To characterize the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and food effect of orally administered irinotecan formulated as new semisolid matrix capsules.

Although there is general consensus concerning the efficacy of colorectal cancer screening, there is a lack of agreement about which routine screening strategy should be adopted. We compared the participation and detection rates achievable through different strategies of colorectal cancer screening.

Molecular predictors for the effectiveness of adjuvant chemotherapy in colorectal cancer are of considerable clinical interest. To this aim, we analyzed the serine threonine receptor-associated protein (STRAP), an inhibitor of TGF-beta signaling, with regard to prognosis and prediction of adjuvant 5-FU chemotherapy benefit.

Neuroblastoma (NB) is a pediatric cancer of highly variable clinical outcome. Much effort is devoted to detection of minimal residual (MRD) disease through RT-PCR or immunology of tissue-specific markers. Tyrosine hyrdroxylase (TH) has demonstrated a high utility to assess disease dissemination, although this marker can be lost due to clonal variability. Here we propose the use of the doublecortin (DCX) gene as a new molecular marker of neuroblastoma cells. DCX specifically appears in migrating neurons of the central and peripheral nervous system and interacts with and regulates the microtobule cytoskeleton. We have studied this gene by real-time quantitative RT-PCR in a total of 47 primary tumors and 202 samples of bone marrow or peripheral blood from 34 high-risk neuroblastoma patients as well as in 41 normal controls. The expression of DCX demonstrated a good specificity and concordance with TH, showing a higher expression rate in all the sample types studied as well as at different time points from diagnosis. We conclude that DCX would be a more efficient marker of minimal disease in neuroblastoma and perhaps other tumors of neuronal lineage.

To evaluate the effectiveness and cost-effectiveness of two complementary interventions, using familial breast cancer as a model condition. The primary care intervention consisted of providing computerised referral guidelines and related education to GPs. The nurse counsellor intervention evaluated genetic nurses as substitutes for specialist geneticists in the initial assessment and management of referred patients.

Due to the complexity of information surrounding BRCA1/2 counseling and testing and its time consuming nature, efforts to facilitate the genetic counseling and education process are needed. Using a 2 x 2 factorial design, two strategies were examined: a CD-ROM program for patients and a feedback checklist to the genetic counselor on patients' prior misconceptions. A total of 197 women attending a breast and ovarian cancer risk evaluation clinic for BRCA1/2 counseling were randomized into one of four conditions: standard care, CD-ROM only, feedback to counselor only, and both CD-ROM and feedback. Counseling outcomes included face-to-face time with the genetics team, knowledge acquisition, changes in worry about having a gene mutation, and genetic testing decisions. Overall, women who viewed the CD-ROM spent less time with the genetic counselor and were less likely to undergo genetic testing compared to women who did not view the CD-ROM. Feedback to the genetic counselor resulted in greater gains in knowledge of genetics and breast cancer. Among women less worried at baseline, those who viewed the CD-ROM showed no changes in worry following genetic counseling, in contrast to those who did not view the CD-ROM who increased in worry over time. This latter finding raises concerns about the impact of the increased worry on genetic testing decisions. No interaction effects of the two intervention arms were found. The study results support the importance of both strategies as valuable supplements to clinical BRCA1/2 counseling.

The role of all-trans retinoic acid (ATRA) in pediatric acute promyelocytic leukemia (APL) is the topic of several ongoing studies. The results of the Italian pediatric experience with the multicentric Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA)-Italian Pediatric Hematology and Oncology Group (AIEOP) "AIDA" (ATRA and idarubicin) trial are presented. Of the 983 patients with APL enrolled in this protocol between January 1993 and June 2000, 124 (13%) had younger than 18 years. Treatment consisted of ATRA and idarubicin induction followed by 3 polychemotherapy consolidation courses. Molecular response by reverse transcriptase-polymerase chain reaction (RT-PCR) was assessed after consolidation and patients who were PCR- were randomized for different maintenances. One hundred and seven children were eligible and evaluable for induction: 103 (96%) achieved a hematologically complete remission. Overt ATRA syndrome was observed in 2 patients and pseudotumor cerebri was observed in 10 patients. Ninety-four patients were evaluable for RT-PCR analysis at the end of consolidation: 91 (97%) proved PCR+ and 3 PCR-. The overall survival and event-free survival (EFS) are 89% (95% confidence interval [c.i.]: 83%-95%) and 76% (c.i.: 65%-85%), respectively, at more than 10 years. A white blood cell (WBC) count at diagnosis of greater than 10 x 10(9)/L had a significant impact on EFS (59% vs 83% at 10 years). These results highlight the efficacy and feasibility of the AIDA protocol in the pediatric APL population.

