Bioassay for quantitating circulating tumor cells in a syngeneic mouse tumor system. (65/487)

A bioassay is described for the quantitation of tumor cells in blood specimens in a syngeneic mouse tumor system (Sarcoma 1 in A/J mice). The procedure involved i.m. injection of blood containing tumor cells into each thigh of normal recipient mice and, 14 days later, examination of the sites of injection for evidence of tumor growth. For each specimen, a tumor index was calculated based on the number of tumor takes and the size of the tumors. The number of tumor cells was determined by comparison with tumor indices from standard specimens with known number of tumor cells. Optimal conditions for this assay were investigated. We have used this bioassay to quantitate tumor cells in the venous blood of tumor-bearing animals under various treatments and manipulations. At the same time, the incidence of regional node metastasis was obtained by direct histological examination. Surgical removal of a well-established primary tumor enhanced the dissemination of the tumor, as evidenced by an increased incidence in regional node metastasis and an increase in the number of tumor cells reaching the venous circulation. Similar results were obtained when the tumor-bearing feet were ligated to produce ischemia of the primary tumor. Repeated physical trauma to the primary tumor resulted in increased dissemination of tumor cells into the venous circulation, but it did not increase the incidence of regional node metastasis. Immunosuppression of the tumor-bearing animals increased the dissemination of tumor cells, whereas immunostimulation decreased the dissemination.  (+info)

Human granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia: a Children's Cancer Group Study. (66/487)

PURPOSE: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on hematopoietic toxicities, supportive care requirements, time to complete intensive therapy, and event-free survival (EFS) and overall survival (OS) in children with high-risk acute lymphoblastic leukemia (HR-ALL). PATIENTS AND METHODS: A total of 287 children with HR-ALL were randomly assigned to intensive chemotherapy regimens (New York I [NY I] or NY II) as part of the Children's Cancer Group (CCG)-1901 protocol. The induction phases consisted of five drugs (vincristine, prednisone, l-asparaginase, daunorubicin, and cyclophosphamide). Initial consolidation comprised six-agent chemotherapy combined with 18 Gy of total-brain irradiation. Patients were randomly assigned to receive G-CSF (5 microg/kg/day) during either induction or initial consolidation. A crossover study analysis was done on the 259 patients who completed both phases of therapy. RESULTS: The mean time to neutrophil recovery (>/= 0.5 x 109/L) was reduced with G-CSF (16.7 v 19.1 days, P =.0003); however, patients who received G-CSF did not have significantly reduced episodes of febrile neutropenia (149 v 164, P =.41), positive blood cultures (57 v 61, P =.66), or serious infections (75 v 79, P =.62). Hospitalization (14.0 v 13.9 days, P =.87) and induction therapy completion times (NY I, 30.3 v 31.3 days, P =.11; NY II, 33.4 v 32.3 days, P =.40) were not significantly altered. There were no differences in 6-year EFS (P =.24) or OS (P =.54) between patients receiving or not receiving G-CSF on CCG-1901, NY I and NY II. CONCLUSION: Children with high-risk ALL do not appear to benefit from prophylactic G-CSF.  (+info)

Treatment outcome of adult acute lymphocytic leukemia with VPD(L) regimen: analysis of prognostic factors. (67/487)

BACKGROUND: Because of the relative paucity of data regarding the clinical outcome in adult patients with acute lymphocytic leukemia (ALL) in Korea, we analyzed clinical courses in adult ALL patients treated with VPD (L) regimen (vincristine, prednisolone, daunorubicin, L-asparaginase) at the Seoul National University Hospital, and evaluated prognostic factors influencing the outcome. METHODS: Patients with ALL newly diagnosed between October 1994 and June 2000 at our hospital were analyzed retrospectively. Fifty-three patients were evaluable. Induction chemotherapy consisted of VPD with (46 cases) or without L-asparaginase (7 cases). After complete remission (CR), consolidation therapy, CNS prophylaxis and maintenance chemotherapy were administered. RESULTS: Ages ranged from 16 to 67 (median 30). CR rate was 86.8% (46/53) and no significant prognostic factor was found for the CR rate. With a median follow-up time of 27.2 months (range 12.9-83.0 months) in living patients, the median overall survival (OS) for all cases was 16.7 months (13.4-20.1 months, 95% C.I.) and the estimated 4-year OS rate was 25.4% +/- 8.9%. The median relapse-free survival (RFS) was 12.2 months (8.4-16.0 months, 95% C.I.), and 3-year RFS rate was 29.9% +/- 10.2%. Poor prognostic factors for OS were Ph chromosome (p = 0.005) and T-cell immunophenotype (p = 0.03). For RFS they were Ph chromosome (p = 0.01) and the presence of a mediastinal mass (p = 0.03). CONCLUSION: Despite an initial excellent response to the VPD (L) regimen, newer therapeutic strategies, including more intensive postremission therapies, are urgently needed because of the high relapse rate. Future therapeutic approaches need to be stratified according to several prognostic factors.  (+info)

Dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin. (68/487)

BACKGROUND: The goals of the current study were to examine the incidence and severity of toxicity resulting from dexamethasone and prednisone during induction therapy for children with precursor B-cell acute lymphoblastic leukemia (ALL) and to determine whether the addition of daunomycin affected toxicity. METHODS: Medical records of patients with precursor B-cell ALL from January 1996 through June 2000 were reviewed retrospectively for toxicity during the 4-week induction phase and the 2 weeks after the induction phase. RESULTS: One hundred seventy-six patients age < 14 years were diagnosed with precursor B-cell ALL from January 1996 through June 2000. Of the 156 evaluable patients, 106 were treated with prednisone and 50 with dexamethasone. Fifty-two patients received steroids, L-asparaginase, and vincristine, whereas 104 high-risk patients received daunomycin in addition to these 3 agents. The incidence of gastritis was significantly higher among patients receiving dexamethasone (P = 0.01); incidence rates of hyperglycemia, hypertension, and myopathy were similar for all treatment groups. Dexamethasone led to more weight gain than did prednisone (+11.9% vs. +5.4%; P = 0.002). Serious infections were observed in 27 (25.5%) and 18 (36%) patients receiving prednisone and dexamethasone, respectively (P < or = 0.2). Five patients, four of whom received prednisone and one of whom received dexamethasone, died of infection. The addition of daunomycin to treatment regimens increased overall toxicity (P < 0.01). When daunomycin was included in treatment regimens, toxicity was greater among patients receiving dexamethasone; in contrast, when daunomycin was not included, toxicity was equal for both treatment groups. Regardless of daunomycin use, there was no difference in the incidence of serious infection between the two groups. ALL treatment was not compromised by steroid-related toxicity in either group. CONCLUSIONS: The addition of daunomycin led to a much larger increase in dexamethasone-related toxicity compared with the increase in prednisone-related toxicity. Although the use of daunomycin enhanced dexamethasone-related toxicity, this enhancement did not result in a higher mortality rate or the alteration of planned ALL therapy.  (+info)

Clinico-biologic features and treatment outcome of adult pro-B-ALL patients enrolled in the GIMEMA 0496 study: absence of the ALL1/AF4 and of the BCR/ABL fusion genes correlates with a significantly better clinical outcome. (69/487)

To elucidate the biologic and clinical heterogeneity of adult pro-B acute lymphoblastic leukemia (ALL) (ie, terminal deoxynucletidyl-transferase-positive[TdT+], CD19+, CD10-, surface immunoglobulin-negative [SIg-]), we evaluated 66 patients enrolled in the Italian multicentric Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 0496 study between October 1996 and December 1999. The ALL1/AF4 fusion transcript, originating from the t(4;11) translocation, was detected in 24 patients (36.4%), and the BCR/ABL chimeric product was found in 6 patients (9%), while the remaining 36 cases (54.6%) were ALL1/AF4-BCR/ABL-negative. A white blood cell (WBC) count higher than 50 x 109/L was found in 13 of 24, 2 of 6, and 6 of 36 of the ALL1/AF4-positive, BCR/ABL-positive, and ALL1/AF4-BCR/AB-negative patients, respectively (P =.007). None of the 24 ALL1/AF4-positive patients coexpressed the CD13 and/or CD33 myeloid antigens. By contrast, CD13 and CD33 molecules were detected, respectively, in 3 of 6 and in 14 of 33 cases of the BCR/ABL-positive patient group, and in 2 of 6 and 9 of 35 cases of the ALL1/AF4-BCR/ABL-negative patient group. These differences still remained statistically significant even if the BCR/ABL-positive patients were excluded from the analysis. A complete remission (CR) was achieved in 52 (83.4%) of the 62 patients with ALL evaluable for response to treatment. CR rates were similar in the 3 genotypic groups. By contrast, comparing patients with or without the ALL1/AF4 gene the probability of remaining in continuous complete remission (CCR) at 3.5 years was 16% and 49.8%, respectively (P =.005). Our data demonstrate that in adult pro-B-ALL a distinction should be made between pro-B-ALL cases with and without the ALL1/AF4 or the BCR/ABL chimeric genes, since the absence of both of these fusion genes correlates with a significantly better clinical outcome after intensive polychemotherapy treatment without hematopoietic stem cell transplantation.  (+info)

