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Publications and source records attributed to Paolo Corradini.
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The introduction of imatinib mesylate has changed attitudes towards hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Information on the current use and results of HSCT is warranted. Data from 592 teams in 42 European countries described their use of HSCT for CML from 1990 to 2004. Outcomes were analyzed for 13,416 patients, with a median age of 36 years (range 1-71 years); 60% were male. The analysis considered three time cohorts, 1980 to 1990, 1991 to 1999 and 2000 to 2003. Survival, transplant-related mortality and relapse incidence were assessed at 20 years for the first cohort and compared at 2 years between the three cohorts. The numbers of HSCT for CML increased from 540 allogeneic HSCT in 1990 to 1,396 HSCT in 1999 and declined to 802 in 2004. One third of all patients and half of those with a low risk were alive at 20 years. Survival at 2 years has improved from 53% to 61% in the most recent years due to a reduction in transplant-related mortality from 41% to 30% in all patients and from 31% to 17% in low-risk patients. Stage, donor type, time interval, age and donor-recipient sex combination remain the main risk factors; patients with a risk score of 0 or 1 have a survival probability of 80% at 2 years. HSCT remains an important treatment option for patients with CML. The data describe the current status of this option and the outcome a patient can expect today. They provide an objective basis for decision making.
Propene-hexene copolymers crystallize in a new polymorphic form of isotactic polypropylene when the concentration of hexene is higher than nearly 10-15 mol %. The hexene units are included in the crystals, inducing an increase of density that allows crystallization of 3-fold helical chains in a trigonal unit cell according to the space group R3c or Rc, where the helical symmetry of the chains is maintained in the crystal lattice. The structure of this new form is similar to those of isotactic polybutene and polystyrene and does not crystallize in polypropylene homopolymer because it would have too low density. The crystal structure of isotactic polypropylene is therefore no longer an exception to the principles of polymer crystallography, but the new structure represents the fulfillment of these principles and indicates that the packing of polymer molecules is mainly driven by density.
OBJECTIVE: To explore new treatments specifically targeting malignant plasma cells (PCs), we examined CD52 antigen expression on primary PCs as well as multiple myeloma (MM) cell lines, and investigated in vivo the antimyeloma activity of alemtuzumab. MATERIALS AND METHODS: PCs were enriched from the marrow of MM patients (n = 39) according to CD138 expression and then analyzed by 3-color flow cytometry and quantitative PCR. The in vivo activity of alemtuzumab was evaluated in a xenotransplant model of MM in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. RESULTS: CD52 expression revealed a substantial heterogeneity in terms of both percentage of positive cells and fluorescence intensity, with 25/39 (64%) MM patients showing >or=30% CD138(+) PCs expressing the CD52 antigen (mean = 79%; range, 33-100%). Similarly to primary cells, cell lines showed heterogeneous CD52 expression. Expression of CD52 mRNA by quantitative PCR analysis strongly correlated with CD52 antigen detection by flow cytometry. In vivo, alemtuzumab treatment significantly increased the median survival of animals with an early- (64 vs 77 days, p <or= 0.0005) or advanced-stage (66 vs 75 days, p <or= 0.02) disease. CONCLUSION: We conclude that: 1) CD52 is expressed on PCs of a significant proportion of MM patients; 2) alemtuzumab used as a single agent exerts a good antitumor activity in NOD/SCID mice bearing an early-stage disease; and 3) alemtuzumab might have therapeutic potential in a subset of MM patients.
A new view of the concepts of crystallinity and crystals in synthetic macromolecules is discussed. In polymeric materials, crystallinity may be present with the concomitant occurrence of large amounts of structural disorder and in the absence of true three-dimensional long-range order. The structures of semicrystalline polymeric materials are discussed in terms of idealized limit models of crystals, where long-range order may be achieved for structural features that are not necessarily coincident with single atoms and are not necessarily point-centered. Typical examples of non-point-centered structural features are the straight lines corresponding to the chain axes of polymer molecules. This view explains the unusual ability of polymers to crystallize even in the presence of a high degree of structural disorder.
