Search

The effects of radiotherapy (RT) after chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) remain unclear; several trials have yielded conflicting results. This study examined the effect of RT after cyclophosphamide, doxorubicin, vincristine, and prednisone + rituximab (R-CHOP) treatment on event-free (EFS) and overall (OS) survival. Data from 216 patients with DLBCL who were enrolled in two clinical trials at Italian Lymphoma Study Group sites and were subjected to six R-CHOP cycles and involved-field radiotherapy (IFRT) were retrospectively analyzed. IFRT treatment yielded significant EFS benefit, with a 66% reduction in the risk of death and/or disease progression. Cox analysis, when adjusted for age, gender, stage, performance status (PS), lactate dehydrogenase (LDH), and disease bulk, confirmed the significant EFS benefit of IFRT. The role of RT in DLBCL in the rituximab era is unclear. Future studies must take into account new radiation techniques and the response to chemotherapy based on functional imaging. Prospective randomized trials incorporating response-adapted therapy and modern radiation techniques are needed.

The aim of this study was to show a lower incidence of febrile episodes in multiple myeloma patients receiving lenograstim vs. filgrastim after high-dose cyclophosphamide for stem cell mobilization. Patients treated with cyclophosphamide were randomly assigned to receive filgrastim or lenograstim. Primary endpoint was the incidence of febrile episodes. 5.1% patients developed a febrile episode, 9.1% with filgrastim and 1.1% with lenograstim. Lenograstim group presented a significantly higher absolute CD34+ cell number compared with the filgrastim group but no differences were detected for collection efficacy. The study demonstrated a lower incidence of febrile episodes with lenograstim compared to filgrastim., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

To retrospectively assess the efficacy of bendamustine alone and with rituximab (R-B), 109 patients with relapsed chronic lymphocytic leukaemia (CLL) were enrolled in 24 Italian centres. The median age was 66 years (range 39-85). Forty-three percent of patients had relapsed and 57% were resistant (median previous therapies = 3; range 1-8). Twenty-two patients received bendamustine alone and 87 patients received R-B (median B dosage: 100 mg/m(2) per day, range 90-130 mg/m(2) per day). The overall response rate was 69·6% (complete response 28·6%; partial response 41%), and was significantly higher in patients treated with R-B (P = 0·014) and in those responsive to the previous treatment (P=0·04). After a median follow-up of 7·9 months (range 1-148), the median progression-free survival was 16 months and the median duration of response was 13 months. Median overall survival (OS) was 16·8 months for the whole cohort; patients not responding to the treatment had a significantly worse outcome than those who attained a response (P = 0·0001). In multivariate analysis, only resistant disease status at start of bendamustine treatment (HR 3·2, 95% CI 1·4-7·3, P = 0·006) had an independent prognostic value for OS. Toxicity was manageable and mostly haematological. In conclusion, in our experience R-B was an effective and well-tolerated treatment for relapsed/refractory CLL patients, producing a remarkable high CR rate and mild toxicity., (© 2011 Blackwell Publishing Ltd.)

Highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3), are expressed in a recurrent fraction of patients affected by chronic lymphocytic leukemia (CLL). We investigated the IGHV status of 1131 productive IG rearrangements from a panel of 1126 CLL patients from a multicenter Italian study group, and correlated the presence and class of HCDR3 stereotyped subsets with the major cytogenetic alterations evaluated by FISH, molecular prognostic factors, and the time to first treatment (TTFT) of patients with early stage disease (Binet A). Stereotyped HCDR3 sequences were found in 357 cases (31.7%), 231 of which (64.7%) were unmutated. In addition to the previously described subsets, 31 new putative stereotypes subsets were identified. Significant associations between different stereotyped HCDR3 sequences and molecular prognostic factors, such as CD38 and ZAP-70 expression, IGHV mutational status and genomic abnormalities were found. In particular, deletion of 17p13 was significantly represented in stereotype subset #1. Notably, subset #1 was significantly correlated with a substantially reduced TTFT compared to other CLL groups showing unmutated IGHV, ZAP-70 or CD38 positivity and unfavorable cytogenetic lesions including del(17)(p13). Moreover, subset #2 was strongly associated with deletion of 13q14, subsets #8 and #10 with trisomy 12, whereas subset #4 was characterized by the prevalent absence of the common cytogenetic abnormalities. Our data from a large and representative panel of CLL patients indicate that particular stereotyped HCDR3 sequences are associated with specific cytogenetic lesions and a distinct clinical outcome.

Aim: The lack of sensitivity of chronic myeloid leukemia (CML) stem cells to imatinib mesylate (IM) commonly leads to drug dose escalation or early disease relapses when therapy is stopped. Here, we report that packaging of IM into a biodegradable carrier based on polyelectrolyte microcapsules increases drug retention and antitumor activity in CML stem cells, also improving the ex vivo purging of malignant progenitors from patient autografts., Materials & Methods: Microparticles/capsules were obtained by layer-by-layer (LbL) self-assembly of oppositely charged polyelectrolyte multilayers on removable calcium carbonate (CaCO(3)) templates and loaded with or without IM. A leukemic cell line (KU812) and CD34(+) cells freshly isolated from healthy donors or CML patients were tested., Results & Discussion: Polyelectrolyte microcapsules (PMCs) with an average diameter of 3 microm, fluorescently labelled multilayers sensitive to the action of intracellular proteases and 95-99% encapsulation efficiency of IM, were prepared. Cell uptake efficiency of such biodegradable carriers was quantified in KU812, leukemic and normal CD34(+) stem cells (range: 70-85%), and empty PMCs did not impact cell viability. IM-loaded PMCs selectively targeted CML cells, by promoting apoptosis at doses that exert only cytostatic effects by IM alone. More importantly, residual CML cells from patient leukapheresis products were reduced or eliminated more efficiently by using IM-loaded PMCs compared with freely soluble IM, with a purging efficiency of several logs. No adverse effects on normal CD34(+) stem-cell survival and their clonogenic potential was noticed in long-term cultures of hematopoietic progenitors in vitro., Conclusion: This pilot study provides the proof-of-principle for the clinical application of biodegradable IM-loaded PMC as feasible, safe and effective ex vivo purging agents to target CML stem cells, in order to improve transplant outcome of resistant/relapsed patients or reduce IM dose escalation.

