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Robin Foà

Publications and source records attributed to Robin Foà.

36 records · Page 2Linked to original sources
PubMed2005

New developments in the diagnosis, prognosis and treatment of chronic lymphocytic leukemia.

PURPOSE OF REVIEW: The remarkable progress witnessed over the past few years in the diagnosis, prognosis, and therapy of chronic lymphocytic leukemia has profoundly changed the clinical approach to this disease. This review focuses on the most recent advances in the diagnostic and prognostic examination of patients with chronic lymphocytic leukemia, with particular emphasis on their implications in clinical management, taking into account the broadening of the therapeutic possibilities available today. RECENT FINDINGS: Through the biologic improvements achieved during the past few years it is now possible to effectively stratify chronic lymphocytic leukemia patients prognostically at presentation on the basis of several laboratory parameters. Furthermore, the availability of purine analogs and monoclonal antibodies and the extension of autografting and allografting procedures have allowed the achievement of higher response rates, including molecular remissions. With the aim of investigating whether early and aggressive treatment intervention may improve the survival of patients with a poor prognosis, new therapeutic trials have been specifically designed. SUMMARY: A complete biologic and clinical examination now allows the establishment of a correct diagnostic characterization of patients with chronic lymphocytic leukemia and to identify patients with early disease with a different prognostic likelihood. Multicenter prospective trials, in which the enrolled patients are stratified and treated according to their prognostic risk, will determine the best treatment for the different categories of patients. It is likely that in the near future each chronic lymphocytic leukemia patient can be offered a targeted treatment algorithm based on the clinical and biologic characteristics at presentation.

Antibodies, Monoclonal↗
PubMed2005

The prognostic value of CD38 expression in chronic lymphocytic leukaemia patients studied prospectively at diagnosis: a single institute experience.

The purpose of this study was to assess in chronic lymphocytic leukaemia (CLL) patients the prevalence and clinical impact of CD38 expression, evaluated prospectively at disease presentation, and to verify whether this parameter changes over time. In 242 consecutive and untreated CLL patients, the percentage of CD38+ cases, according to the 7%, 20% and 30% cut-off points, was 21%, 17% and 14%, respectively. Using the 7% threshold, CD38 positivity correlated with male sex, intermediate and high-risk (Rai I-IV) disease, lower Hb and platelet levels, and higher lymphocyte count. Furthermore, patients with a CD38 expression>or=7% showed a significantly lower 3-year probability of treatment-free survival (TFS) than CD38- patients (P<0.0001). At multivariate analysis, CD38 expression remained significantly associated to TFS, together with stage, lymphocyte count and morphology. Also, in the 146 patients with stage 0 CLL a CD38 expression>or=7% identified a subgroup of patients with a significantly lower 3-year probability of TFS (P=0.0005). Furthermore, this parameter did not change in 30 of 31 (97%) re-evaluated patients. In conclusion, this study indicates that, when tested at diagnosis and on fresh material, a CD38 expression>or=7% is an important parameter for the identification of early CLL patients with more aggressive disease and that its expression remains stable over time.

ADP-ribosyl Cyclase↗
PubMed2005

Breakthrough Candida krusei fungemia during fluconazole prophylaxis followed by breakthrough zygomycosis during caspofungin therapy in a patient with severe aplastic anemia who underwent stem cell transplantation.

We report a case of breakthrough invasive zygomycosis in a stem cell transplant recipient who was receiving caspofungin for treatment of a breakthrough Candida krusei fungemia that occurred during fluconazole prophylaxis. Also, patients receiving the echinocandin caspofungin remain at risk for pathogens, such as zygomycetes, that are intrinsically resistant to this agent.

Adolescent↗
PubMed2005

Is bone marrow trephine biopsy always mandatory in staging Hodgkin's disease?

