RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia.

We explored the relationship of RAS gene mutations with epidemiologic and cytogenetic factors in a case series of children with leukemia. Diagnostic bone marrow samples from 191 incident leukemia cases from the Northern California Childhood Leukemia Study were typed for NRAS and KRAS codon 12 and 13 mutations. A total of 38 cases (20%) harbored RAS mutations. Among the 142 B-cell acute lymphoblastic leukemia (ALL) cases, RAS mutations were more common among Hispanic children (P=0.11) or children born to mothers <30 years (P=0.007). Those with hyperdiploidy at diagnosis (>50 chromosomes) had the highest rates of RAS mutation (P=0.02). A multivariable model confirmed the significant associations between RAS mutation and both maternal age and hyperdiploidy. Interestingly, smoking of the father in the 3 months prior to pregnancy was reported less frequently among hyperdiploid leukemia patients than among those without hyperdiploidy (P=0.02). The data suggest that RAS and high hyperdiploidy may be cooperative genetic events to produce the leukemia subtype; and furthermore, that maternal age and paternal preconception smoking or other factors associated with these parameters are critical in the etiology of subtypes of childhood leukemia.     

The clinical value of serum CEA, CA19-9, and CA242 in the diagnosis and prognosis of pancreatic cancer.

AIM: Serum tumour markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and CA242 were investigated to evaluate the values of single and combined test in the diagnosis and prognosis of pancreatic cancer. METHODS: Pre-operative serum CEA, CA19-9 and CA242 were measured in 105 pancreatic cancers, 70 non-pancreatic malignancies and 30 benign pancreatic diseases. RESULTS: The sensitivity of CA19-9 alone was the highest in pancreatic cancer patients (80%), but the specificity was significantly lower than that of CEA and CA242 (P<0.01). The combination of CEA and CA242 could increase the specificity to 92%. In serum CA242 positive patients, the survival time was remarkably shorter than that of patients with negative result (P<0.01). The survival time in patients with more than two markers positive expression of CEA, CA19-9 and CA242 was obviously shorter than that of only one or no marker positive expression (P<0.05). CONCLUSION: The diagnostic rate of CA19-9 in pancreatic cancer is better than that of CEA and CA242. Combined detection of CEA and CA242 can improve the diagnostic specificity obviously. High levels of serum markers are associated with advanced stage of the disease. Patients with two or three markers positive expression of CEA, CA19-9, and CA242 simultaneously had a shorter survival time.     

Cost-effectiveness analysis of breast cancer adjuvant treatment: FEC 50 versus FEC 100 (FASG05 study).

BACKGROUND: The aim of the study was to assess the incremental cost-effectiveness ratio (ICER) of the FEC 100 compared with the FEC 50 in the FASG05 trial. MATERIALS AND METHODS: A cost-effectiveness analysis was performed using a multi-state Markov process model. Relevant clinical data introduced into the model were obtained from 10-year follow-up of the clinical trial FASG05. Survival curves for each health state were assessed by survival parametric model. The model allowed assessments from the start of adjuvant chemotherapy until death. The costs of adjuvant treatment and follow-up were estimated. The costs of recurrence were evaluated from the medical records of 146 patients. A prospective survey was performed on a cohort of 87 patients to quantify the resources external to the hospital (including cost of transportation). The inpatient costs were evaluated using the French diagnosis-related groups. The ambulatory costs were assessed using the French nomenclature. Costs were expressed in 2002 Euro (), according to the French societal perspective. The ICER assessed the cost of one additional life year saved. A discount rate of 5% per year was used for cost, and alternatively 0%, 3% and 5% for effectiveness. We validated the results with a probabilistic sensitivity analysis incorporating parametric and non-parametric bootstraps, and with the acceptability curves. RESULTS: The mean total discounting cost of adjuvant treatments was 11 465 for FEC 50 and 13 815 for FEC 100; the mean total discounting cost of recurrences was 14 636 and 13 503, respectively. According to the discount rate of effectiveness, the life expectancy was 16.5, 11.4 and 9.3 years for FEC 50 and 18.4, 12.5 and 10.2 years for FEC 100. The ICER (cost per life year saved) were 642, 1084 and 1460, respectively. The probability according to which FEC 50 is strictly dominated by FEC 100 was 0.15. CONCLUSION: The clinical benefit of FEC 100 generates a negligible cost increase when compared with FEC 50.     

Enhanced growth suppression of Philadephia1 leukemia cells by targeting bcr3/abl2 and VEGF through antisense strategy.