Inhibition of multiple myeloma (MM) plasma cells in their permissive bone marrow microenvironment represents an attractive strategy for blocking the tumor/vessel growth associated with the disease progression. However, target specificity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)-receptor beta (PDGFRbeta) and pp60c-Src as shared constitutively activated tyrosine-kinases (TKs) in plasma cells and endothelial cells (ECs) isolated from MM patients (MMECs). Our cellular and molecular dissection showed that the PDGF-BB/PDGFRbeta kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Interestingly, pp60c-Src TK-activity was selectively induced by VEGF in MM tumor and ECs, and the use of small-interfering (si)RNAs validated pp60c-Src as a key signaling effector of VEGF loop required for MMEC survival, migration, and angiogenesis. We also assessed the antitumor/vessel activity of dasatinib, a novel orally bioactive PDGFRbeta/Src TK-inhibitor that significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel antimyeloma drugs (ie, melphalan, prednisone, bor-tezomib, and thalidomide). Overall data highlight the biologic and therapeutic relevance of the combined targeting of PDGFRbeta/c-Src TKs in MM, providing a framework for future clinical trials.

Purpose: Vasculogenesis is a physiologic process typical of fetal development in which new blood vessels develop from undifferentiated precursors (or angioblasts). In tumors, near angiogenesis, vasculogenesis contributes to the formation of the microvascular plexus that is important for diffusion. Here, we show that hematopoietic stem and progenitor cells (HSPC) of multiple myeloma (MM) patients are able to differentiate into cells with endothelial phenotype on exposure to angiogenic cytokines., Experimental Design: Circulating HSPCs were purified with an anti-CD133 antibody from patients with newly diagnosed MM before autologous transplantation and exposed to vascular endothelial growth factor (VEGF), fibroblast growth factor-2 and insulin-like growth factor in a 3-week culture., Results: HSPCs gradually lost CD133 expression and acquired VEGF receptor-2, factor VIII-related antigen, and vascular endothelial-cadherin expression. The expression pattern overlapped with paired MM endothelial cells (MMEC). During culture, cells adhered to fibronectin, spread, and acquired an endothelial cell shape. Differentiated HSPCs also became capillarogenic in the Matrigel assay with maximal activity at the third week of culture. Bone marrow biopsies revealed HSPCs inside the neovessel wall in patients with MM but not in those with monoclonal gammopathy of undetermined significance., Conclusions: In patients with MM, but not in those with monoclonal gammopathy of undetermined significance, HSPCs contribute to the neovessel wall building together with MMECs. Therefore, besides angiogenesis, HSPC-linked vasculogenesis contributes to neovascularization in MM patients. Tentatively, we hypothesize that in HSPC cultures a multipotent cell population expressing low VEGF receptor-2 levels corresponds to the endothelial progenitor cell precursor and seems to be the MMEC precursor.

Autoimmune hemolytic anemia (AIHA) is a well-known complication of chronic lymphocytic leukemia (CLL). In recent years the anti-CD20 monoclonal antibody rituximab has been used for the therapy of steroid-refractory AIHA and autoimmune thrombocytopenia, either idiopathic or in association with CLL. We report the results of rituximab treatment for 14 patients suffering from CLL-associated AIHA. They developed a direct antiglobulin test positive AIHA at a mean time of 47 months (range 0-135 months) from the diagnosis of CLL. In 3 cases AIHA was diagnosed at the same time as CLL. Only 1 patient had fludarabine-related AIHA. All patients received steroids as first-line treatment. At a mean time of 46 days (range 1-210 days) from the diagnosis of AIHA all patients received rituximab at a dosage of 375 mg/m(2)/weekly for 4 weeks. All patients except 3 (2 died of cardiac failure or sepsis soon after the third cycle and 1 HCV-positive patient experienced a rise in serum amino transferases) completed the scheduled four programmed cycles. First injection side effects of rituximab were minimal. All but 2 patients showed an increase in hemoglobin levels in response to rituximab (mean value 3.6 g/dl; range 0.7-10 g/dl) and a reduction in the absolute lymphocyte count and lymph nodes and spleen volume. Nine patients required packed red cell transfusions before starting rituximab; 5 no longer needed transfusions just after the second cycle and another patient after the fourth cycle. Three patients (22%) were considered to fully respond and 7 (50%) only responded partially. At a mean follow-up of 17 months, 8 patients were still alive, 6 of them transfusion-free. Our results prove that the anti-CD20 monoclonal antibody is an effective and well-tolerated alternative treatment for CLL-associated AIHA.