We reviewed data from 690 adult patients with Hodgkin's disease (HD) to determine whether bone marrow trephine biopsy (BMTB) is mandatory for all patients. The data suggest that it is not necessary in clinical stage I-IIA. However, bilateral BMTB is recommended in the presence of B symptoms also in patients with localized stage disease.

Adult↗
PubMed2005

TRAIL decoy receptors mediate resistance of acute myeloid leukemia cells to TRAIL.

BACKGROUND AND OBJECTIVES: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, many cancer cells are resistant to apoptosis induction by TRAIL. The present study was designed to evaluate the sensitivity to TRAIL-induced apoptosis in acute myeloblastic leukemias (AML). DESIGN AND METHODS: TRAIL/TRAIL receptor (TRAIL-R) expression and sensitivity to TRAIL-mediated apoptosis were explored in 79 AML patients, including 17 patients with acute promyelocytic leukemia (APL). RESULTS: In non-APL AML we observed frequent expression of TRAIL decoy receptors (TRAIL-R3 and TRAIL-R4), while TRAIL-R1 and TRAIL-R2 expression was restricted to AML exhibiting monocytic features. Total leukemic blasts, as well as AML colony-forming units (AML-CFU), were invariably resistant to TRAIL-mediated apoptosis. APL express membrane-bound TRAIL on their surface and exhibit a pattern of TRAIL-R expression similar to that observed in the other types of AML. Before, during and after retinoic acid treatment APL cells are TRAIL-resistant. The induction of granulocytic maturation of APL cells by retinoic acid was associated with a marked decline of TRAIL expression. INTERPRETATION AND CONCLUSIONS: The analysis of experimental APL models (i.e., U937 cells engineered to express PML/RAR-Eo and NB4 cells) provided evidence that PML/RAR-Eo expression was associated with downmodulation of TRAIL-R1 and with resistance to TRAIL-mediated apoptosis. We suggest that AML blasts, including APL blasts, are resistant to TRAIL-mediated apoptosis, a phenomenon seemingly related to the expression of TRAIL decoy receptors on these cells. Finally, APL blasts express membrane-bound TRAIL that could confer an immunologic privilege to these cells.

Acute Disease↗
PubMed2005

Expansion of natural killer cells with lytic activity against autologous blasts from adult and pediatric acute lymphoid leukemia patients in complete hematologic remission.

BACKGROUND AND OBJECTIVES: Natural killer (NK) cells constitute an important area of research for hematologic malignancies. The anti-leukemic activity of NK cells against acute myeloid leukemia (AML) blasts has been described, but very few data are available for acute lymphoid leukemia (ALL). The present study was designed to investigate whether: (i) NK effectors could be expanded from adult and pediatric ALL patients in complete remission; (ii) the signal transduction machinery of these cells was preserved; (iii) NK cells showed cytotoxic activity against autologous blasts; (iv) interleukin (IL)-2, IL-12 and IL-15 were able to increase lytic activity in our in vitro model; (v) any differences in cytotoxic activity could be found between expanded effectors from adult and pediatric patients. DESIGN AND METHODS: We co-cultured patients' peripheral blood mononuclear cells (PBMC) with the feeder cell line RPMI 8866 and analyzed the NK cells' expansion capacity by cell count and cytofluorimetric analyses. Signal transduction of expanded effector cells was evaluated by Western blot. 51Cr release assays, before and after stimulation with activating cytokines, were performed to analyze the cytotoxic potential of effector cells against tumor cell lines and autologous blast cells. Data were analyzed with t-tests for paired data. RESULTS: We obtained an average 40-fold increase in NK cells. Signal transduction through the CD16 receptor was preserved. Patients' expanded cells showed cytotoxic activity against target cell lines comparable to that of normal donors. More significantly, these cells also exerted a lytic effect against autologous blasts. In addition, incubating these effectors for 24 hours with IL-2 + IL-15 significantly increased this cytotoxic function. No differences in expansion and cytotoxic activity were found between pediatric and adult patients. INTERPRETATION AND CONCLUSIONS: These findings document for the first time the possibility of expanding ex vivo cytotoxic effectors with autologous killing capacity from ALL patients in remission, and suggest a new potential immunotherapeutic strategy for the management of early disease recurrence or of residual disease.

