This study sought to evaluate physical activity in women at moderate risk for breast cancer, the correlates of engaging in regular physical activity, and whether physical activity relates to psychological well-being. The results revealed that 55% of women were regularly active. Logistic regression models indicated that positive affect was associated with increased and negative affect was associated with decreased overall and leisure activity. Older, married, and employed women were more likely to engage in household/occupational activity, whereas women who perceived their risk for breast cancer as high were less likely. More educated women and those with higher perceived risk were more likely to engage in leisure activity, and married women were less likely. These results suggest a need to increase activity levels in women at moderate risk for breast cancer, provide variables upon which interventions can be tailored to promote activity, and point to psychological benefits of activity in this population.

The purpose of this study was to investigate the prognostic implications of BCL6 rearrangement in a uniformly treated population of patients with diffuse large B-cell lymphoma (DLBCL) and to characterise the relationship between BCL6 rearrangement and prognostic factors. A total of 269 patients with DLBCL entered a randomised trial comparing the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) to the MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) regimen. In 44 cases, frozen tissue was available for assessment of BCL6 status by Southern blot analysis. BCL6 was rearranged in six of 43 evaluable cases (14%), and was associated with elevated lactate dehydrogenase (LDH), and a higher patient age. No association between BCL6 status and expression of BCL2, Ki-67 or TP53 was found. Patients presenting with BCL6 rearrangement displayed a weak trend towards better overall and failure-free survival (67 and 67% at 5 years), compared to patients with germline BCL6 (63 and 52%), but the difference was not statistically significant. In accordance with previously published series, the presence of BCL6 rearrangement does not define a prognostically distinct subgroup of DLBCL. Assessment of BCL6 status may, however, be of clinical interest when related to other prognostic variables.

Manipulations capable of breaking host tolerance to induce tissue-specific T cell-mediated inflammation are of central importance to tumor immunotherapy and our understanding of autoimmunity. We demonstrate that androgen ablative therapy induces profuse T cell infiltration of benign glands and tumors in human prostates. T cell infiltration is readily apparent after 7-28 days of therapy and is comprised predominantly of a response by CD4+ T cells and comparatively fewer CD8+ T cells. Also, T cells within the treated prostate exhibit restricted TCR Vbeta gene usage, consistent with a local oligoclonal response. Recruitment/activation of antigen-presenting cells in treated prostate tissues may contribute to local T cell activation. The induction of T cell infiltration in prostate tissues treated with androgen ablation may have implications for the immunotherapeutic treatment of prostate cancer as well as other hormone-sensitive malignancies, including breast carcinoma.

Cyclosporine A (CsA) inhibits P-glycoprotein (Pgp)-mediated cellular export of anthracyclines at clinically achievable concentrations. This randomized controlled trial was performed to test the benefit of CsA addition to treatment with cytarabine and daunorubicin (DNR) in patients with poor-risk acute myeloid leukemia (AML). A total of 226 patients were randomly assigned to sequential treatment with cytarabine and infusional DNR with or without intravenous CsA. Remitting patients received one course of consolidation chemotherapy that included DNR with or without CsA as assigned during induction. Addition of CsA significantly reduced the frequency of resistance to induction chemotherapy (31% versus 47%, P =.0077). Whereas the rate of complete remission was not significantly improved (39% versus 33%, P =.14), relapse-free survival (34% versus 9% at 2 years, P =.031) and overall survival (22% versus 12%, P =.046) were significantly increased with CsA. The effect of CsA on survival was greatest in patients with moderate or bright Pgp expression (median 12 months with CsA versus 4 months for controls) compared to patients with absent or low Pgp expression (median 6 months in both arms). The frequency of induction deaths was 15% with CsA and 18% in controls. Steady-state serum concentrations of DNR (P =.0089) and daunorubicinol (P <.0001) were significantly higher in CsA-treated patients. Survival (P =.0003) and induction response (P =.028) improved with increasing DNR concentration in CsA-treated patients but not in controls, suggesting a targeted interaction by CsA to enhance anthracycline cytotoxicity. These results indicate that addition of CsA to an induction and consolidation regimen containing infusional DNR significantly reduces resistance to DNR, prolongs the duration of remission, and improves overall survival in patients with poor-risk AML.

Bile has been implicated in the pathogenesis of duodenal polyps in patients with familial adenomatous polyposis. In vitro experiments have shown that familial adenomatous polyposis bile is capable of producing DNA adducts. This effect can be ameliorated by increasing the pH of the incubate. The aim of this double-blind randomized placebo-controlled trial was to examine the effect of oral ranitidine on duodenal polyposis in a group of patients with familial adenomatous polyposis.