Objectives: To compare two different schedules of two different anthracycline-containing regimens, where length of treatment is modulated according to the international prognostic index (IPI) in patients with aggressive non-Hodgkin's Lymphoma (NHL)., Methods: In 1993 the Gruppo Italiano per lo Studio dei Linfomi (GISL) started a randomized 2 x 2 factorial phase III clinical trial for patients with newly diagnosed aggressive NHL comparing ProME(Epidoxorubicin)CE-CytaBOM (PE-C) to ProMI(Idarubicin)CE-CytaBOM (PI-C) and a fixed to a flexible treatment schedule where anthracycline dose was to be modulated according to observed hematological toxicity. Patients with low or low-intermediate IPI (IPI 0-2) and those with intermediate-high or high IPI (IPI 3-5) should receive six or eight courses, respectively. Involved-field radiotherapy was allowed for patients with initial bulky disease or with residual masses., Results: Three hundred and fifty-six patients were registered into the study and randomized. Patients were well balanced among the four study arms in terms of clinical characteristics and prognostic factors. Three hundred and forty-five patients were available for evaluation of study endpoints. At the end of induction therapy complete remission rate was 61%, 5-year failure-free survival (FFS) rate was 40% and 5-year overall survival (OS) rate was 59%; no differences were observed according to treatment arms. Patients in the flexible arm received higher dose intensity of anthracycline (P < 0.001) with no apparent increase in toxicity. However, the flexible schedule was not superior to the fixed one. Patients with IPI 3-5 showed lower response rates (45% vs. 67%: P < 0.0001) and lower 5-year FFS (29% vs. 45%: P < 0.0001) compared to those with IPI 0-2., Conclusions: six courses of fixed or flexible PE-C or PI-C can determine a promising success rate in patients with advanced aggressive NHL with IPI 0-2, whereas the same regimens are less effective in patients with IPI 3-5, even if two additional courses are delivered. For the latter group of patients innovative approaches are warranted.

Patients with aggressive NHL who fail initial treatment or subsequently relapse have a very poor outcome and less than 20-25% achieve a prolonged disease-free interval with salvage therapies. To improve the outcome of patients with refractory aggressive NHL not suitable for High Dose Therapy (HDT) and Autologous Stem Cell Transplant (ASCT), the efficacy of a combination of gemcitabine, vinorelbine, procarbazine and prednisone (ViGePP) were tested. Between November 1999 and September 2002, 69 patients with relapsed or refractory aggressive NHL were treated with ViGePP regimen, every 4 weeks up to six courses. At the end of planned chemotherapy patients could receive additional radiotherapy on residual masses or on sites of previously bulky disease. Sixty-six patients were available for evaluation of study end-points. Thirty patients were refractory to therapy and 36 patients had relapsed after remission obtained with previous therapy. At the end of therapy, complete remission (CR) rate was 23%, 3-year relapse free survival rate was 40% and 3-year overall survival rate was 25% for the whole series (29% and 20% for relapsed and refractory patients, respectively). Patients achieving CR with ViGePP had a significantly better survival as compared with the remaining ones (p = 0.0003). ViGePP as used in the present setting has demonstrated a promising activity, comparable to other conventional dose regimens. Although CR was achieved only in a minority of patients, this was durable in a significant proportion of them. This regimen should be tested in less heavily pre-treated patients and probably in combination with new active agents such Rituximab. Further developments of this combination are warranted.

Primary breast lymphomas (PBL) are uncommon neoplasms. Seven PBL were diagnosed between March 1993 and October 2002. A lumpectomy (n=4) or radical mastectomy (n=3) was performed; 5 patients were in clinical stage (CS) II and 2 in CS IV; 6 patients received the CEOP regimen (cyclophosphamide, vincristine, epirubicin and prednisone) after surgery and 4 also had additional radiotherapy; 1 patient did not receive any treatment after local excision. Five patients (71%) achieved complete remission and 2 (29%) partial remission, with an overall response rate of 100%. All remitter patients are alive and well after a median follow-up of 75 months (range 10--121 months). Two patients in partial remission died of progressive disease. After a median follow-up of 99 months (range 84--111 months) for surviving patients, the 10 year overall and disease-free survival rates are both 71%, with 5 patients well and still free of disease. We conclude that the optimal sequence of full-dose anthracycline-containing regimens and radiation therapy should be the treatment of choice for patients with PBL.

Objective: The aim of this phase I study was to find the maximum tolerated dose of weekly docetaxel in association with estramustine in hormone-refractory prostate cancer., Methods: Eleven patients with hormone-refractory prostate cancer were treated with escalating weekly doses of docetaxel (level I, 3 patients, 30 mg/m2; level II, 3 patients, 35 mg/m2, level III, 3 patients, 40 mg/mz; level IV, 2 patients, 45 mg/m2) associated with fixed dosage of estramustine (840 mg/day)., Results: In level I, there was only one episode of grade 3 neutropenia; grade 1 nausea and vomiting were registered in 1 patient; in 1 patient mild edema of the lower limbs was noted. In level II, grade 2 stomatitis and grade 1 sensory symptoms occurred in 1 patient, and grade 1 edema in 1 case. In level Ill, grade 2 edema was noted in 2 patients, damage to nails in 1 patient, asthenia in 1 patient, grade 1 neuropathy in 2 patients, and grade 1 nausea in 1 patient. In level IV, grade 2 edema was present in 1 patient, grade 3 edema in 1 patient, changes with fall of nails and grade 2 erythema of face in 2 patients, asthenia in 2 patients, grade 1 neuropathy in both patients. Nine patients had a more than a 50% decrease in PSA after 2 cycles of therapy., Conclusions: The results of the study suggest a good tolerability of weekly 35 Mg/m2 docetaxel in hormone-refractory prostate cancer in association with estramustine.