An antisense strategy by targeting both bcr3/abl2 and VEGF was designed to suppress the growth of Philadephia1 leukemia cells in vitro and in vivo in mice. In vitro, although bcr3/abl2 or VEGF antisense oligodeoxyribonucleotides (AS-ODNs) alone was able to inhibit the proliferation of K562 cells, the combination of bcr3/abl2 and VEGF AS-ODNs produced an additive inhibitory effect on the growth of K562 cells and significantly enhanced the sensibility of K562 cells to apoptosis-inducing stimuli including STI571. In vivo, the nude mice xenografted with K562 cells received intratumoral injections of bcr3/abl2 and VEGF AS-ODNs showed a significant reduction in leukemia tumor size and microvessel density and an increase of apoptosis in the tumors when compared to the mice that received an individual agent. These results demonstrate that targeting both bcr3/abl2 and VEGF can result in an additive tumor-suppressive action and may represent an excellent strategy to augment the efficacy of chemotherapy in CML.     

FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis.

FGFR3 and Tp53 mutations have been proposed as defining two alternative pathways in the pathogenesis of transitional bladder cancer. FGFR3 mutations are associated with low-grade tumors and a favorable prognosis. Tp53 alterations are associated with advanced tumors and, possibly, with a poor prognosis. We focus here on the subgroup of T1G3 superficial tumors because they are a major clinical challenge. Patients (n = 119) were identified from a prospective study of 1,356 cases. Mutations in FGFR3 (exons 7, 10, and 15) and Tp53 (exons 4-9) were analyzed using PCR and direct sequencing. All cases were followed for recurrence and death. Survival was analyzed using Kaplan-Meier curves and multivariable Cox regression. FGFR3 mutations were detected in 20 (16.8%) tumors; 100 mutations in Tp53 were found in tumors from 78 (65.5%) cases. Multiple alterations in Tp53 were present in 19 tumors (16%). Inactivating mutations were present in 58% of tumors. The combined mutation distribution (FGFR3/Tp53) was: wt/wt (34.5%), mut/wt (7.6%), wt/mut (48.7%), and mut/mut (9.2%), indicating that the presence of either mutation did not depend on the other (P value = 0.767). FGFR3 and Tp53 mutations were not associated with clinicopathologic characteristics of patients and did not predict, alone or in combination, recurrence or survival. Taking the risk of the wt/wt group as reference, the mutation-associated risks of cancer-specific mortality were: mut/wt 1.42 (0.15-13.75), wt/mut 0.67 (0.19-2.31), mut/mut 1.62 (0.27-9.59). These molecular features support the notion that T1G3 tumors are at the crossroads of the two main molecular pathways proposed for bladder cancer development and progression.     

Randomized phase II trial of three schedules of pemetrexed and gemcitabine as front-line therapy for advanced non-small-cell lung cancer.

PURPOSE: A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-na?ve patients with non-small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8. RESULTS: One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms. CONCLUSION: Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.     

Results of 58872 and 58921 trials in acute myeloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow transplantation in first complete remission: the EORTC Children Leukemia Group report.

The first EORTC (European Organization of Research and Treatment of Cancer) acute myeloblastic leukemia (AML) pilot study (58872) was conducted between January 1988 and December 1991. Out of 108 patients, 78% achieved complete remission (CR), and event-free survival (EFS) and survival rates (s.e., %) at 7 years were 40 (5) and 51% (6%), respectively. It indicated that mitoxantrone could be substituted for conventional anthracyclines in the treatment of childhood AML without inducing cardiotoxicity. The aim of the next EORTC 58921 trial was to compare the efficacy and toxicity of idarubicin vs mitoxantrone in initial chemotherapy courses, further therapy consisting of allogeneic bone marrow transplantation (alloBMT) in patients with an HLA-compatible sibling donor or chemotherapy in patients without a donor. Out of 177 patients, recruited between October 1992 and December 2002, 81% reached CR. Overall 7-year EFS and survival rates were 49 (4) and 62% (4%), respectively. Out of 145 patients who received the first intensification, 39 had a sibling donor. In patients with or without a donor, the 7-year disease-free survival (DFS) rate was 63 (8) and 57% (5%) and the 7-year survival rate was 78 (7) and 65% (5%), respectively. Patients with favorable, intermediate and unfavorable cytogenetic features had a 5-year EFS rate of 57, 45 and 45% and a 5-year survival rate of 89, 67 and 53%, respectively.