It remains uncertain whether members of hereditary breast and ovarian cancer (HBOC) families experience psychological distress with genetic testing and whether pre-test counseling can have a moderating effect on client well-being. One purpose of this study was to assess change in psychological well-being from baseline to 6-9 months follow-up and the effect of a problem-solving training (PST) intervention on psychological well-being. Two hundred and twelve members of 13 HBOC families were offered BRCA1/2 testing for a previously identified family mutation. Participants received education and were randomized to one of two counseling interventions; PST or client-centered counseling. Psychological well-being was assessed at baseline and again at 6-9 months following the receipt of test results, or at the equivalent time for those participants who chose not to undergo testing. Well-being was assessed using measures of depressive symptoms (CESD), intrusive thoughts (IES), cancer worries, and self-esteem. Comparisons were made between those who chose testing and those who did not as well as between those who received positive and negative test results. One hundred eighty one participants elected to undergo genetic testing (85%) and 47 of these (26%) were identified as BRCA1/2 mutation carriers. Breast and ovarian cancer worries decreased significantly (p = 0.007 and 0.008, respectively) in those who tested negative while there was no appreciable change in psychological well-being from baseline to follow-up in either those who tested positive or in non-testers. Among all participants, particularly testers, those randomized to PST had a greater reduction in depressive symptoms than those randomized to client-centered counseling (p < 0.05 and p = 0.02, respectively). Regardless of the decision to test, individuals with a personal history of cancer (n = 22) were more likely to have an increase in breast cancer worries compared to those who had never been diagnosed with cancer (p < 0.001). Results suggest that a problem-solving counseling intervention may help to enhance psychological well-being following testing and that a personal history of cancer may increase psychological distress associated with genetic testing.

The aim of this study was to evaluate the usefulness of DNA flow cytometry to determine tumor nuclear DNA index (DI), and nucleolar organizer region protein counts visualized by the argyrophil (AgNOR) technique, in confirming diagnosis and predicting clinical outcome of patients with parathyroid carcinoma (PC). We reviewed paraffin-embedded tissue sections, from 15 patients (median age 63 years, range 30-68 years) with PC who died of the disease, which were randomly compared with tissue sections from 15 age- and sex-matched patients with parathyroid adenoma (PA). The proliferative activity in parathyroid tumours as detected by DI and AgNOR counts was evaluated in all specimens. Both DI (1.37 +/- 0.33 vs 1.0 +/- 0.1) and AgNOR (3.01 +/- 0.31 vs 1.54 +/- 0.35) counts were higher (P < 0.001) (Student's t-test) in patients with PC than in those with PA. Diploid (DI = 1), aneuploid (DI > 1) and hypoploid (DI < 1) neoplasms were found in 11 (PC = 4, PA = 7), 14 (PC = 11, PA = 3) and five (PC = 0, PA = 5) patients respectively. The average postoperative survival in patients with PC was 46.9 +/- 37.4 months (range 21-146 months). The survivals of patients with aneuploid (n = 11) and diploid (n = 4) PC were 74.0 +/- 58.1 and 34.1 +/- 18.4 months (P=0.21) respectively. There was a significant relationship between DI and AgNOR counts (R=0.69, P < 0.01), but no correlation was found between survival and both DI (Rho = 0.17, P = 0.55) and AgNOR counts (Rho = 0.26, P = 0.35). Moreover, there was no correlation (P = NS) between the main preoperative biochemical parameters and survival. In conclusion, DI and AgNOR are useful in confirming the diagnosis of PC, but they are of little value in predicting the clinical outcome of patients with PC.

The identification of an interaction between BRCA1 and acetyl-CoA carboxylase alpha (ACCalpha), a key enzyme in lipid synthesis, led us to investigate the role of ACCalpha in breast cancer development, where it might contribute to the energy-sensing mechanisms of malignant transformation. In order to investigate if certain ACCalpha alleles may be high-risk breast cancer susceptibility alleles, 37 extended breast and breast/ovarian cancer families negative for BRCA1 and BRCA2 mutations were exhaustively screened for sequence variations in the entire coding sequence, intron-exon junctions, 5'UTR, 3'UTR (untranslated regions) and the promoter regions of the ACCalpha gene. Two possibly disease-associated ACCalpha variants were each identified in a single family and were not present in 137 controls. Multiple polymorphisms were detected in breast cancer families, including 12 single nucleotide polymorphisms where the frequency of the rare allele estimated in controls was >0.10. The observed lack of variation in the ACCalpha coding region along with the presence of extended areas of linkage disequilibrium and low haplotype diversity indicates an overall high preservation of this gene. The prevalence of the ACCalpha haplotypes composed of common polymorphisms was determined in 453 breast cancer cases and 469 female controls. One haplotype was found to be associated with a substantial and highly significant increase in breast cancer risk (odds ratio = 3.10, 95% confidence interval 1.87-5.14, P < 0.0001), whereas three other haplotypes were found to have a protective effect. Our results indicate that mutations in the ACCalpha gene are unlikely to be a major cause of high-risk breast cancer susceptibility; however, certain common ACCalpha alleles may influence breast cancer risk. This study provides the first insight into the involvement of the ACCalpha gene in breast cancer predisposition and calls for further, large-scale studies that will be needed to understand the role of ACCalpha in tumour susceptibility and development.