High-dose chemotherapy followed by autologous bone marrow or peripheral blood progenitor cell transplantation represents a recognized option in the treatment of solid tumors and hematologic diseases. Patients receiving high-dose chemotherapy are traditionally supported with parenteral nutrition with the aim to prevent malnutrition secondary to gastrointestinal toxicity and metabolic alterations induced by the conditioning regimens. Nevertheless, well-defined guidelines for its use in this clinical setting are lacking and there are several areas of controversy.

Background: Based on the results of previous phase I studies, in the current phase II trial we evaluated the efficacy and toxicity of cisplatin plus weekly docetaxel in the treatment of advanced non-small cell lung cancer (NSCLC)., Patients and Methods: The eligibility criteria for the study included newly diagnosed stage IIIB/IV NSCLC, age < or = 75 years, Eastern Cooperative Oncology Group performance status of 0-2, adequate organ functions, and signed informed consent. The chemotherapy regimen consisted of cisplatin, 80 mg/m2 on day 1, and docetaxel, 25 mg/m2 on days 1, 8 and 15 every 4 weeks., Results: Between January 2002 and December 2003, 31 patients with NSCLC were enrolled in the study. An objective response rate of 40% (95% CI, 21-60) was obtained in 27 assessable patients. The median time to progression was 6.4 months (range, 2.5-26.3) and median overall survival was 10.01 months (range, 5-28.3). The regimen was well tolerated with no grade 4 toxicity., Conclusions: Cisplatin plus weekly docetaxel is an effective and well-tolerated regimen in chemo-naive patients with advanced NSCLC. A phase III study of weekly versus the conventional regimen of every three weeks should be conducted to compare the survival benefits, toxicity profile and quality of life.

We report a case of Guillain-Barré Syndrome (GBS) which appeared after mobilization therapy in a patient with B-cell chronic lymphocytic leukemia (B-CLL). After obtaining a partial remission with four cycles of fludarabine at standard dose, the patient underwent to high-dose Cytoxan in order to mobilize CD34+ hematopoietic progenitor cells. During neutropenia the patient experienced fever of unknown origin (FUO) and subsequently developed GBS with normalization of his neurologic condition after 2 months. It is possible that a viral-induced activation of an antigen-specific T and B-cell clone caused a local inflammation and toxicity of Schwann cells with demyelination and axonal damage with a self-limited course.

We report an episode of severe bradycardia that occurred in a 49-year-old woman with fever and malignant jaundice during antibiotic therapy with linezolid, a new oxazolidinone with activity against Gram-positive cocci. In our case, the strict temporal dependence between bradycardia and linezolid therapy seems to provide strong evidence for a causal relationship. To our knowledge, this is the first report of linezolid-induced bradycardia. This adverse event confirms that the new antibiotic linezolid should be administered with caution in patient with jaundice and hepatic insufficiency.

Purpose: To determine whether high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT) should be included in the initial consolidative treatment of patients with advanced, unfavorable Hodgkin's lymphoma (HL)., Patients and Methods: One hundred sixty-three patients achieving complete remission (CR) or partial remission (PR) with four initial courses of doxorubicin, bleomycin, vinblastine, and dacarbazine, or other doxorubicin-containing regimens, were randomly assigned to receive HDT plus ASCT (83 patients) versus four courses of conventional chemotherapy (80 patients). Unfavorable HL was defined as the presence of at least two of the following poor prognostic factors: high lactate dehydrogenase level, large mediastinal mass (greater than at least 33% of the thoracic diameter), more than one extranodal site, low hematocrit level, and inguinal involvement., Results: At the end of the treatment program, 92% of patients in arm A and 89% in arm B achieved a CR (P =.6). After a median follow-up of 48 months, the 5-year failure-free survival rates were 75% (95% confidence interval [CI], 65 to 85) in arm A and 82% (95% CI, 73 to 90) in arm B (P =.4). The 5-year overall survival rates were 88% (95% CI, 80 to 96) in arm A and 88% (95% CI, 79 to 96) in arm B (P =.99). The 5-year relapse-free survival rates were 88% in arm A (95% CI, 80 to 96) and 94% in arm B (95% CI, 88 to 100), and the difference was not significant (P =.3)., Conclusion: Patients with advanced unfavorable HL achieving CR or PR after four courses of doxorubicin-containing regimens have a favorable outcome with conventional chemotherapy. No benefit from an early intensification with HDT and ASCT was shown.

