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Twenty-five patients (22 adults and 3 infants) withALL1/AF4-positive acute lymphoblastic leukemia (ALL) were prospectively monitored by reverse transcriptase-polymerase chain reaction (RT-PCR) between January 1992 and July 1999. After high-dose induction and consolidation chemotherapy without bone marrow transplantation, all patients had a complete hematologic remission. Using nested RT-PCR (sensitivity 10-4), we observed conversion to PCR negativity in 11 (44%) of the patients. Thirteen of the 14 patients who did not have a molecular remission had a relapse at a median time of 4 months (range, 1 - 20 months). Of the 11 patients who had a conversion to PCR negativity, 5 reconverted to PCR positivity within 1 to 14 months. These 5 patients all progressed to hematologic relapse after 2, 3, 4, 4, and 7 months, respectively. Of the remaining 6 patients, 4 are in persistent hematologic and molecular remission at 12, 14, 88, and 96 months, whereas 2 are early in their follow-up. Actuarial probabilies of relapse and overall survival were 100% and 0% at 14 and 24 months and 67% and 43% at 96 and 100 months, respectively, in patients who had persistent RT-PCR positivity and in those who had a molecular remission. For both relapse and survival, the differences observed between the two groups were significant (P = .003 andP < .005, respectively). This study, which represents the first prospective analysis of residual-disease monitoring carried out in a substantial series of patients with t(4;11)-positive ALL, emphasizes the clinical relevance of RT-PCR-based methods to monitor minimal residual disease in this leukemia subset. (Blood. 2000;95:96-101)

Cytokines secreted by alloreactive donor T cells play a crucial role in the pathogenesis of both acute and chronic GvHD, a complication of allogeneic hematopoietic transplants that occurs at a lower incidence and severity when human umbilical cord blood (HUCB) is used. Our five-dimensional flow cytometric study performed on 20 HUCB and 20 peripheral blood (PB) samples from healthy adults was focused on the Th1/Th2 cytokine profile of activated HUCB T cells. Lymphocytes of all samples were stimulated by specific mitogens, and cytokine secretion was blocked at the cytoplasmic level. CD4+ and CD8+ cells were then analyzed for surface expression of the very early human activation antigen CD69 and for IFN-gamma and IL-4 intracellular production as expression of Th1-like and Th2-like T cell cytokine response, respectively. HUCB T lymphocytes were shown to be unable to perform both a Th1-like and Th2-like response, as compared with normal PB T cells. However, all lymphocytes from both sources were normally activated, as indicated by regular expression of the CD69 molecule. These data suggest that the low response of HUCB T lymphocytes to mitogens may be responsible for the decreased incidence of acute and chronic GvHD and provide possible explanations for the clinical results in HUCB transplantation.

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.

Clinical and biological parameters were retrospectively reviewed in 34 cases of T-lineage acute lymphoblastic leukemia (T-ALL), classified as ““early”” (20 cases) or ““late”” (14 cases) subgroups, according to the degree of blast cell differentiation, assessed by immunophenotyping.In ““early”” T-ALL, age, co-expression of ““immature”” (CD34 and HLA-Dr) or myeloid (My+) anti-gens, proliferative activity (as evaluated by Ki67 monoclonal antibody), and expression of the ““multidrug-resistance”” (MDR) phenotype (as determined by C-219 monoclonal antibody) were significantly higher, while WBC count and expression of CD10 were significantly lower, than in ““late”” T-ALL. Furthermore, although no statistically significant difference was found between the two groups, ““late”” T-ALL more frequently displayed a greater extramedullary tumor mass (““lymphoma-like”” syndrome), LI FAB morphology and a normal karyotype. A single patient, with ““late”” T-ALL, also showed positivity for TCR gamma/delta chains, specific monoclonal antibodies.On the whole, 30 patients (88.2%) achieved complete remission: 16 (80%) were ““early”” and 14(100%) ““late”” T-ALL. No statistical difference was found between the two groups with respect to disease free survival (42% vs 54% at six years), whereas median overall survival was significantly shorter in ““early”” T-ALL (23 months vs median not yet reached at six years for ““late”” T-ALL, p < 0.05). We conclude that ““early”” and ““late”” T-ALL show clinical and biological differences, that could perhaps justify differential therapeutic approaches.