We retrospectively evaluated the efficacy of bortezomib in 23 patients with multiple myeloma who had relapsed after allografting. Bortezomib was given as single agent to 9 patients (39%) and in combination with steroids in the other 14 (61%). Major toxicities were thrombocytopenia (10/23, 43%) and peripheral neuropathy (12/23, 52%). The overall response rate was 61% (14/23), including 22% (5/23) immunofixation-negative complete remissions. No significant differences in toxicity and response rates were seen between patients treated with bortezomib plus steroids and bortezomib alone. After a median follow-up of 6 months, progression free survival was 6 months. Twenty-one patients are alive, two and five in continuous very good partial and complete remissions, respectively.
BACKGROUND: The objective of this study was to identify prognostic factors for predicting survival in patients with advanced renal cell carcinoma (RCC) who had undergone an allogeneic stem cell transplantation after failure on immunotherapy. METHODS: The authors studied 70 patients with advanced RCC who underwent allogeneic transplantation with a fludarabine-based, reduced-intensity regimen. Ten parameters were analyzed at the time of transplantation for their power to predict survival. Clinical features were examined first univariately; then, variables that were correlated significantly with survival in the univariate analysis were included in a multivariate Cox regression model. RESULTS: Factors that were found to be associated significantly with limited survival were performance status, the number of metastatic sites, the presence of mediastinal metastasis, hemoglobin level, C-reactive protein (CRP) level, lactate dehydrogenase (LDH) level, and neutrophil counts. All these variables were included in a multivariate Cox regression model, and three were retained in the final model. Patients were classified according to the score estimated by the final Cox model in two groups (above or below the median value): The median survival was 3.5 months for patients who had a poor prognosis patients versus 23 months for patients who had a good prognosis. CONCLUSIONS: The current findings suggested that three easily available parameters (performance status, CRP level, and LDH level) could be used to stratify patients with advanced RCC who are candidates for allografting and to assist clinicians in decision-making and selection of an appropriate treatment program.
PURPOSE: To study the antiangiogenic effect of thalidomide. PATIENTS AND METHODS: The expression of key angiogenic genes was studied in bone marrow endothelial cells (ECs) of patients with active and nonactive multiple myeloma (MM), monoclonal gammopathies unattributed/unassociated (MG[u]), diffuse large B-cell non-Hodgkin's lymphoma, in a Kaposi's sarcoma (KS) cell line, and in healthy human umbilical vein ECs (HUVECs) following exposure to therapeutic doses of thalidomide. RESULTS: Thalidomide markedly downregulates the genes in a dose-dependent fashion in active MMECs and KS cell line, but upregulates them or is ineffective in nonactive MMECs, MG(u)ECs, NHL-ECs, and in HUVECs. Secretion of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hepatocyte growth factor also diminishes according to the dose in culture conditioned media (CM) of active MMECs and KS, whereas it does not change in the other CM. CONCLUSION: Inhibition by thalidomide is probably confined to the genes of active MMECs and KS. This would account for its higher efficacy in these diseases.
OBJECTIVE: In vivo administration of alemtuzumab (an anti-CD52 antibody) is effective to decrease the incidence of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). However, posttransplant immune reconstitution is impaired, increasing the infection risk. We investigated the effect of in vivo administration of a low-dose alemtuzumab on GVHD prevention and kinetics of immune reconstitution. PATIENTS AND METHODS: Twenty-seven patients entered a pilot study employing reduced-intensity conditioning and low-dose alemtuzumab (15 or 7.5 mg/m2) before peripheral blood allo-SCT from human leukocyte antigen-identical or one antigen-mismatched sibling donors. All lymphoid subsets were longitudinally studied at 1-3, 6, 9, 12 months after transplantation. T-cell receptor (TCR) spectratyping and T-cell receptor excision circles (TRECs) were also analyzed at various time points after allo-SCT. RESULTS: All patients but one were engrafted. The probability of nonrelapse mortality at 100 days and 1 year were 7 and 11%, respectively; the overall survival at 2 years was 77%. The cumulative incidence of grade II-IV acute GVHD at day 100 was 11%. The overall incidence of chronic GVHD was 28%. The median time to achieve more than 200 CD4+/microL and 500 CD8+/microL were 6 and 9 months, respectively. Natural killer cells remained between the value of 300/microL and 500/microL throughout the period of follow-up whereas the median time to reach CD19+ blood concentrations of >200 cells/microL was 9 months. The normalization of TCR repertoire and increase of TREC counts began at 6 months after allo-SCT. CONCLUSION: We have shown that low-dose alemtuzumab is effective for GVHD prevention, but its use still impairs the immune reconstitution.
