Adult patients with acute lymphoblastic leukemia (ALL) and t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4 have a poor outcome. We have evaluated the impact of an intensified post-remission therapy using a high-dose chemotherapy course followed by allogeneic or autologous SCT on the outcome of 58 patients with t(1;19)/E2A-PBX1 (E2A group, n=24) or t(4;11)/MLL-AF4 (MLL group, n=34) treated in the LALA-94 multicenter prospective study. Patients in the MLL group had higher WBC counts and more frequent DIC. CR rates achieved by MLL and E2A groups were similar to other B-cell ALL (87, 82 and 86% respectively). While in CR, patients with a donor were assigned to alloSCT (n=22), the remaining patients with were randomized between autoSCT (n=15) or chemotherapy (n=8). Five-year overall survival was 31 and 45% for E2A and MLL groups, respectively. In both groups, DFS was higher in the alloSCT arm as compared to autoSCT and chemotherapy arms. The results of this study show that chemotherapy intensification did not overcome the poor prognosis of adults with t(1;19)/E2A-PBX1. Allogeneic SCT should thus be offered in first CR to patients with t(1;19)/E2A-PBX1 or t(4;11)/MLL-AF4. New therapeutic approaches are needed for patients without donor.

A prospective randomized phase III study was performed to evaluate whether intensified cytarabine would induce a higher response rate and longer event-free interval as compared to low-dose cytarabine in chronic myeloid leukemia (CML). One hundred and eighteen patients with CML in early chronic phase entered the study. Twenty-eight out of 32 patients assigned to group A received two cycles of a combination of intensified cytarabine and idarubicin followed by interferon alfa (IFN-alpha) maintenance, 28 patients in group B received standard treatment by a combination of low-dose cytarabine and IFN-alpha. Forty-nine patients with a human leukocyte antigen-identical sibling donor proceeded to allogeneic stem cell transplantation (allo-SCT) and nine patients were excluded from the analysis. Hematological response was observed in 97% of the patients in group A vs 86% of the patients in group B during the first year of treatment. In group A, 16 patients (50%) achieved a major cytogenetic response, which compared to seven patients (25%) with a major cytogenetic response in group B. With a median follow-up of 58 months (range 34-76), event-free survival was not significantly different between arms A and B. The estimated 5-year survival rate was 56% in the intensified arm and 77% in the low-dose arm (P = 0.05). Recipients of allo-SCT showed a 5-year estimated survival rate of 55%. Although intensified cytarabine induced a higher initial percentage of major and complete cytogenetic responses, responses were not sustained by IFN-alpha maintenance therapy.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of monoclonal mature B cells. The G protein Galphas subunit has been linked to proapoptotic processes in cancer cell lines. The TT genotype of the GNAS1 T393C polymorphism is associated with increased Galphas transcript levels and a more favorable clinical course in different solid cancers.

Thymidylate synthase [TS, (EC 2.1.1.45)] is the target enzyme in 5-fluorouracil treatment. Recently, the DNA polymorphism of this gene has been found to affect TS protein (pTS) expression. However, no prospective studies have been performed to evaluate the influence of this polymorphism on the clinical efficacy of 5-FU-based adjuvant chemotherapy for colorectal cancer (CRC). In this study, we investigated the genotype of TS and immunopathological findings of pTS in 161 colon cancer specimens from patients who were registered in a prospective adjuvant immunochemotherapy clinical trial. The clinical course and prognosis of these patients were checked after the study had been completed. This study comprised 11 (6.8%) cases of 2R/2R, 40 (24.8%) of 2R/3R, and 110 (68.3%) of 3R/3R genotypes. All of the 2R/2R cases were still alive at the time of analysis although this finding was not statistically significant. In this prospective examination on a randomized controlled trial, the patients with colon cancer of the 2R/2R TS genotype may be good responders to 5-FU-based adjuvant chemotherapy. Furthermore, differences in the proportions of the TS genotypes can account for the interracial differences in the adverse effects of 5-FU-based chemotherapy.

Thiopurine metabolism was investigated in children with acute lymphoblastic leukemia treated in the United Kingdom Medical Research Council trial ALL97. This trial compared the efficacy and toxicity of thioguanine (INN, thioguanine) versus mercaptopurine.

Gene expression analysis in breast cancer patients undergoing neoadjuvant chemotherapy is an interesting tool for identification of gene signatures and new markers to predict tumor response. However, the detection of predictive markers strongly depends on the drugs used in the specific therapeutic setting. There is growing evidence that topoisomerase II-alpha (TOPO IIalpha) is a marker for anthracycline-, and microtubule-associated protein tau (MAPT) for taxane sensitivity. HER-2 has been described as a marker of both anthracycline and taxane sensitivity. We performed gene expression profiling of 50 patients within the GEPARTRIO study, an anthracycline and taxane neoadjuvant chemotherapy trial. Here we investigate the predictive value of TOPO IIalpha, MAPT and HER-2 mRNA expression for pathological complete response (pCR) in this setting. Interestingly, HER-2 gene expression was strongly predictive of pCR (P=0.017) as well as overall response (P=0.037) and clinical complete response (cCR, P=0.050). In contrast, for both TOPO IIalpha and MAPT no correlation with pCR was observed in our sample group.