Adult↗
PubMed2005

New therapies in onco-hematology and new infectious risk factors.

The biologic, clinical and therapeutic setting is nowadays such that risk factors for infectious complications are constantly changing and progressively increasing in patients suffering from onco-hematologic conditions. In addition to situations that are well known or that are gradually being recognized related both to the underlying disease and to treatment, such as neutropenia, neutrophil dysfunction, mucosal damage, concomitant monocytopenia and lymphopenia, abnormalities within the host cellular and humoral compartments, impairments in cytokine networks, alterations in T lymphocytes/tumor interactions, crosstalks between neoplastic cells and accessory cells, etc, over the last few years we are witnessing important changes in the overall management of patients with hematologic malignancies. Historically, the categories at risk were represented by patients with acute leukemia and patients undergoing an allogeneic stem cell transplant. In both, the likelihood of eradicating the disease requires necessarily a myeloablative therapeutic strategy, complicated in the allografted patients by the risks of graft-versus-host disease (GvHD), the required immunosuppressive treatment and the recently documented role that cytokines may play in the development of acute GvHD. Considerable changes have occurred in recent years. From the identification of "new" diseases at risk (e.g. lymphomas occurring in HIV+ individuals), to the progressive and constant increase in allotransplant procedures, to the development of new transplant procedures (cord blood, matched-unrelated or mismatched donor transplant, mini-transplant, the administration of donor lymphocytes), to the development of new drugs that can induce immunosuppression, to the clinical use of certain monoclonal antibodies (MoAb), to the combined use of chemotherapy plus MoAb. These developments are associated with other general considerations. Within these: 1) the growing use of ablative therapies in diseases for which for many years the approach has been less aggressive or indeed conservative; 2) the progressive recognition of categories of patients with unfavorable prognosis for whom an aggressive approach is required; 3) the constant improvement in mean life expectancy and "biologic" age of patients; thus, the progressive changes in the definition of "old age". Taken together, this has led, on the one hand, to an increase in the categories of onco-hematologic patients at risk of infective complications and to a major focus on the immune compartment of the affected patients, and, on the other hand, to an overall broadening of the infective scenario.

Combined Modality Therapy↗
PubMed2004

Apoptosis susceptibility and cell-cycle distribution in cells from myelodysplastic syndrome patients: modulatory in-vitro effects of G-CSF and interferon-alpha.

Susceptibility to apoptosis varies in different forms of myelodysplastic syndromes (MDS). Our in vitro study aimed at better defining the cell kinetic profile by investigating whether G-CSF and interferon-alpha (IFNalpha) were capable of controling apoptotic/proliferative mechanisms in RAEB as well as in RAEB-t forms. Apoptosis and cell-cycle distribution were measured in mononuclear and in CD34+ cells from bone marrow samples of 27 MDS patients with RAEB (n = 15) and RAEB-t (n = 12). In selected samples, the in vitro influence of G-CSF and lymphoblastoid (Ly)-IFNalpha on the apoptotic susceptibility and on the cell kinetics of the above MDS populations was evaluated. RAEB samples showed a significantly greater apoptosis than RAEB-t ones, both in mononuclear cells (14.76%+/-8.73 vs. 5.95%+/-3.88, P= 0.0058) and in CD34+ cells (24.66%+/-16.08 vs. 3.96%+/-2.57, P = 0.0007). Short-term cell culture in the presence of G-CSF reduced apoptosis in CD34+ cells in all 4 RAEB samples tested (39.1%+/-40.7 vs. 21.0%+/-23.5, P = n.s.); the percentage of cells in S-phase significantly increased in 3/4 samples (19.90%+/-4.40 vs. 32.40%+/-7.85, P = 0.03). Ly-IFNalpha protected CD34+ cells from apoptosis in 3/4 RAEB samples (25.7%+/-8.06 vs. 10.9%+/-8.8, P = n.s.), but did not modulate cell-cycle distribution. G-CSF and Ly-IFNalpha failed to affect apoptosis and proliferation in RAEB-t. These observations indicate that in RAEB forms increased apoptosis can be efficiently counteracted in most of the samples by both G-CSF and Ly-IFNalpha, suggesting that only in these forms a retained regulatory mechanism on the apoptotic/ proliferative balance may allow therapeutic intervention with apoptotic regulators.