Patients with T-cell acute lymphoblastic leukemias (T-ALLs) within the Leucemies Aigues Lymphoblastiques de l'Adulte-94 (LALA-94) prospective trial were treated with a 4-drug per 4-week induction, with intermediate-dose cytarabine and mitoxantrone salvage treatment for patients not achieving complete remission (CR) in 1 course. Only the latter received allografts, if possible, thus providing an informative setting for assessing early response. Representative patients with T-ALL (91 patients) were classified into surface T-cell receptor (TCR)-expressing T-ALL patients (TCRalphabeta+ or TCRgammadelta+), pre-alphabeta T-ALL patients (cTCRbeta+, TCR-), and immature (IM) cTCRbeta-, TCR- T-ALL patients; 81 patients underwent genotyping for SIL-TAL1, CALM-AF10, HOX11, and HOX11L2. Overall, CR was obtained in 81 (89%) patients; relapse rate was 62% at 4 years and overall survival (OS) rate was 38%. CR rate was significantly lower in IM T-ALL patients after 1 course (45% vs 87%; P < .001) and after salvage (74% vs 97%; P = .002), with the latter inducing a higher rate of CR (9 [64%] of 14) than initial induction. Once CR was obtained, cumulative relapse rates were similar for IM, pre-alphabeta, and TCR+ T-ALL patients (P = .51), but were higher in HOX11L2 (83%) and SIL-TAL1 (82%) T-ALL patients compared with other genetic subgroups (48%; P = .05). This was associated with an inferior OS for HOX11L2 T-ALLs (13% vs 47% in HOX11L2-T-ALLs; P = .009). The majority of patients with HOX11 T-ALL underwent allografting, predominantly in second CR, but were not associated with a superior OS. Both TCR and genotypic stratification can therefore contribute to risk-adapted management of adult T-ALLs.

Radiotherapy is a very effective adjuvant treatment for rectal cancer with little side effects. Its killing effect on tumor cells seems to be more profound than the effect on normal tissue. The molecular events caused by irradiation are mainly analyzed in in vitro and animal models; investigations on human material are rare. In the current study, we analyzed the effects of irradiation on gene expression in normal and tumor tissue of rectal cancer patients.

cDNA arrays and proteomic analyses have allowed the rapid identification of specific genes and proteins implicated in multiple tumor types. These molecules must then be validated as clinically relevant prognostic and predictive markers, and this translational research is best conducted in the context of clinical trials. Outcomes data and clinical specimens collected in the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) study, for example, can now be used to compare the expression of biomarkers with clinical outcomes. In this study, adjuvant tamoxifen and anastrozole ('Arimidex') were compared alone and in combination in more than 9000 women with breast cancer. Anastrozole was found to be superior to tamoxifen in terms of disease-free survival, time to recurrence, and reduction in the incidence of contralateral tumors. Importantly, tissue specimens from surgical excision, local relapse, and contralateral breast cancer were collected and paraffin-embedded for storage. In the TA01 (TransATAC) program, these specimens will be studied (after obtaining patient consent) using tissue microarrays; tissue biopsy cores 0.6 mm in diameter will be removed from donor blocks and placed on recipient blocks, which will be sectioned to allow the simultaneous analysis of the same samples for multiple biomarkers. These analyses can help determine differential benefits of treatment with anastrozole or tamoxifen, depending on the expression of particular biomarkers in tumor cells. This research also should clarify de novo and acquired resistance mechanisms, and the validation of relevant molecular pathways could guide the development of new drugs. Ultimately, the TA01 program has the potential to favorably impact treatment choices for breast cancer.

The likelihood of distant recurrence in patients with breast cancer who have no involved lymph nodes and estrogen-receptor-positive tumors is poorly defined by clinical and histopathological measures.