PURPOSE: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of malignancies characterized by a poor prognosis. We performed a pilot study to investigate the role of reduced-intensity conditioning (RIC) followed by allogeneic stem-cell transplantation in relapsed or refractory PTCLs. PATIENTS AND METHODS: We have conducted a phase II trial on 17 patients receiving salvage chemotherapy followed by RIC and allogeneic transplantation of hematopoietic cells. The RIC regimen consisted of thiotepa, fludarabine, and cyclophosphamide. The acute graft-versus-host disease prophylaxis consisted of cyslosporine and short course methotrexate. RESULTS: Patients had a median age of 41 years (range, 23 to 60 years). Two patients were primary chemorefractory, and 15 had relapsed disease; eight patients (47%) had a disease relapse after an autologous transplantation. After a median follow-up of 28 months from the day of study entry (range, 3 to 57 months), 14 of 17 patients were alive (12 in complete remission, one in partial remission, and one with stable disease), two died as a result of progressive disease, and one died as a result of sepsis concomitant to acute graft-versus-host disease. The estimated 3-year overall and progression-free survival rates were 81% (95% CI, 62% to 100%) and 64% (95% CI, 39% to 89%), respectively. The estimated probability of nonrelapse mortality at 2 years was 6% (95% CI, 1% to 17%). Donor lymphocyte infusions induced a response in two patients progressing after allografting. CONCLUSION: RIC followed by allogeneic stem-cell transplantation is feasible, has a low treatment-related mortality, and seems to be a promising salvage treatment for relapsed PTCL. These findings suggest that the existence of a graft-versus-T-cell lymphoma effect.
PURPOSE: To evaluate the prognostic relevance of molecular monitoring of minimal residual disease in indolent lymphomas receiving high-dose sequential chemotherapy and autografting. PATIENTS, MATERIALS, AND METHODS: A polymerase chain reaction- (PCR-)based strategy was used to evaluate the presence of residual tumor cells in a panel of 70 indolent lymphoma patients: 40 with follicular (FCL), 14 with small lymphocytic (SLL), and 16 with mantle-cell (MCL) lymphomas. They were treated either with first-line (n = 61) or second-line (n = 9) therapy with an intensified high-dose chemotherapy program followed by peripheral-blood progenitor cells autografting. The Bcl-1, Bcl-2, and immunoglobulin gene rearrangements were used as lymphoma-specific markers. Overall, a molecular marker was obtained from the diagnostic tissue in 60 of 70 patients (86%). Results The collection of PCR-negative cells and the achievement of posttransplantation molecular remission (MR) were common in patients with FCL subtype (54% and 70%, respectively), whereas they were not frequent among SLL and MCL (25% and 12.5%, respectively) patients. With a median molecular follow-up of 75 months, an 88% incidence of relapse was observed among patients never attaining MR. In contrast, relapse incidence was only 8% among patients attaining a durable MR (P <.005). At present, 26 patients (20 with FCL and six with non-FCL) are long-term survivors in absence of clinical and molecular disease. CONCLUSION: Our results indicate that among indolent lymphomas, FCL and non-FCL subtypes show a significantly different behavior in terms of MR achievement, and MR after intensive chemotherapy and autografting is predictive for a prolonged disease-free survival, whereas persistent PCR positivity is associated with a high risk of relapse.