Background: The objective of the current study was to evaluate in a multicenter setting the feasibility and efficacy of a high-dose sequential (HDS) chemotherapy regimen that combined intensive debulking and high-dose therapy (HDT) with peripheral blood progenitor cell (PBPC) autografting in patients with refractory or recurrent Hodgkin lymphoma (HL)., Methods: Data were collected from 102 patients with HL who were treated with the HDS regimen at 14 centers associated with the Intergruppo Italiano Linfomi. Twenty-four patients had primary refractory HL, 59 patients had their first recurrence of HL (within 1 year in 32 patients and > 1 year in 27 patients), and 19 patients had multiple disease recurrences. The HDS regimen included the sequential delivery of high-dose (hd) cyclophosphamide with PBPC harvesting, methotrexate, etoposide, then HDT (usually hd mitoxantrone plus L-phenylalanine mustard) with PBPC autografting. In addition, radiotherapy was delivered to 36 patients at sites of bulky or persistent disease., Results: Ninety-two patients (90%) completed the HDS program. There were five toxic deaths (treatment-related mortality rate, 4.9%) and six secondary malignan cies (five patients developed myelodysplastic syndrome/acute myelogenous leukemia, and one patient developed colorectal carcinoma). At a median follow-up of 5 years, the 5-year overall survival (OS) and event-free survival (EFS) projections were 64% (95% confidence interval [95% CI], 54-74%) and 53% (95% CI, 43-63%), respectively. Patients with their first recurrence had the most favorable outcome, with 5-year OS and EFS projections of 77% (95% CI, 66-88%) and 63% (95% CI, 50-76%), respectively. There were no significant differences between patients with early first recurrence and late first recurrence. The poorest outcome was observed in patients with refractory HL, with 5-year OS and EFS projections of 36% (95% CI, 16-55%) and 33% (95% CI, 14-52%), respectively. Patients who received HDS chemotherapy after multiple recurrences had an intermediate outcome. Multivariate analysis showed that refractory disease and systemic symptoms at the time of initial presentation were associated significantly associated with poor OS and EFS., Conclusions: The use of HDS chemotherapy for patients with refractory and/or recurrent HL is feasible at the multicenter level. The combination of intensive debulking and HDT with PBPC autografting offers a good chance of prolonged disease free survival for patients with their first recurrence of HL., (Copyright 2003 American Cancer Society.)

B-cell chronic lymphoproliferative disorders have been recognized as a heterogeneous group of neoplastic diseases affecting the lymphoid system. They are frequently characterized by leukemic manifestations with peripheral blood and/or bone marrow involvement. B-cell chronic lymphocytic leukemia (B-CLL), a disease which is now accepted as derived from immunologicallycompetent antigen-activated B-cells, is the most common in the western countries. Although for several decades it was considered as a unique entity, a body of evidences is now emerging indicating the biological heterogeneity of B-CLL. Molecular and immunophenotypic data induce to consider two main subgroups of B-CLL exist at the cellular level: in fact, B-CLL cases can be divided into two categories according to IgV gene mutation status. One group develops from "memory" B-cells after antigenic stimulation in the germinal center of secondary follicles, displays mutated gene IgV and lacks CD38 expression; the second one derives from the so-called "naïve" antigen inexperienced B-cells, does not present IgV gene mutations and displays CD38 surface molecule. The two groups seem to be characterised by different clinical outcomes with the "mutated" group expected to have a more benign course than that arising from a "naïve" B-cell. Thus, the definition of the biological features of these different groups could be of help for clinicians in order to recognize patients needing more intensive therapeutic approaches.

Background and Objectives: This multinational retrospective study compares the outcomes of patients with primary mediastinal large B-cell lymphoma (PMLBCL) with sclerosis after first-generation (dose-intensive regimens), third-generation (alternating regimens) and high-dose chemotherapy strategies, frequently with adjuvant radiation therapy., Design and Methods: Between August 1981 and December 1999, a total of 426 previously untreated patients with confirmed diagnosis were enrolled in 20 institutions to receive combination chemotherapy with either first generation (CHOP or CHOP-like) regimens, third generation (MACOP-B, VACOP-B, ProMACE CytaBOM) regimens or high-dose chemotherapy (HDS/ABMT)., Results: With chemotherapy, complete response (CR) rates were 49% (50/105), 51% (142/277) and 53% (23/44) with first generation, third generation and high-dose chemotherapy strategies, respectively; partial response (PR) rates were 32%, 36% and 35%, respectively. All patients who achieved CR and 124/142 (84%) with PR had radiation therapy on the mediastinum. The final CR rates became 61% for CHOP/CHOP-like regimens, 79% for MACOP-B and other regimens, and 75% for HDS/ABMT. After median follow-ups from attaining CR of 48.5 months for CHOP/CHOP-like regimens, 51.7 months for MACOP-B type regimens and 32.4 months for HDS/ABMT, relapses occurred in 15/64 (23%), 27/218 (12%) and 0/33 (0%) patients, respectively. Projected 10-year progression-free survival rates were 35%, 67% and 78%, respectively (p=0.0000). Projected 10-year overall survival rates were 44%, 71% and 77%, respectively (p=0.0000), after median follow-ups from diagnosis of 52.3 months, 54.9 months and 35.8 months, respectively., Interpretation and Conclusions: In patients with PMLBCL with sclerosis, MACOP-B plus radiation therapy may be a better strategy than other treatments; these retrospective data need to be confirmed by prospective studies. The encouraging survival results after high dose chemotherapy require confirmation in selected high-risk patients.

Single-center experiences have shown that intensified treatments with autologous transplantation are a promising therapeutic strategy for patients with high-risk follicle-center lymphoma (FCL) at diagnosis, whereas data from prospective multicenter trials are still lacking. This paper describes the results of a prospective multicenter study of an intensified purging-free high-dose sequential (i-HDS) chemotherapy schedule with peripheral blood progenitor cell (PBPC) autografting. The main feature of this program is harvesting stem cells after intensified chemotherapeutic debulking, with no ex vivo manipulation of PBPCs. Ninety-two previously untreated patients aged 60 or younger with advanced-stage FCL were enrolled by 20 Italian centers and evaluated on an intention-to-treat basis. i-HDS proved feasible with limited toxicity (87% patients completed the planned treatment schedule). i-HDS led to a complete remission rate of 88%. The projected overall survival and disease-free survival (DFS) were, respectively, 84% and 67% at 4 years. Centralized molecular analysis showed that polymerase chain reaction-negative harvests could be collected in 47% of cases. Following autograft, 65% of molecularly evaluable patients achieved clinical and molecular remission. The projected DFS at 4 years of this subgroup is 85%. This result emphasizes the importance of achieving maximal tumor reduction in these patients. In conclusion, our data show that highly effective intensified treatments can now be routinely offered to young patients with poor-risk FCL even at small institutions, with no need for sophisticated and expensive cell manipulation procedures.