Barrett's oesophagus is a major risk factor for developing oesophageal adenocarcinoma. Ablation by argon plasma coagulation (APC) and photodynamic therapy (PDT) is currently under investigation for the removal of metaplastic and dysplastic Barrett's oesophagus. This study examined the effect of ablative therapy on Barrett's oesophagus at cell-cycle and genetic levels. The premalignant potential of residual or recurring Barrett's oesophagus was assessed by p53 immunohistochemistry, Ki67-related proliferative capacity, and DNA ploidy status (ie an abnormal chromosome 1 number) as measured by interphase in situ hybridization. Twenty-nine patients with Barrett's oesophagus (23 male and 6 female, mean age 58 years, mean length of Barrett's oesophagus 4 cm) were treated with APC or PDT. Intestinal metaplasia without dysplasia was present in 16 patients, low-grade dysplasia in five, and high-grade dysplasia in eight patients. Biopsy samples were obtained at regular intervals (mean follow-up 20 months, range 6-36 months). One month after the first ablation, Barrett's oesophagus was no longer identified, either endoscopically or histologically, in nine patients (32%). At this time point, significant down-grading was achieved for abnormal chromosome 1 numbers (p = 0.020) and Ki67-defined proliferation (p = 0.002). Patients with residual Barrett's oesophagus were additionally treated with APC, resulting in the elimination of Barrett's oesophagus in 76% of all patients. However, at the last follow-up endoscopy, metaplasia without dysplasia was still present in five patients, and low- and high-grade dysplasia were each present in one patient. An abnormal chromosome 1 number and p53 protein overexpression were detected only in the high-grade dysplastic lesion, but increased proliferation was still present in the majority of these persisting cases. Although endoscopic removal of Barrett's oesophagus by ablative therapies is possible in the majority of patients, histologically complete elimination cannot be achieved in all cases. Persistent Barrett's oesophagus may still harbour molecular aberrations and must therefore be considered still to be at risk of progression to adenocarcinoma.

Overexpression of erbB2 in breast tumours can predict resistance to tamoxifen therapy. We conducted a small trial to determine if erbB2 status correlates with tumour response and biochemical changes in postmenopausal women receiving neoadjuvant therapy with the aromatase inhibitor, anastrozole. Twenty-four postmenopausal women with oestrogen receptor (ER)-rich, large, operable breast tumours received three months of neoadjuvant anastrozole, 1 or 10 mg daily, then surgery, followed by another five years of anastrozole 1 mg daily. Response to the treatment was based on changes in clinical and ultrasound measurements of tumour volume and changes in tumour proliferation and progesterone receptor (PgR) status. After follow-up for a median duration of four years therapy, there was no apparent difference between erbB2 0/1+ and erbB2 3+ tumours in clinical response or changes in proliferation and PgR expression. In conclusion, anastrozole appears to be an effective endocrine option in this patient population, irrespective of the erbB2 status.

To evaluate the predictive value of HER-2 in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin (A) or with single-agent docetaxel (T).

The combination of irinotecan and a fluoropyrimidine has been widely accepted as a treatment for advanced colorectal carcinoma. However, there have been no evaluable data on the feasibility of these combinations. To assess the significance of such combinations, we attempted to identify gene expression patterns in response to irinotecan and two different types of fluoropyrimidines. In 12 patients dispositioned to receive preoperative chemotherapy for colorectal carcinoma, pre-therapy tumor biopsies and final resected specimens were available for analysis. Patients were randomly assigned to receive one of the following four regimens: (I), oral doxifluridine; (II), intravenous infusion of 5-FU; (III), intravenous infusion of irinotecan; (IV), combination of doxifluridine and irinotecan (I+III). To identify genes whose expressions changed, we analyzed the gene expression profiles prior to and after these therapies using an oligonucleotide microarray consisting of 12,000 genes. Next, we focused on the genes that demonstrated similar kinetics of altered expression in all patients in each of the regimens. We identified two proto-oncogenes, nuclear receptor of T-cells (NOT) and c-fos, that were up-regulated in doxifluridine- and irinotecan-related regimens but unchanged in the 5-FU-related regimen. Moreover, group IV tumors showed the highest apoptotic rate and lowest proliferation activity following the combined chemotherapy. These results suggest that doxifluridine has a synergistic impact on the therapeutic effect of irinotecan by up-regulating proto-oncogenes such as NOT and c-fos, and thus justify the use of one of the irinotecan and fluoropyrimidine combinations.