A Phase I-II trial of polyethylene glycol-conjugated L-asparaginase in patients with multiple myeloma. (70/487)

BACKGROUND: Multiple myeloma remains an incurable disease. New agents are needed to improve therapy for patients with this disease. Previous investigators evaluated in vitro sensitivity of myeloma cells to polyethylene glycol-conjugated L-asparaginase (PEG-L-asparaginase) using the human tumor clonogenic assay. Of the 19 myeloma samples evaluated, 63% were inhibited at 0.075 IU/mL, and 74% were inhibited at 0.75 IU/mL. PEG-L-asparaginase is a form of Escherichia coli-derived L-asparaginase that is bound covalently to polyethylene glycol. Compared with the native form, it has a longer half-life and is less likely to cause allergic reactions. METHODS: The authors conducted a Phase I-II trial using PEG-L-asparaginase as a single agent in patients with recurrent and/or refractory multiple myeloma. RESULTS: Twenty-two patients received a median of two doses of PEG-L-asparaginase. In the 17 patients who are evaluable for response, a complete response was observed in one patient after four doses, and stable disease was observed in eight patients. Progression of disease was the reason for termination from study in the remaining eight patients. The median survival was 31.7 months, with four patients who were alive at 72 months after the start of therapy. Grade 3-4 toxicity was noted by the PEG-L-asparaginase 2000 mg/m(2) level. Severe allergic reactions were noted only at the highest dose level. CONCLUSIONS: Current data suggest that the maximal tolerated dose for single agent PEG-L-asparaginase in relapse/refractory multiple myeloma patients is 1000 mg/m(2) every 4 weeks. We could not identify any correlation between dose, plasma level and response. In this advanced group of patients we noted stable disease and/or response in 52% of evaluable patients. PEG-L-asparaginase has lower tolerance when used in the standard dosage as a single agent in this group of patients. We therefore recommend further studying of PEG-L-asparaginase dose of 1000 mg/m(2) on alternate weeks with steroids and/or other immune modulators.  (+info)

Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia. (71/487)

Resistance of leukemic cells to chemotherapeutic agents is associated with an unfavorable outcome in pediatric acute lymphoblastic leukemia (ALL). To investigate the underlying mechanisms of cellular drug resistance, the activation of various apoptotic parameters in leukemic cells from 50 children with ALL was studied after in vitro exposure with 4 important drugs in ALL therapy (prednisolone, vincristine, l-asparaginase, and daunorubicin). Exposure to each drug resulted in early induction of phosphatidylserine (PS) externalization and mitochondrial transmembrane (Deltapsim) depolarization followed by caspase-3 activation and poly(ADP-ribose) polymerase (PARP) inactivation in the majority of patients. For all 4 drugs, a significant inverse correlation was found between cellular drug resistance and (1) the percentage of cells with PS externalization (<.001 < P <.008) and (2) the percentage of cells with Deltapsim depolarization (.002 < P <.02). However, the percentage of cells with caspase-3 activation and the percentage of cells with PARP inactivation showed a significant inverse correlation with cellular resistance for prednisolone (P =.001; P =.001) and l-asparaginase (P =.01; P =.001) only. This suggests that caspase-3 activation and PARP inactivation are not essential for vincristine- and daunorubicin-induced apoptosis. In conclusion, resistance to 4 unrelated drugs is associated with defect(s) upstream or at the level of PS externalization and Deltapsim depolarization. This leads to decreased activation of apoptotic parameters in resistant cases of pediatric ALL.  (+info)

Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia. (72/487)

PURPOSE: To confirm the prognostic value of a drug resistance profile combining prednisolone, vincristine, and l-asparaginase (PVA) cytotoxicity in an independent group of children with acute lymphoblastic leukemia (ALL) treated with a different protocol and analyzed at longer follow-up compared with our previous study of patients treated according to the Dutch Childhood Leukemia Study Group (DCLSG) ALL VII/VIII protocol. PATIENTS AND METHODS: Drug resistance profiles were determined in 202 children (aged 1 to 18 years) with newly diagnosed ALL who were treated according to the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL)-92 protocol. RESULTS: At a median follow-up of 6.2 years (range, 4.1 to 9.3 years), the 5-year disease-free survival probability (pDFS) rate +/- SE was 69% +/- 7.0%, 83% +/- 4.4%, and 84% +/- 6.8% for patients with resistant (PVA score 7 to 9), intermediate-sensitive (PVA score 5 to 6), and sensitive (SPVA score 3 to 4) profiles, respectively (sensitive and intermediate-sensitive v resistant, P +info)