Beta2-microglobulin (B2m) was measured on serum samples in 274 patients with acute and chronic lymphoproliferative disorders (85 non-Hodgkin lymphomas - NHL, 30 Hodgkin lymphomas - HL, 34 B-cell chronic lymphocytic leukemias - B-CLL, 8 Waldenström macro-globulinemias - WM, 76 multiple myelomas - MM, 31 acute lymphoblastic leukemias - ALL, 10 hairy cell leukemias - HCL). Two hundred and four patients were studied at the time of diagnosis, and results were correlated to clinical stage, and histologic subtype in NHL, immunoglobulin type in MM, and immunologic phenotype in ALL. Moreover, B2m was tested during and after chemo- and/or radiotherapy, and results were correlated to response, progression or relapse. Elevated pretreatment B2m values were found in widespread forms of NHL and HL, in patients with B symptoms and in the unfavorable histologic subgroups of NHL. Rapid falls in levels followed therapy institution. In B-CLL and in MM a close relationship between B2m and cell mass was found. A significant B2m level reduction followed treatment, whereas its increase could detect a relapse. In ALL, serum B2m was only slightly above the normal range. B2m seems to reflect the total burden of malignant cells mainly in MM and B-CLL; in other lymphoproliferative disorders it provides less prognostic information.

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 « 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.

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.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haemolytic disorder caused by the absence of glycosyl phosphatidylinositol (GPI)-anchored surface proteins resulting from a defect in one step of GPI-anchor biosynthesis. Recent analysis has shown that mutations at the PIG-A (phosphatidylinositoglycan-class A) gene are responsible for GPI-anchor deficiency in all PNH patients. In the current study, we describe three new mutations of the PIG-A gene in Italian patients with PNH. The analysis has been performed by RNA/single-strand conformation polymorphism using genomic DNA purified from nucleated peripheral blood cells. An abnormal pattern of migration of polymerase chain reaction amplified fragments containing exons 2 and 5 was observed. Sequencing analysis led to the identification of three mutations: a transversion C-to-A creating a stop codon (Y98X), an A insertion at position 460 (460insA), and a C deletion (1114delC). All the mutations cause a premature termination of the translation of the PIG-A protein.

The immunocytochemical characterization of neoplastic cells recognized by a large panel of monoclonal antibodies in fine needle aspirates obtained from 16 subjects with superficial or profound tumoral masses of unknown origin was carried out using alkaline phosphatase anti-alkaline phosphatase (APAAP) immunoenzymatic method. The patients were selected on the basis of particular clinical criteria or since a correct cytohistological diagnosis was not available. APAAP immunophenotyping allowed to establish the existence of non-Hodgkin lymphoma in 6 cases, hairy cell leukemia in 1 case and carcinoma in 5 cases, while in other 2 patients the existence of Hodgkin’s disease was suspected and subsequently confirmed; only in 2 subjects diagnostic informations were lacking. Furthermore, the evaluation of growth fraction by means of Ki 67 monoclonal antibody revealed a high degree of malignancy in all cases of lymphoma. Although some cautions have to be considered in the interpretation of results, APAAP immunocytochemical typing of fine needle aspirates appears a simple and reliable noninvasive diagnostic tool in selected patients.

A randomized trial was designed in order to compare the efficacy and feasibility of ProMECE-CytaBOM (P-C) and MACOP-B (M-B) in patients with advanced, aggressive non Hodgkin's lymphoma (NHL). P-C and M-B were chosen due to their association with a very high complete remission rate when compared to other published protocols. The study was conducted on 210 patients with intermediate or high-grade NHL in stage I bulky, or stages II-IV, randomized to receive either 6 courses of P-C delivered every 28 days (106 patients), or 12 weeks of M-B chemotherapy (104 patients). In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin (i.e. 30 mg/m2 of the analog). At the end of induction therapy patients could receive additional radiotherapy to residual masses or to sites of previous bulky disease. The two groups of patients were compared for response rates, number and severity of therapy related side effects, overall survival, disease-free survival, and time to treatment failure.Sixty-five patients (62%) treated with P-C and 69 patients (67%) treated with M-B achieved a complete remission, with no significant differences between the two treatment arms (P = 0.13). The overall objective response rate (complete + partial remission) was 74% for patients treated with P-C, and 81% for patients treated with M-B, respectively. The 4-year relapse-free survival rate was 59% for P-C and 69% for M-B, respectively (P = 0.11). We observed an eventual total of 120 treatment failures, 64 (61%) in the group treated with P-C and 56 (54%) among those treated with M-B (P = 0.29). Patients alive without disease at four years were estimated to be 42% in the P-C arm and 49% in the M-B arm (P = 0.27). The estimated 4-year overall survival was 54% for P-C and 61 % for M-B, and the differences were also not significant (P = 0.29). Patients treated with M-B experienced more and more severe side effects, including mucositis, infections, neurologic, pulmonary and cardiac abnormalities. Patients treated with P-C had a 1.3 g mean decrease of hemoglobin over the induction therapy, while patients treated with M-B experienced a 2.2 g mean decrease (P = 0.01).In conclusion, both P-C and M-B resulted in effective treatment for patients with aggressive NHL, and provided similar activity. However P-C was more manageable in an outpatient setting and produced less acute toxic effects.

