serum of both systemic sclerosis and ...