Background and Objectives: Our aim was to identify risk factors in adults with diffuse large cell lymphoma at first relapse., Design and Methods: We studied 474 patients observed at 45 centers in Italy. Median time from diagnosis to relapse was 395 days, median age at relapse was 55 years and median follow-up from relapse was 3.3 years. Salvage therapy consisted of polychemotherapy in 79% of patients, monochemotherapy and/or radiotherapy and/or surgery alone in 16%, and palliative therapy in 5%. Salvage treatment was intensified with high-dose chemotherapy + stem cell transplant in 20% of patients. OS and PFS were compared by sex, International Prognostic Index at diagnosis, histology, B/T phenotype, initial treatment, salvage therapy, and features at relapse: time from diagnosis, LDH, stage, performance status and bone marrow involvement. Cox models, adjusted for salvage therapy, were performed with factors related to overall survival (OS) and progression-free survival (PFS)., Results: Overall response (complete + partial) was 63%, OS at 3 years 35% and PFS at 3 years 26%. Relapse within 12 months from diagnosis, elevated serum lactic dehydrogenase (LDH), advanced stage and poor performance status were independent adverse factors for OS and PFS. The cumulative number of adverse factors is proposed as prognostic index for DLCL at first relapse since it identifies risk groups (p<0.0001) and has been validated (p=0.01). Moreover, it predicts OS and PFS in the selected group of patients with a responsive relapse (p<0.0001)., Interpretation and Conclusion: Delay from initial diagnosis, LDH, stage and performance status at relapse should be balanced in comparative studies of salvage therapy of adults with DLCL. Patients with more than 2 adverse factors are one third of all cases and deserve more effective salvage treatments.

CD38 identifies a surface molecule with multi-functional activity. Its prognostic importance in B-cell chronic lymphocytic leukemia (B-CLL) is currently under investigation in view of the fact that two different groups have recently indicated that CD38 expression could be an independent prognostic marker in B-CLL. We analyzed the clinico-biological features of 61 immunologically typical (CD5+CD23+) B-CLL patients stratified according to the CD38 expression. Twenty-two (36%) patients expressed CD38 in more than 30% of CD19-positive cells and were considered as CD38-positive B-CLL. Atypical morphology (p 0.02), peripheral blood lymphocytosis (p 0.01) and diffuse histopathologic bone marrow pattern (p 0.003) were findings found to be closely associated with CD38 expression. On the other hand, A and B Binet stages (p 0.02) and interstitial bone marrow involvement (p 0.005) were more represented in the CD38-negative B-CLL group. Trisomy 12 was detected more frequently in the CD38-positive B-CLL group, while 13q14 deletions mainly occurred in CD38-negative group (p 0.005). Finally, median survival of CD38-positive B-CLL patients was 90 months, while it was not reached at 180 months in CD38-negative patients. Taken together, our data strongly suggest that the evaluation of CD38 expression may identify two groups patients with B-CLL greatly differing in their clinico-biological features.

The receptor for hepatocyte growth factor (HGF) is a transmembrane tyrosine kinase that is encoded by the proto-oncogene c-met. Recently, c-MET was detected in Reed-Sternberg (RS) cells from Epstein-Barr virus-positive (EBV(+)) Hodgkin disease (HD). The c-MET, EBER-1, and LMP-1 expression in 45 lymph node biopsies and 12 bone marrow biopsies obtained from patients with HD was analyzed. In addition, HGF levels in serum samples from 80 healthy individuals and 135 HD patients in different phases of disease. In all 45 lymph node and 12 bone marrow samples examined, RS cells expressed c-MET but not HGF(+). These results were independent of the EBV infection. Interestingly, several HGF(+) dendritic-reticulum cells were found scattered around c-MET(+) RS cells. The mean +/- SEM serum HGF levels in HD patients at diagnosis and at the time of relapse were 1403 +/- 91 (95% confidence interval [CI], 1221-1585) and 1497 +/- 242 pg/mL (95% CI, 977-2017), respectively. HGF values were significantly higher than those of healthy individuals (665 +/- 28 pg/mL; 95% CI, 600-721; and P <.001 for both groups of patients) and of HD patients in remission (616 +/- 49 pg/mL; 95% CI, 517-714; and P <.001 for both groups of patients). A significant correlation was found between serum HGF levels and B symptoms at diagnosis (P =.014). In conclusion, this study indicates that HGF and c-MET constitute an additional signaling pathway between RS cells and the reactive cellular background, thereby affecting adhesion, proliferation, and survival of RS cells. Furthermore, the serum concentration of HGF in HD patients may be a useful tool in monitoring the status of disease.