There is an increased risk of colorectal carcinoma (CRC) in patients with longstanding, extensive colonic inflammatory bowel disease (IBD). Primary sclerosing cholangitis, family history of CRC, mucosal dysplasia and DNA-aneuploidy are other risk factors. Recently, results from animal studies have shown that the bile acid ursodeoxycholic acid (UDCA) has a favourable impact on experimentally-induced CRC/neoplasia in rats. The aim of this proof of the concept study was to explore the possible preventive/reverting effects of UDCA in patients with colorectal IBD with existing findings of low grade dysplasia and/or DNA-aneuploidy.

Colorectal carcinoma is one of the most common malignancies in the world, and its incidence has increased in recent years. We have reported that expression of hypoxia-inducible factor (HIF)-1alpha correlates with expression of vascular endothelial growth factor (VEGF), tumor stage, lymphatic invasion, venous invasion, and liver metastasis. It has also been reported that a single nucleotide polymorphism (SNP) in exon 12 of HIF-1alpha gene is present in renal cell carcinoma and head and neck squamous cell carcinoma patients. We investigated the C1772T polymorphism in colorectal cancer patients and healthy control subjects to clarify the mechanism of HIF-1alpha activation in colorectal carcinoma. The exon 12 genotype was not associated with sex or age. The distribution of HIF-1alpha genotypes in controls was 89 C/C (89%), 11 C/T (11%), and 0 T/T (0%). The distribution of HIF-1alpha genotypes in colorectal cancer patients was 100 C/C (100%), 0 C/T (0%), and 0 T/T (0%). The difference in genotype distribution between patients and control subjects was significant (p<0.0005). These results suggest that the C1772T polymorphism in HIF-1alpha is not involved in progression or metastasis of colorectal carcinoma.

Most clear cell renal cell cancer (RCC) is caused by biallelic loss of the von Hippel-Lindau gene. One consequence of this loss is up-regulation of vascular endothelial growth factor via a pathway involving accumulation of hypoxia inducible factor. Vascular endothelial growth factor, a potent angiogenic factor, is secreted by many human cancers, but clear cell RCC as a group produces particularly high levels and has a highly vascular histologic appearance. In a randomized, placebo-controlled, double-blind trial, we tested the use of a neutralizing antibody to vascular endothelial growth factor, bevacizumab, in patients with metastatic RCC. At 3 or 10 mg/kg every 2 weeks, toxic effects were minimal, with hypertension and proteinuria the most substantial events. There were four partial responses (10% response rate) and a highly substantial prolongation of time to tumor progression in patients who received the higher dose of bevacizumab. With a crossover design and very sensitive criteria for disease progression, no difference in survival was shown. Four patients have been undergoing long-term bevacizumab therapy without tumor progression for 3 to 5 years. Three have substantial proteinuria but retain normal renal function. A small pilot trial combining bevacizumab and thalidomide showed no unexpected toxic effects. Future trials should consider combination therapies and strategies in which patients are treated through initial disease progression with antiangiogenic agents such as bevacizumab.

Little research is available on the level of knowledge about ovarian cancer risk management options in women at increased risk for this disease. The study objectives were to evaluate this together with the information and ovarian cancer risk management preferences of high-risk women. One hundred and twenty-nine women were assessed after their attendance at one of six familial cancer clinics in relation to knowledge of surveillance and/or preventative strategies for reduction of ovarian cancer risk, preferences for particular strategies, and information preferences. Screening was selected by 57 (44%) women as the preferred risk management option. One hundred and five women (82%) indicated a wish for as much information as possible about ovarian cancer, including both good and bad outcomes and 114 (89%) reported a preference for sharing treatment decisions with their health professional. Participants' knowledge about ovarian cancer risk management options was significantly associated with educational levels (Z = -3.2, p=0.001) and whether or not ovarian cancer was included in the family history (Z = -2.3, p = 0.018). Findings from this present study indicate that women at increased risk of ovarian cancer who attend familial cancer clinics want as much information as possible about this disease and they want to be involved in the decision-making process. Women who reported a lower level of education (no post-school qualifications) may be most likely to benefit from additional educational strategies designed to supplement genetic counseling to improve their knowledge levels.

To study efficacy of maintenance therapy of patients with acute promyelocytic leukemia (APL) in the APL treatment Russian multicenter trial.