To test if treatment with GnRH analogue, which leads to a significant reduction in myoma volume, changes expression of leptin genes and gene coding leptin receptor isoforms in uterine myomas and in the surrounding unaltered myometrium.

Women with a family history of breast cancer have several menopausal therapy options, including tamoxifen, hormone therapy (HT), alternative medications, or no treatment. This complex decision should be based on each woman's risk to develop breast cancer, menopausal symptoms, preferences, and risks for other conditions. The authors determined the effects of a personalized risk assessment and genetic counseling intervention on knowledge, risk perception, and decision making in a group of healthy women who had a first-degree relative with breast cancer.

Despite being relatively uncommon, testicular germ cell tumors (TGCT) are the most common malignant disease in young men. Epidemiological studies concerning patients with testicular cancer indicate that the most of them have poor semen quality or testicular dysgenesis. However, many studies have shown that the Y chromosome harbors many candidate genes responsible for spermatogenesis process and development and maintenance of the germ cells. The Y chromosome is thought to have a relationship with the formation and progression of TGCT.

Cigarette use is associated with greater risk for colorectal adenoma, a colorectal cancer precursor. N-acetyltransferases, NAT1 and NAT2, are important enzymes involved in the metabolism of aromatic amine carcinogens present in cigarette smoke. Our interest is in the polymorphisms within the NAT1 and NAT2 genes that influence the tobacco-colorectal tumor relationship by impacting on the metabolic activation and detoxification of tobacco smoke-derived carcinogens.

We evaluated the therapeutic usefulness of adjuvant chemotherapy in patients with completely resected non-small cell lung cancer (NSCLC). We also examined the relation between DNA ploidy pattern and the response to chemotherapy. A total of 267 patients with NSCLC (pathologically documented stage I, II, or IIIA) underwent complete resection, and DNA ploidy pattern was analysed. Patients with stage I disease (n=172) were randomly assigned to receive surgery alone (group A) or surgery followed by adjuvant chemotherapy (UFT (oral anti-cancer drug, a combination of Uracil and Tegaful) 400 mg day-1 for 1 year after surgery; group B). Stage II or IIIA disease patients (n=95) were randomly assigned to surgery alone (group C) or surgery followed by chemotherapy (two 28-day courses of cisplatin 80 mg m-2 on day 1 plus vindesine 3 mg m-2 on days 1 and 8, followed by UFT 400 mg day-1 for at least 1 year; group D). Eight-year overall survival rate in patients with stage I disease was 74.2% (95% confidence interval (CI): 64.4-84.0%) in group B and 57.6% (95% CI: 46.4-68.8%) in group A (P=0.045 by log-rank test). In patients with stage II and IIIA disease, no difference was found between groups C and D. Analysis according to DNA ploidy pattern revealed no difference between the groups. Postoperative chemotherapy with UFT was suggested to be useful in patients with completely resected stage I NSCLC. No difference was seen in relation to DNA pattern in any treatment group.

Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem.

Delayed-type diarrhea is a common side effect of irinotecan and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestine. Based on a pilot study, we hypothesized that concomitant administration of the antibiotic neomycin would diminish exposure of the gut to SN-38 and ameliorate the incidence and severity of diarrhea.

Peripheral T-cell lymphomas (PTCLs) are rare and have a dismal prognosis. The most frequent subtype is PTCL, unspecified. Epstein-Barr virus (EBV) has been detected in around 40% of cases, but its prognostic significance is not fully established. Lymph node samples from 110 patients with PTCL, unspecified included in LNH87 and LNH93 trials were available. EBV status was studied by EBV-encoded small RNA in situ hybridization (EBER-ISH). EBER-ISH showed positive cells in 45 (41%) of 110 patients. Pretreatment characteristics were comparable between positive and negative cases, except for male sex (80% versus 60%, respectively, P = .02). Only 50% of patients achieved complete remission with a 5-year event-free survival (EFS) and overall survival (OS) of 21% and 30%, respectively. EBER-ISH positivity was the sole factor linked with worse EFS, with a 5-year probability of 11% for positive patients. In univariate analysis, factors affecting OS were EBER-ISH positivity, high LDH level, and age older than 60 years. In multivariate analysis, EBER-ISH was associated with a worse OS in the elderly population. Time-dependent analysis showed that the negative impact of EBV was essentially seen in the first 2 years following diagnosis. These results warrant further studies regarding pathogenesis and specific treatment approaches for EBV-associated PTCL patients.