We have investigated whether the quantitative flow cytometry is an useful tool to better characterize B-cell chronic lymphoproliferative disorders (CLDs). Peripheral blood samples from 104 patients with leukemic B-cell disorders and 20 healthy donors were analyzed. Directly phycoerythrin-conjugated CD19, CD20, CD22, CD23, CD79b, and CD5 monoclonal antibodies (MoAbs) and QuantiBRITE pre-calibrated beads were used to calculate the number of antigen molecules per cell, expressed as antibody binding capacity (ABC). As compared to normal controls, in chronic lymphocytic leukemias (CLL) all MoAbs tested, with the exception of CD23 and CD5, showed lower ABC levels. In prolymphocytic leukemias (PL), CD5 and CD23 antigens were constantly absent while lower CD19 and CD22 ABC levels were observed. Hairy cell leukemias (HCL) displayed very high levels of CD20 and CD22. Of interest, splenic lymphomas with villous lymphocytes (SLVL) could be discriminated from HCL for higher CD79b and lower CD19 ABC values. Finally, higher CD20 levels were detected in follicular lymphomas (FL), whereas higher CD79b and CD5 levels characterized mantle cell lymphomas (MCL). Seven out of 61 CLL cases were defined as morphologically atypical. When compared with typical forms, lower levels of CD19 and CD23 and higher CD20 and CD22 ABC values were detected. However, we failed to demonstrate quantitative differences between atypical CLL and MCL. Our results suggest that quantitative flow cytometry may be a useful additional tool to better identify some types of B-cell CLDs., (Copyright 2000 Wiley-Liss, Inc.)

Background and Objectives: To evaluate the feasibility, toxicity and preliminary results of a potentially less toxic variant of the MOPPEBVCAD chemotherapy regimen for advanced Hodgkin's disease: MOPPEBVCyED, in which cyclophosphamide and etoposide replace lomustine and melphalan, respectively, with the remaining components being unaltered., Design and Methods: The study was multicenter, prospective and randomized, and enrolled 67 patients with newly diagnosed stage IIB, III, IV Hodgkin's disease (62 were expected on the grounds of statistical considerations). Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. Median follow-up was 48 months., Results: Comparing MOPPEBVCAD vs. MOPPEBVCyED, the results were as follows: complete remissions 35/35 vs. 30/32 (plus one partial remission and one disease progression); relapses 5 vs. 8; deaths 2 (one of myelodysplasia) vs. 2; delivered mean dose intensity (DI): lomustine 0.79+/-0.67 vs. cyclophosphamide 0.82+/-0.32; melphalan 0.80+/-0.13 vs. etoposide 0.86+/-0.18; average DI of the 7 drugs common to both regimens 0.73+/-0.10 vs. 0.83+/-0.11; all 9 drugs 0.75+/-0.13 vs. 0.84+/-0.09 (p=0.002); projected 5-year failure-free survival 0.79 vs 0.62; second cancers, two myelodysplasias vs. one carcinoma of the kidney. Toxicities were not statistically different except for heavier thrombocytopenia being recorded with MOPPEBVCAD., Interpretation and Conclusions: The higher cumulative and single drug DI recorded with MOPPEBVCyED may reflect better short-term tolerability, but it does not lead to better disease control. Its late toxicity may be expected to be lower in the future but at present it does not seem to be a sufficient reason to substitute MOPPEBVCyED for MOPPEBVCAD.

Background and Objective: To compare the efficacy of ProME(Epidoxorubicin)CE-CytaBOM (PE-C) and ProMI(Idarubicin)CE-CytaBOM (PI-C) in the treatment of adult patients with aggressive non Hodgkin's lymphoma in a multicenter randomized controlled trial performed by 18 centers of the Italian Lymphoma Study Group (GISL)., Design and Methods: One hundred and twenty-eight and 122 patients were randomly assigned to receive either 6 courses of PE-C or PI-C, respectively. Some patients achieving complete remission with induction therapy participated in another randomized study comparing no further therapy versus maintenance therapy consisting of four blocks of two drugs., Results: The rate of CRs was 62% and 64% for patients treated with PE-C and PI-C, respectively (p = 0.51). The 5-year relapse-free survival was 60% for PE-C and 53% for PI-C (p = 0.29). The estimated relapse-free disease survival rates at 4 years were 75% for patients in the consolidation group and 57% for those in the observation group (p = 0.11). Patients alive in first complete remission 4 years after study entry were estimated to be 39% in the PE-C arm and 38% in the PI-C arm (p = 0.90). The 3-year and 5-year estimated survival rates were 61% and 55% for the PE-C group and 56% and 47% for the PI-C group (p = 0.26). Fatal toxicities occurred in 7 patients (2.9%) with active disease and in 4 patients (1.7%) in complete remission. Stage (p = 0.04), bulky disease (p = 0.02), serum LDH (p = 0.0006), serum albumin (p = 0.0051), hemoglobin (p = 0.0011), performance status (p = 0.0001), International prognostic index (p < 0.0001) and the index proposed by the French group G.E.L.A. (p < 0.0001) were of prognostic value. In a multivariate analysis (Cox regression model) alternatively IPI alone or G.E.L.A. index plus performance status emerged as independent prognostic factors., Interpretation and Conclusions: The present study indicates that epirubicin and idarubicin in a combined chemotherapy regimen, have similar activities. The toxic profile also indicates the safety of both anthracyclines at the dosages employed, suggesting their possible dose escalation in a combined chemotherapy setting. PE-C and PI-C were both effective and feasible regimens in an outpatient setting, with acceptable cardiovascular toxicity. The trend toward a better outcome in patients undergoing consolidation therapy after the achievement of a complete remission, warrants further investigation.