Adult↗
PubMed2003

Trisomy 13 in a patient with common acute lymphoblastic leukemia: description of a case and review of the literature.

Trisomy 13 occurring as a single cytogenetic abnormality has been associated with undifferentiated or biphenotypic acute leukemias and with an adverse prognostic outcome. We describe for the first time a case of B-cell common acute lymphoblastic leukemia (ALL) with trisomy 13 at diagnosis in an 18-year-old boy. The leukemic cells did not express myelocytic or T-cell associated antigens and no molecular abnormalities were detected. Following treatment, according to the GIMEMA ALL 0496 protocol, the patient achieved a brief (2 months) complete remission. At relapse, cytogenetic analysis showed karyotypic evolution that included two novel subclones carrying a del(6q), a del(7q), and an add(17q) in association with trisomy 13. In addition, immunophenotypic analysis revealed the coexpression of the CD33 and CD7 antigens on common ALL blasts, in accordance with other reported cases that displayed a predominant biphenotypic leukemia profile. The patient failed to obtain a second remission and died soon after due to infective complications. This report indicates that trisomy 13 can be found also in B-lineage ALL and underlines that this cytogenetic abnormality may identify a subgroup of male patients with clonal evolution potential and an adverse clinical outcome.

Adolescent↗
PubMed2003

Outcome prediction by immunophenotypic minimal residual disease detection in adult T-cell acute lymphoblastic leukaemia.

Flow-cytometric detection of minimal residual disease (MRD) identifies patients with high relapse risk in childhood acute lymphoblastic leukaemia (ALL). We studied the efficacy of this method in adult T-ALL treated with the Italian co-operative GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) LAL0496 protocol. Bone marrow samples from 53 patients were taken at fixed treatment time points and MRD was analysed using a leukaemia-specific immunophenotype (cytoplasmic-CD3/nuclear-terminal desoxynucleotidyl transferase). The median follow-up was 17 months (range 3-61) and a median of 4.5 analyses/patient was performed (range 3-12). Six out of 53 (11.3%) patients were refractory to treatment, 30/53 (56.6%) relapsed and 17/53 (32.1%) remain in continuous complete remission. The probability of relapse at 2 years for MRD-positive patients at preconsolidation was 81.5%vs 38.9% for MRD-negative patients (P = 0.00078). This risk was still 54.5% for MRD-positive vs 15.8% for MRD-negative patients pre-third reinduction (P = 0.0098) and 50.0% for MRD-positive vs 16.4% for MRD-negative patients pre-sixth reinduction (P = 0.032). The relapse-predicting value of MRD did not depend on features at diagnosis such as age, sex and leucocyte count. Our data suggest that immunophenotypic MRD monitoring in the first year of treatment is a useful outcome predictor for adult T-ALL patients.

Flow Cytometry↗
PubMed2003

A multiplex reverse transcriptase-polymerase chain reaction strategy for the diagnostic molecular screening of chimeric genes: a clinical evaluation on 170 patients with acute lymphoblastic leukemia.