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.

Cerebrospinal fluid thymidine kinase (CSF-TK) was measured at diagnosis in 62 patients with acute lymphoblastic leukemia (ALL) without initial neurological manifestations, who achieved a complete remission after chemotherapy. During the follow-up period, 10 patients developed central nervous system (CNS) involvement. At the onset of the disease mean CSF-TK levels in these subjects were found to be significantly higher than those observed in patients without subsequent CNS complications. In particular, 7/10 (70%) of these patients who presented CSF-TK levels above the upper limit of normal (1.4U/μ1) had evidence of a neurological relapse, while 49/52 (94.2%) of subjects with presenting CSF-TK levels of up to 1.4 U/μl did not develop a neurological leukemic disease (p < 0.00001). The white blood cell count at diagnosis was significantly increased, but not directly correlated to CSF-TK levels, in the group with CNS involvement, while age, serum thymidine kinase levels and lactic dehydrogenase, FAB classification or immunophenotype were not different in patients with or without neurological relapse. In conclusion, increased levels of CSF-TK at presentation correlate with a high risk of subsequent CNS involvement in patients with responsive ALL.

The clinical significance of plasma cell acid phosphatase (PCAP) was evaluated in 143 patients with monoclonal gammapathies, using a semiquantitative cytological scoring method. Significantly higher PCAP scores were measured in overt myelomas than in MGUS or in smouldering myelomas, during the phases of activity (diagnosis, progression, relapse), and in patients with extended disease. Among various clinical and laboratory parameters, PCAP was significantly related to the percentage of bone marrow plasma cells, the neoplastic growth fraction, as determined by Ki67 monoclonal antibody, and to serum levels of C-reactive protein. An inverse relationship was also found between PCAP and hemoglobin levels.Although the patients with "flaming" plasma cells exhibited low PCAP scores and poor prognosis, on the whole, myeloma patients with PCAP scores < 200 showed a significantly longer median overall survival than those with PCAP > 200 (46 vs 20 months, p < 0.003). However, in the multivariate analysis, beta2-microglobulin, growth fraction, performance status, and serum levels of thymidine kinase and C-reactive protein, but not PCAP, maintained a significant prognostic relevance.In conclusion, although PCAP may be considered a marker of disease activity, other parameters provide better prognostic information in myeloma patients.

Two patients with multiple myeloma and in vivo macroscopic nodular lesions of the liver are presented. The clinical aspects of this very unusual condition are briefly reviewed. In particular, the expression on neoplastic plasma cells of the cytoadhesion molecules CD56 and CD11a, which are involved in the cellular process of recirculation and homing, suggests a possible role for such markers in this atypical localization of the disease.

Riassunto La glicemia e l'insulina immunoreattiva (IRI) sono state misurate, nel corso delle 24 h, prima ed esattamente 1 h dopo glucosio, in soggetti sani cui venivano somministrati, dopo una notte di digiuno, tre carichi di glucosio (50 g p.o.) ad uguali intervalli di tempo, ovvero alle ore 8, 16 e 24. Il test era ripetuto tre giorni più tardi, ma il primo carico di glucosio veniva somministrato alle ore 16, dopo 14 h di digiuno, e così via agli stessi intervalli di tempo. È stato rilevato che la variazione diurna della tolleranza glicidica può dipendere strettamente dalla durata del digiuno e che non esiste un ritmo circadiano. Al contrario, la risposta insulinemica allo stimolo glicemico è sempre più elevata al mattino. Tale comportamento potrebbe essere in accordo con l'ipotesi di una ritmica variazione della secrezione dell'insulina, indipendente dalla durata del digiuno ma collegata a fattori ancora sconosciuti.

A case of early cutaneous involvement by an acute myeloid leukemia in a Caucasian man, previously affected by a « classical » Kaposi's sarcoma is reported. The diagnoses were based upon histologic examinations and appropriate hematologic investigations. After reviewing extensively the literature about the association of lymphoreticular system malignancies and Kaposi's sarcoma, possible implications and hypothetical etiopathogenetic mechanisms are discussed.

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