Helicobacter pylori infection, the dominant risk factor for gastric cancers, has been shown to elicit T helper type 1 (Th1) polarized immunological responses. We conducted a population-based study of 305 gastric cancer cases and 427 age- and gender-matched controls in Warsaw, Poland, to evaluate the association with several variants in genes responsible for Th1-cell-mediated response. Genotyping was performed on genomic DNA by TaqMan(TM) assays to determine TNFA (-308 G>A, -417 G>A, -555 G>A, -1036 C>T, -1042 C>A, -1210 T>C), IL1A (-889 C>T), IFNGR2 (Ex7-128 T>C, Ex2-34 C>G and Ex2-16 A>G) and IL12A (IVS2-798 T>A, IVS2-701 C>A and Ex7+277 G>A) polymorphisms. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for sex, age, education and smoking status. Out of six single nucleotide polymorphisms (SNPs) tested in TNFA, gastric cancer risk was significantly associated with the TNFA (-308 G>A) polymorphism, with ORs of 1.4 (95% CI: 1.0-2.0) for the G/A and 2.5 (95% CI: 1.3-4.9) for the A/A genotype carriers, when compared with the more frequent genotype (G/G) (P-trend < 0.001). Among the three tested SNPs in the IFNGR2 gene, only the Ex7-128C>T polymorphism was associated with increased risk, with ORs of 1.5 (95% CI: 1.0-2.3) for T/C and 1.7 (95% CI: 1.1-2.7) for C/C carriers when compared with T/T carriers (P-trend = 0.01). Subjects carrying both IFNGR2 Ex7-128 C/C and TNFA -308 A/A genotypes had the highest risk (OR = 5.5, 95% CI: 1.5-19.4), although the interaction was not statistically significant. IL1A (-889 C>T) and the three examined IL12A variants were unrelated to gastric cancer risk. Our findings suggest that two Th1-related polymorphisms (TNFA -308 A>G and IFNGR2 Ex7-128 C>T) may increase the risk of gastric cancer.

The effects of sorafenib--an oral multikinase inhibitor targeting the tumour and tumour vasculature--were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with > or =25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with > or =25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had > or =25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had > or =25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

To carry out a randomized controlled trial of a decision aid for women at increased risk of developing ovarian cancer to facilitate decision making regarding risk management options.

A clinical trial was recently conducted to evaluate the safety and efficacy of a selective inhibitor of cyclooxygenase-2 (celecoxib) in hereditary nonpolyposis colon cancer patients. In a randomized, placebo-controlled phase I/II multicenter trial, hereditary nonpolyposis colon cancer patients and gene carriers received either celecoxib at one of two doses or placebo. The goal was to evaluate the effects of these treatment arms on a number of endoscopic and tissue-based biomarker end points after 12 months of treatment. As part of this trial, we analyzed gene expression by cDNA array technology in normal descending (rectal) colonic mucosa of patients before and after treatment with celecoxib or placebo. We found that treatment of patients with celecoxib at recommended clinical doses (200 and 400 mg p.o. bid), in contrast to treatment with placebo, leads to changes in expression of >1,400 genes in the healthy colon, although in general, the magnitude of changes is <2-fold. Twenty-three of 25 pairs of colon biopsies taken before and after celecoxib treatment can be classified correctly by the pattern of gene expression in a leave-one-out cross-validation. Immune response, particularly T- and B-lymphocyte activation and early steps of inflammatory reaction, cell signaling and cell adhesion, response to stress, transforming growth factor-beta signaling, and regulation of apoptosis, are the main biological processes targeted by celecoxib as shown by overrepresentation analysis of the distribution of celecoxib-affected genes across Gene Ontology categories. Analysis of possible cumulative effects of celecoxib-induced changes in gene expression indicates that in healthy colon, celecoxib may suppress the immune response and early steps of inflammation, inhibit formation of focal contacts, and stimulate transforming growth factor-beta signaling.

This study compared genetic nurse counsellors with standard services for breast cancer genetic risk counselling services in two regional genetics centres, in Grampian region, North East Scotland and in Cardiff, Wales. Women referred for genetic counselling were randomised to an initial genetic counselling appointment with either a genetic nurse counsellor (intervention) or a clinical geneticist (current service, control). Participants completed postal questionnaires before, immediately after the counselling episode and 6 months later to assess anxiety, general health status, perceived risk and satisfaction. A parallel economic evaluation explored factors influencing cost-effectiveness. The two concurrent randomised controlled equivalence trials were conducted and analysed separately. In the Grampian trial, 289 patients (193 intervention, 96 control) and in the Wales trial 297 patients (197 intervention and 100 control) returned a baseline questionnaire and attended their appointment. Analysis suggested at least likely equivalence in anxiety (the primary outcome) between the two arms of the trials. The cost per counselling episode was 11.54 UK pounds less for nurse-based care in the Grampian trial and 12.50 UK pounds more for nurse-based care in Cardiff. The costs were sensitive to the grade of doctor (notionally) replaced and the extent of consultant supervision required by the nurse. In conclusion, care based on genetic nurse counsellors was not significantly different from conventional cancer genetic services in both trial locations.