BACKGROUND AND OBJECTIVES: In the last few years molecular methods have allowed the identification of leukemia-associated genetic lesions, which may represent the most accurate predictors of clinical outcome. These considerations strengthen the need for rapid identification of the abnormalities. Our aim was to demonstrate whether a modified multiplex reverse transcription polymerase chain reaction (RT-PCR) system might be successfully used to screen a large number of patients with acute lymphoblastic leukemia (ALL). DESIGN AND METHODS: In this study we adapted the multiplex RT-PCR assay, previously described by Pallisgaard et al., to detect all the most frequent genetic lesions with their characteristic splicing variants occurring in acute lymphoblastic leukemia, such as the MLL/AF4, MLL/ENL, BCR/ABL p190 (e1a2) and p210 (b2a2,b3a2) isoforms, E2A/PBX1, TEL/AML1, SIL/TAL1 and the novel NUP98/RAP1GDS1 transcript, recently described in a T-ALL leukemic subtype. RESULTS: We used the multiplex RT-PCR assay to screen 170 ALL patients (70 children and 100 adults). PCR positivity was detected in 67 (39%) of the 170 ALL patients studied. The comparison between cytogenetic and molecular analyses showed complete correspondence between the two assays in all patients with an evaluable karyotype. Finally, the observed incidence of genetic lesions in our ALL patients was similar to the frequency usually reported both in children and in adults with ALL. INTERPRETATION AND CONCLUSIONS: These results show that, compared to single RT-PCR reactions, our multiplex RT-PCR system allows rapid, specific, simultaneous as well as a less expensive, laborious and time-consuming detection of the most frequent fusion transcripts in ALL patients. Therefore, it might be recommended for rapid diagnostic molecular screening of large numbers of patients, such as those enrolled in multicenter, co-operative studies. Furthermore, we have shown that multiplex RT-PCR is an open system that can easily be adapted to detect new leukemic genes.

Adult↗
PubMed2002

Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia.

Fusions of the TET-proteins (TLS/FUS, EWSR1, and TAF15/RBP56) to different transcription factors are involved in various malignancies including Ewing's sarcoma, primitive neuroectodermal tumors, and acute myeloid leukemia. These are thought to arise through transcriptional deregulation, with the transcription factor defining the tumor phenotype. We show that, as result of a t(12;17)(p13;q11) or its variant t(12;22)(p13;q12), the transcription factor gene CIZ/NMP4 is recurrently involved in acute leukemia through fusion with either EWSR1 or TAF15. The fusions possess transforming properties in NIH3T3 cells but do not affect the expression of CIZ target genes, suggesting a contribution to oncogenesis that is independent of the transactivating properties of the fusion protein. These results also extend the involvement of TET-protein fusions to acute lymphoblastic leukemia and suggest a role for CIZ/NMP4 in lymphoid and myeloid development.

3T3 Cells↗
PubMed2002

MDR1 protein expression is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia.

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.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Philadelphia-positive acute lymphoblastic leukemia with multiple subclones including duplication of the Philadelphia chromosome and Abelson oncogene.

A case of Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL) with multiple subclones including duplication of the BCR-ABL1 fusion gene and of the Abelson oncogene (ABL1) is reported. Cytogenetically, two different rearrangements of chromosome 9 not involved in the t(9;22) were found in two subclones. In one subclone the normal 9 was lost and replaced by an acrocentric marker, which contained an additional copy of the BCR-ABL1 fusion gene. Reverse transcriptase polymerase chain reaction detected the fusion transcripts p210 (e13a2 junction) and p190 (e1a2 junction), whereas fluorescence in situ hybridization showed the major BCR-ABL1 junction in both Ph chromosomes, strongly suggesting that the presence of the p210 and p190 proteins in this case was due to mechanisms of alternative or mis-splicing at the transcriptional level. The second subclone showed the classic t(9;22) plus an add(9)(p24) containing two copies of the ABL1 gene. Other molecular events involving chromosome 9 were a monoallelic loss of JAK2 in both subclones and an additional loss of P15/P16 in the subclone with the acrocentric marker bearing the extra Ph chromosome.

Acute Disease↗