The activity of recombinant human growth hormone (rhGH) in enhancing CD34(+) cell mobilization elicited by chemotherapy plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) was evaluated in 16 hard-to-mobilize patients, that is, those achieving a peak of circulating CD34+ cells 10/microL or less, or a collection of CD34(+) cells equal to or less than 2 x 10(6)/kg. Patients who had failed a first mobilization attempt with chemotherapy plus rhG-CSF (5 microg/kg/d) were remobilized with chemotherapy plus rhG-CSF and rhGH (100 microg/kg/d). As compared with rhG-CSF, the combined rhGH/rhG-CSF treatment induced significantly higher (P < or =.05) median peak values for CD34(+) cells/microL (7 versus 29), colony-forming cells (CFCs)/mL (2154 versus 28,510), and long-term culture-initiating cells (LTC-ICs)/mL (25 versus 511). Following rhG-CSF and rhGH/rhG-CSF, the median yields of CD34(+) cells per leukapheresis were 1.1 x 10(6)/kg and 2.3 x 10(6)/kg (P < or =.008), respectively; the median total collections of CD34(+) cells were 1.1 x 10(6)/kg and 6 x 10(6)/kg (P < or =.008), respectively. No specific side effect could be ascribed to rhGH, except a transient hyperglycemia occurring in 2 patients. Reinfusion of rhGH/rhG-CSF-mobilized cells following myeloablative therapy resulted in prompt hematopoietic recovery. In conclusion, our data demonstrate that in poor mobilizers addition of rhGH to rhG-CSF allows the patients to efficiently mobilize and collect CD34(+) cells with maintained functional properties.
Stereoselective polymerization of 1-alkenes was discovered 50 years ago. However, a detailed knowledge of the traditional and industrially used Ziegler-Natta catalytic systems is still missing. Recently, well-defined homogeneous and octahedral complexes that polymerize propene to polypropylenes with microstructures extremely similar to those of polymers produced with the traditional catalysts were discovered. These catalysts offer the exciting opportunity to achieve insights into the mechanism of stereocontrol operative with the traditional catalytic systems.
OBJECTIVES: Perceiving the need for rigorous recommendations to facilitate decisions concerning the management of patients with multiple myeloma (MM), the Italian Society of Hematology (SIE) and the two affiliate societies (SIES and GITMO) commissioned a project to develop guidelines for the therapy of MM using evidence-based knowledge and consensus formation techniques. METHODS: After a comprehensive systematic review of 1,450 papers, an Expert Panel formulated and graded sixty recommendations according to the supporting evidence. Evidence gaps were filled with twenty-two consensus-based statements. High grade recommendations (grade A) are reported below. RESULTS: Treatment should be immediately initiated in MM patients with related organ damage: those patients aged below 65 years who do not have severe co-morbidities should receive autologous stem cell transplantation, while patients not candidates for autologous stem cell transplantation should receive oral melphalan and prednisone. Interferon-a should not be associated with conventional chemotherapy, but it can be offered with or without steroids as a maintenance therapy to patients who have reached a plateau phase. High-dose dexamethasone-containing regimens or high-dose dexamethasone alone are recommended as a first-line therapy when cytoreduction is urgently required (i.e., MM with spinal cord compression or with rapidly progressive renal failure). MM patients with moderate-to-severe anemia should receive erythropoietin, while patients with bone disease or osteopenia should receive long-term bisphophonates. Recommendations for the management of the clinical manifestations caused by the monoclonal protein (i.e. hyperviscosity, cast nephropathy, AL amyloidosis) and of solitary bone and extramedullary plasmacytoma were also elaborated. CONCLUSIONS: A substantial proportion of clinical care for MM can be guided by evidence-based treatment recommendations.
BACKGROUND AND OBJECTIVES: Tumor necrosis factor a is one of the principal cytokines involved in the pathogenesis of acute graft-versus-host-disease (GVHD). Infliximab is an antibody to this cytokine. DESIGN AND METHODS: We performed a retrospective analysis to evaluate the activity of infliximab in 32 patients with severe steroid-refractory acute GVHD. The patients received a median of 3 weekly courses of infliximab. The main organs involved in the patients were skin (n=2) liver (n=1), bowel (n=19), liver and bowel at the same stage (n=10). RESULTS: Nineteen out 32 patients (59%) responded to infliximab with 6 (19%) complete and 13 (40%) partial responses. Age younger than 35 years, intestinal involvement and a longer time between hematopoietic stem cell transplantation and infliximab administration were factors predicting a favorable response. Infective episodes developed in 23/32 (72%) patients. All the 13 unresponsive patients died of GVHD shortly after infliximab. Thirteen of 19 responsive patients were alive at a median follow-up of 449 days (range 155-842) after infliximab, with no signs of chronic GVHD (n=5), limited (n=5) or extensive involvement (n=3). Six patients who responded subsequently died, one of chronic lung GVHD, the others of vascular complications or infections (2 fungal diseases). INTERPRETATION AND CONCLUSIONS: We conclude that infliximab is active in the treatment of severe steroid-refractory acute GVHD, particularly when the intestine is involved. Infections commonly followed its administration. The clinical activity of infliximab and the possibility that it increases the risk of infections are worth investigating in prospective trials.