The purpose was to verify the 5-year results of the MOPPEBVCAD chemotherapy regimen with limited radiotherapy in relation to the promising preliminary data. Mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, melphalan, and vindesine were delivered according to a schedule derived through hybridization, intensification, and shortening of the corresponding alternating CAD/MOPP/ABV regimen. Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. This multicenter, controlled, nonrandomized trial involved 145 eligible patients. Radiotherapy was administered to 47 patients, 46 of whom were in complete remission after chemotherapy. Remissions were complete in 137 patients (94%), partial in 4 (3%), and null in the remaining 4. Tumor-specific, overall, relapse-free, and failure-free survival at 5 years were 0.89, 0.86, 0.82, and 0.78, respectively. Hematologic toxicity was considerable, whereas nonhematologic side effects were fully acceptable. Most of the unfavorable prognostic factors lost their clinical weight. Only age and lymphocyte depletion histologic type were statistically correlated with major follow-up endpoints; performance status and bone marrow involvement were subordinate to age. Seven patients developed a second cancer (including 3 myelodysplasias). MOPPEBVCAD with selected radiotherapy is a highly effective regimen in advanced Hodgkin's disease. Early and late toxicity are no more severe than what would be expected with other alternating or hybrid regimens. A comparison with ABVD, which is currently considered the standard regimen for advanced Hodgkin's disease, is needed.

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 multivariate model. High sCD30 and advanced stage were independently associated with an unfavorable prognosis. Their combined evaluation identified patients at high risk (stages III and IV and sCD30 >/=100 U/mL: EFS, 46.9%) and low risk (stages I and II with sCD30 <100 U/mL: EFS, 88. 7%) of treatment failure (P < .001). We conclude that the combined evaluation of sCD30 serum level and stage at presentation identifies patients with HD at high risk of an unfavorable outcome.

The purpose of this study was to test the efficacy and safety of thymostimulin (TS) administered in addition to conventional chemotherapy in patients with intermediate- and high-grade non-Hodgkin's lymphoma (IG, HG-NHL). A total of 150 patients with newly diagnosed IG- or HG-NHL were entered in a multicenter trial to compare the effectiveness of two different third-generation regimens (MACOP-B versus ProMACE-CytaBOM) and were randomized to receive chemotherapy (CT) alone or CT + TS. In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin. TS was administered i.m. at a dose of 1 mg/kg daily on days 22-28 of each drug course to patients treated with ProMACE-CytaBOM, and on days 22-29, 50-57, and 77-85 to patients treated with MACOP-B. There were 134 fully evaluable patients: 68 treated with CT alone and 66 treated with CT + TS. Patients treated with CT + TS had a higher complete remission (CR) rate compared to patients given CT alone (59.1% vs 42.4%; P = .05). CR were significantly higher for patients treated with CT + TS in the groups with IG-NHL (P = .01), in those aged less than 60 years (P = .05), with good performance status (P = .05), and normal hemoglobin levels (P = .05). Four-year survival rates are 64.5% for patients treated with CT + TS and 43.0% for those treated with CT alone (P = .30). No difference between the two treatment arms have been observed as regards drug-related toxicity and the number and severity of infectious episodes. The use of TS during the 7 days before chemotherapy has been associated with a significantly superior CR rate. The advantage of CT + TS was mostly obtained in patients with IG-NHL, and those with good performance status or normal hemoglobin levels. In these patients TS may have potentiated the host reactions against the tumor, leading to an increase in NK activity and the production of cytokines. This postulated increase in the effectiveness of chemotherapy after TS might also explain the absence of the expected myeloprotective action.

The effects of high frequency hand vibration (150 Hz) on simultaneous ocular and manual tracking performances were investigated in trained human subjects. First, a zero-order pursuit tracking task was performed with and without direct visual control of the hand. Second, eye tracking of an imaginary target linked to the hand was also performed. The results show that hand vibration significantly alters eye and hand tracking performances when the hand is out of sight. However, when the hand is placed in the visual field, tracking performances are less affected by vibration. Visual cues on limb segments may compensate to some extent for the vibration-induced alteration of proprioceptive information otherwise used to control movements. Eye movements are altered during vibration while the subject is tracking or fixating an imaginary target attached to the hand. These findings explicitly show that hand vibration can perturb oculo-manual coordination control. The present results imply that vibration-induced activity of somesthetic mechanoreceptors is likely to contribute to oculomanual coordination alteration and tracking decrement in vibratory environments. Furthermore, direct visual control of the hand and/or arm may be of particular interest in manipulation tasks executed under vibration.

P-glycoprotein (P-170) is the phenotypic marker of tumoral cells that show the phenomenon of multidrug resistance (MDR). Using an immunocytochemical approach, we employed the monoclonal antibody C219 (which recognizes an epitope of such a glycoprotein) to evaluate in cytologic samples the expression of P-170 on neoplastic cells from 52 patients affected by different hematologic malignancies and its eventual correlation to clinical outcome. Longitudinal studies were also performed in 14 patients. Results obtained demonstrated that a) the so-called "MDR phenotype" may be heterogeneously represented (from less than 1 to 100% of positive cells) in hemopoietic tumors at diagnosis (without exposure to pharmacologic agents), as well as during the course of the disease, although a more substantial presence of P-170 occurred in treated patients. There was no correlation between neoplastic kinetic activity (such as expression of Ki 67 recognized nuclear proliferation-associated antigen) and P-170-positive cells. b) Percentage of positive cells as well as intensity of staining seemed to be important in determining MDR; in general, there was a strong correlation between expression of P-170 in more than 20% of neoplastic cells and a lack of response to chemotherapy. However, some false-positive and false-negative cases were observed. c) The detection of scattered P-170-positive cells may predict a pharmacologic selection of intrinsic or mutant-resistant clones.