Among cancer-free women aged 35 years or older, tamoxifen reduced the incidence of estrogen receptor (ER)-positive but not ER-negative breast cancer. The effect of tamoxifen on breast cancer incidence among women at extremely high risk due to inherited BRCA1 or BRCA2 mutations is unknown.

To observe the polymorphism of metabolizing enzyme N-actyltransferase 2 gene in populations with history of colorectal adenoma and polyp and to explore the relationship between NAT2 gene phenotype and colorectal cancer genetic susceptibility.

A randomised, controlled trial in progress in 14 United Kingdom and six Italian centres is evaluating screening for colorectal cancer using a single flexible sigmoidoscopy (FS) at around the age of 60 with removal during FS of all small adenomas, and colonoscopy for "high risk" polyps. The regimen aims to ensure that 95% of people (with either no polyps or only low risk polyps) complete the entire screening process in a single visit. This paper describes the rationale and design of the trial. Participants were patients aged between 55 and 64 on the lists of designated general practitioners (GPs) who were not excluded by their GP. A two stage recruitment procedure was employed to raise compliance rates in the intervention group. Potentially eligible persons were sent an "interest in screening" questionnaire; those who responded positively were randomised to the intervention or control groups. The trial is sufficiently large to estimate within narrow confidence intervals the magnitude of benefit and the duration of effect and optimum age for a single screen. It also examines the feasibility and acceptability of the screening regimen, and will identify training and quality assurance issues. Recruitment and screening are now complete and all baseline data have been collected. The first analysis of the effect on colorectal cancer incidence and mortality rates and suitability for a national screening programme can be expected in 2004.

It has been suggested that primary care should become more involved in providing genetic services, such as basic risk assessment, to enable patients with a moderate/high risk to be referred and those with a low risk to receive reassurance and advice from their general practitioner (GP). However, GPs currently lack knowledge and confidence in this area.

Peripheral blood cell (PBC) rescue has become the mainstay for autologous transplantation in patients with lymphoma, multiple myeloma, and solid tumors. Different methods of hematopoietic progenitor cell (HPC) mobilization are in use without an established standard. Forty-seven patients with relapsed or refractory lymphoma received salvage chemotherapy and were randomized to have HPC mobilization using filgrastim [granulocyte-colony-stimulating factor (G-CSF)] alone for 4 days at 10 microg/kg per day (arm A) or cyclophosphamide (5 g/m(2)) and G-CSF at 10 microg/kg per day until hematologic recovery (arm B). Engraftment and ease of PBC collection were primary outcomes. All patients underwent the same high-dose chemotherapy followed by reinfusion of PBCs. There were no differences in median time to neutrophil engraftment (11 days in both arms; P =.5) or platelet engraftment (14 days in arm A, 13 days in arm B; P =.35). Combined chemotherapy and G-CSF resulted in higher CD34(+) cell collection than G-CSF alone (median, 7.2 vs 2.5 x 10(6) cells/kg; P =.004), but this did not impact engraftment. No differences were found in other PBC harvest outcomes or resource utilization measures. A high degree of tumor contamination, as studied by consensus CDR3 polymerase chain reaction of the mobilized PBCs, was present in both arms (92% in arm A vs 90% in arm B; P = 1). No differences were found in overall survival or progression-free survival at a median follow-up of 21 months. This randomized trial provides clinical evidence that the use of G-CSF alone is adequate for HPC mobilization, even in heavily pretreated patients with relapsed lymphoma.

Recent studies have suggested relative radioresistance in glioblastoma multiforme (GM) tumors in older patients, consistent with their shorter survival. Two common molecular genetic abnormalities in GM are age related: epidermal growth factor receptor (EGFR) overexpression in older patients and p53 mutations in younger patients. We tested whether these abnormalities correlated with clinical heterogeneity in GM response to radiation treatment.

The purpose of this study was to describe and compare patient preferences for a genetic counselor or an interactive computer program for various components of genetic education and counseling for breast cancer susceptibility. As part of a randomized intervention study on genetics education and counseling for breast cancer risk, 29 women at moderate risk were educated by both a genetic counselor and an interactive computer program. After both educational interventions, participants completed Likert-style and open-ended questionnaires about what they liked most and least about each intervention, and whether they preferred the counselor or computer for a variety of tasks. Participants were largely satisfied with both the computer program and the genetic counselor. A majority preferred the genetic counselor for addressing their concerns, discussing options and alternatives, being sensitive to emotional concerns, helping to make a decision, being a good listener, assuring understanding, helping to make a good choice, helping to understand genes and breast cancer, telling them what they needed to know, being respectful, setting a relaxed tone, and putting them at ease. However, a majority of the women either preferred the computer program or were neutral about allowing patients to learn at their own pace, helping to avoid embarrassment, making good use of time, explaining genes and breast cancer, and treating the patient as an adult. Qualitative analysis of open-ended questions affirmed that patients valued the personal interactions with the counselors, and liked having their specific questions answered. They liked that the computer was self-paced, informative and private, and could be used without causing embarrassment. We concluded that a computer literate, mostly white group of women at moderate risk for inherited susceptibility to breast cancer preferred interacting with a genetic counselor for personal, individualized components of the genetic counseling process, but accepted or preferred a computer program for being self-paced, private, and informative. By incorporating such a computer program into the genetic education process, it is possible that genetic counselors would be able to spend more time performing the personal, individualized components of genetic counseling.