Patients in complete clinical remission after myeloablative allogeneic stem cell transplantation (allo-SCT) were enrolled in a longitudinal study to assess the predictive value of molecular monitoring. Using polymerase chain reaction (PCR) for immunoglobulin gene rearrangements it was possible to generate a clone-specific molecular marker in 48 of 70 patients. Of these 48 patients, 16 (33%) attained durable PCR-negativity after transplantation, whereas 13 (27%) remained persistently PCR-positive and 19 (40%) showed a mixed pattern. The cumulative risk of relapse at 5 years was 0% for PCR-negative patients, 33% for PCR-mixed patients, and 100% for PCR-positive patients. Within the group studied it was not possible to identify any clinical feature predictive of durable PCR-negativity. We believe that these findings could prompt the design of prospective studies to evaluate if the treatment of molecular disease can extend remission duration and survival.
PURPOSE: To assess whether nonneoplastic Bcl-2/IgH rearrangements act as a confounding factor in the setting of minimal residual disease analysis by evaluating their incidence in a panel of lymphoma-free subjects, including cancer-free donors and chemotherapy-naive and chemotherapy-treated cancer patients. PATIENTS AND METHODS: A total of 501 nonlymphoma subjects have been assessed: 258 cancer-free patients and 243 patients with malignancies other than lymphoma, 112 of whom were chemotherapy-naive. Patients were primarily assessed by nested polymerase chain reaction (PCR), followed by real-time quantitative PCR if they scored positive. In addition, six initially PCR-positive cancer-free donors were prospectively reassessed by qualitative and quantitative PCR after 30 and 60 days. RESULTS: The overall incidence of Bcl-2/IgH positivity was 9.6%, with a median number of 11 rearrangements per 1,000,000 diploid genomes (range, 0 to 2,845 rearrangements), as assessed by real-time PCR. The incidence was similar in healthy subjects and cancer patients at diagnosis (12% and 12.5%; P = not significant). In contrast, the incidence of this translocation was only 2.3% in chemotherapy-treated patients (P <.001). In addition, three initially PCR-positive cancer-free donors showed persistence of their rearrangements when assessed after 30 and 60 days. CONCLUSION: The low incidence of nonneoplastic Bcl-2/IgH rearrangements following chemotherapy provides further evidence of the prognostic role of persistent PCR-positivity in the posttreatment molecular follow-up of follicular lymphoma patients.
Mantle cell lymphoma (MCL) is rarely cured with standard-dose chemotherapy. From January 1997 to February 2000, 28 previously untreated advanced-stage MCL patients younger than 61 years of age were treated at 9 Italian hematologic departments with 3 cycles of standard-dose debulking chemotherapy followed by a high-dose rituximab-supplemented sequence (R-HDS) including intravenous administration of high-dose cyclophosphamide, high-dose cytarabine, high-dose melphalan, and high-dose mitoxantrone plus melphalan. Study end points included toxicity, clinical and molecular response rates, long-term event-free survival (EFS), and overall survival (OS) rates, as well as the ability to harvest tumor-free peripheral blood stem cells. Optimal amounts of polymerase chain reaction-negative (PCR-negative) CD34+ cells were collected from all 20 informative patients. One patient died of toxicity. All 27 patients assessable for response achieved a complete response (CR), of which 24 remain in continuous complete remission (CCR) after a median follow-up of 35 months. Three patients had transient evidence of PCR-detectable disease in the bone marrow. The OS and EFS rates at 54 months were 89% and 79%, respectively. These results compare with the 42% OS rate and the 18% EFS rate observed in 35 age-matched historic controls treated with standard-dose chemotherapy at the participating centers. The use of rituximab in combination with high-dose chemotherapy represents a very effective in vivo purging method. The R-HDS regimen can be safely applied in a multicenter hematology setting and leads to long-term EFS and OS in the majority of patients with an otherwise incurable disease.