As genetic testing for susceptibility to breast cancer becomes more widespread, alternative methods for educating individuals prior to testing will be needed. Our objective was to compare face-to-face education and counseling by a genetic counselor with education by an interactive computer program, assessing the effects of each on knowledge of breast cancer genetics and intent to undergo genetic testing. We used a randomized, controlled trial. Seventy-two self-referred women with a first-degree relative with breast cancer received outpatient education and counseling at the Clinical Center of the National Institutes of Health (NIH). Twenty-nine received individualized counseling from a genetic counselor (counseling group), 29 received education from an interactive computer program followed by individualized counseling (computer group), and 14 were controls. Both pre- and postintervention assessment of knowledge about breast cancer genetics and intent to undergo genetic testing were measured. The control group participants correctly answered 74% of the knowledge questions; the counselor group, 92%; and the computer group, 96% (P <.0001). Unadjusted mean knowledge scores were significantly higher in the computer group than the counselor group (P =.048), but they were equivalent when adjusted for demographic differences (P = 0.34). Intent to undergo genetic testing was influenced by the interventions: preintervention, a majority in all groups (69%) indicated that they were likely (definitely and most likely) to undergo testing; after either intervention coupled with counseling, only 44% indicated that they were likely to do so (P =.0002; odds ratio = 2.8, 95% CI = 1.7-4.9). We concluded that a computer program can successfully educate patients about breast cancer susceptibility, and, along with genetic counseling, can influence patients' intentions to undergo genetic testing.

To conduct timely epidemiologic investigations of molecular/genetic markers that may contribute to the development of prostate, lung, colorectal, or other cancers within the Selenium and Vitamin E Cancer Prevention Trial (SELECT), and to evaluate interactions between these markers and the study interventions.

The recent identification of several BRCA1/BRCA2 founder mutations among Ashkenazi Jewish individuals has led to increased salience of BRCA1/BRCA2 testing for Jewish individuals. Little is known about interest in BRCA1/BRCA2 testing among Ashkenazi Jews from the general population. Furthermore, previous research has not generally evaluated the impact of education on interest in testing among individuals from the general population. The goal of the current study was to examine whether a brief educational booklet regarding BRCA1/BRCA2 testing would influence knowledge, attitudes, and interest in testing among Ashkenazi Jewish women from the general population.

In acute myeloid leukemia (AML), further prognostic determinants are required in addition to cytogenetics to predict patients at increased risk of relapse. Recent studies have indicated that an internal tandem duplication (ITD) in the FLT3 gene may adversely affect clinical outcome. This study evaluated the impact of a FLT3/ITD mutation on outcome in 854 patients, mostly 60 years of age or younger, treated in the United Kingdom Medical Research Council (MRC) AML trials. An FLT3/ITD mutation was present in 27% of the patients and was associated with leukocytosis and a high percentage of bone marrow blast cells (P <.001 for both). It had a borderline association with a lower complete remission rate (P =.05) and a higher induction death rate (P =.04), and was associated with increased relapse risk (RR), adverse disease-free survival (DFS), event-free survival (EFS), and overall survival (OS) (P <.001 for all). In multivariate analysis, presence of a mutation was the most significant prognostic factor predicting RR and DFS (P <.0001) and was still significant for OS (P =.009) and EFS (P =.002). There was no evidence that the relative effect of a FLT3/ITD differed between the cytogenetic risk groups. More than one mutation was detected in 23% of FLT3/ITD(+) patients and was associated with worse OS (P =.04) and EFS (P =.07). Biallelic disease or partial/complete loss of wild-type alleles was present in 10% of FLT3/ITD(+) patients. The suggestion is made that detection of a FLT3/ITD should be included as a routine test at diagnosis and evaluated for therapeutic management.

The dithiolethione oltipraz is being developed as a chemopreventive agent for many malignancies, including colorectal cancer, on the basis of its in vivo protective activity against chemically induced tumors in a variety of animal models. This protection has been associated with an enhanced capacity to detoxify reactive carcinogens and, more recently, with increased DNA repair. In a previous single-dose study, elevated detoxification gene expression was observed in the days after oltipraz dosing. Now, in this clinical study, we evaluated the effects of oltipraz when given over a 3-month period. Fourteen individuals with increased risk for colorectal cancer were randomly assigned to one of two oral doses (125 or 250 mg/m2) of oltipraz twice weekly for 12 weeks. Two of seven subjects at the 250 mg/m2 dosage required dose reductions, owing to significant fatigue. The 125 mg/m2 dose level was well tolerated by all patients. Blood or colon tissue (or both) for evaluation of glutathione, glutathione S-transferase, DT-diaphorase activity, and DT-diaphorase mRNA expression were obtained prior to treatment and at weeks 6, 12, and 16. No significant modulation of phase II detoxification enzymes was seen at either dose studied during this period. Phase II trials evaluating a tolerable regimen of oltipraz (as demonstrated in this study) and other possible mechanisms that may be responsible for the protective activity of oltipraz should be pursued.

Acute myeloid leukemia (AML) in older adults carries a poor prognosis, and the optimum treatment remains to be determined. In younger patients, treatment stratification is frequently based upon diagnostic karyotype, which was the most important prognostic factor in the UK Medical Research Council (MRC) AML10 trial. Considered here is whether karyotype is also predictive in older adults; this is done by studying 1065 cases from MRC AML11 (median age, 66 years). Three prognostic groups were distinguished on the basis of response to induction therapy and overall survival (OS). Those with t(15;17), t(8;21), or inv(16) composed the favorable risk group. Overall, these abnormalities predicted a superior complete remission (CR) rate (72%), reflecting relatively low levels of resistant disease (RD) (8%), and lower relapse risk (RR) (56%) associated with superior OS (34% at 5 years). Normal karyotype (CR, 63%; RD, 17%; RR, 78%; OS, 15%) and other noncomplex abnormalities (CR, 53%; RD, 32%; RR, 85%; OS, 10%) composed the intermediate group; while complex karyotype predicted an extremely poor prognosis (CR, 26%; RD, 56%; RR, 91%; OS, 2%). Combining MRC AML10 and AML11 (n = 2677) revealed that the most favorable changes were rarer in older patients (younger than 55 years, 24%; 55 years or older, 7%), while complex abnormalities were more common (6% vs 13%). This study suggests that hierarchical cytogenetic classification identifies biologically distinct subsets of AML that are represented in all age groups. Furthermore, it highlights the importance of karyotype as a critical independent determinant of outcome in older patients with AML, providing a potential framework for stratified treatment approaches.

To measure psychological distress and test the feasibility of a psychological intervention to reduce distress in patients undergoing risk assessment.

Thymidylate synthase (TS) is the target enzyme of 5-fluorouracil (5-FU), and dihydropyrimidine dehydrogenase (DPD) is the key enzyme in the 5-FU catabolic pathway. We wanted to determine whether the TS and DPD mRNA expression levels of gastric and colorectal cancer patients would be affected by tegafur (futrafur:FT)-based chemotherapy and whether changes in their expression might be responsible for patient outcome. Thirty-five patients with resectable advanced primary gastric cancer and 36 patients with resectable advanced primary colorectal cancer were the subjects of this study. They all underwent neoadjuvant chemotherapy with protracted infusion of FT alone or FT plus low doses of cisplatin. The TS and DPD mRNA expression levels of endoscopic biopsy specimens before chemotherapy and surgical specimens after chemotherapy were measured by TaqMan reverse transcription-PCR assay using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as the internal standard. There was a significant difference in the DPD mRNA levels during chemotherapy in the colorectal cancers. Although the TS and DPD levels were unrelated to any conventional histopathological grade factors, colorectal cancer patients whose surgical specimens contained lower TS and DPD mRNA levels had longer disease-free intervals. The results of this study suggest that FT may affect DPD mRNA expression in colorectal cancer patients, that TS/DPD expression can be regarded as an independent prognostic factor, and that colorectal cancer patients with low TS and low DPD mRNA are candidates for FT-based adjuvant chemotherapy. In addition, quantitative analysis of the change in TS/DPD mRNA in surgical specimens during FT-based chemotherapy might be a more accurate means of predicting the post-operative disease-free interval of colorectal cancer patients than analysis of endoscopic specimens before chemotherapy. There also seems to be a relation between regulation of TS and DPD during FT chemotherapy. Elucidation of the mechanisms regulating TS and DPD mRNA expression might make it possible to predict sensitivity and/or toxicity to FT.