Several polymorphisms in DNA repair genes have been reported to be associated with lung cancer risk including XPA (-4G/A), XPD (Lys751Gln and Asp312Asn), XRCC1 (Arg399Gln), APE1 (Asp148Glu) and XRCC3 (Thr241Met). As there is little information on the combined effects of these variants, polymorphisms were analyzed in a case-control study including 463 lung cancer cases [among them 204 adenocarcinoma and 212 squamous cell carcinoma (SCC)] and 460 tumor-free hospital controls. Odds ratios (OR) adjusted for age, gender, smoking and occupational exposure were calculated for the variants alone and combinations thereof. For homozygous individuals carrying the Glu variant of APE1, a protective effect was found (OR = 0.77, CI = 0.51-1.16). Individuals homozygous for the variants XPA (-4A) (OR = 1.53, CI = 0.94-2.5), XPD 751Gln (OR = 1.39, CI = 0.90-2.14) or XRCC3 241Met (OR = 1.29, CI = 0.85-1.98) showed a slightly higher risk for lung cancer overall. In the subgroup of adenocarcinoma cases, adjusted ORs were increased for individuals homozygous for XPA (-4A) (OR = 1.62, CI = 0.91-2.88) and XRCC3 241Met (OR = 1.65; CI = 0.99-2.75). When analyzing the combined effects of variant alleles, 54 patients and controls were identified that were homozygous for two or three of the potential risk alleles [i.e. the variants in nucleotide excision repair, XPA (-4A) and XPD 751Gln, and in homologous recombination, XRCC3-241Met]. ORs were significantly increased when all patients (OR = 2.37; CI = 1.26-4.48), patients with SCC (OR = 2.83; CI = 1.17-6.85) and with adenocarcinoma (OR = 3.05; CI = 1.49-6.23) were analyzed. Combinations of polymorphisms in genes involved in the same repair pathway (XPA + XPD or XRCC1 + APE1) affected lung cancer risk only in patients with SCC. These results indicate that lung cancer risk is only moderately increased by single DNA repair gene variants investigated but it is considerably enhanced by specific combinations of variant alleles. Analyses of additional DNA repair gene interactions in larger population-based studies are warranted for identification of high-risk subjects.

To evaluate a shared decision-making intervention (SDMI) for BRCA1/2 mutation carriers who have to make a choice between screening and prophylactic surgery for breasts and/or ovaries.

This trial examined the use of 4-hydroxyphenyl-retinamide (4-HPR), demonstrated to be a potent inhibitor of carcinogenesis in vitro and in animal models, in patients with cervical intraepithelial neoplasia (CIN) grades 2 to 3. Quantitative pathology and chromosome 9 polysomy were used to understand the biology and quantify the clinical histopathologic changes observed.

Depressive symptoms in the non-clinical range have been linked to increased health risks. Recent theorizing raises the possibility that heightened physiologic responses to acute stress and/or slowed stress recovery in individuals with depressive symptoms may contribute to increased risk. We investigated stress-induced catecholamine responses and recovery patterns using a modified version of the Trier Social Stress Test (15 min) with a sample of 52 healthy women and compared subgroups with high normal versus low scores on the Beck Depression Inventory (BDI, median split) to 29 women randomly assigned to a non-stressed control group. The BDI-high normal and BDI-low groups showed similar acute increases in epinephrine immediately post stressor, but only the BDI-high normal group remained significantly elevated above control group levels during the recovery period. No differences were found in norepinephrine responses. Elevations in BDI scores within the normal range may selectively predict slower physiological recovery following acute stress.

As the availability of and demand for genetic testing for hereditary cancers increases in primary care and other clinical settings, alternative or adjunct educational methods to traditional genetic counseling will be needed.

Distinction of high-grade esthesioneuroblastomas from other poorly differentiated tumors arising in the nasal cavity is an important diagnostic challenge because it determines patient management and prognosis. The human achaete-scute homologue (hASH1) gene is critical in olfactory neuronal differentiation and is expressed in immature olfactory cells; therefore, it could have potential use as a diagnostic marker The aim of the present study was to determine the value of hASH1 messenger RNA (mRNA) levels in differentiating esthesioneuroblastoma from other poorly differentiated tumors. A real-time polymerase chain reaction assay was developed, permitting the comparative determination of hASH1 mRNA levels in triplicate in a double-blind pilot study including 24 frozen cases of esthesioneuroblastoma and poorly differentiated tumors. All 4 positive cases were esthesioneuroblastomas, and all 19 poorly differentiated tumors were negative. In addition, there was an inverse association between the grade of esthesioneuroblastomas and hASH1 mRNA levels. The hASH1 mRNA level might represent a useful tool for distinguishing esthesioneuroblastoma from poorly differentiated tumors of the sinonasal region.

The evidence from epidemiological and experimental studies that vegetables reduce the risk of colorectal cancer is convincing. However, the involved genes and genetic pathways are not clear. The aim of this study was to identify genes that are modulated in vivo in colorectal mucosa by vegetables, and to investigate whether colon adenoma patients respond differently compared with healthy controls. Twenty female adenoma patients and eight healthy controls were randomly split into two groups of ten and four persons, respectively, receiving either a 50% decreased (=75 g/day) or doubled (=300 g/day) intake of vegetables for 2 weeks. In order to assess the effects on gene expression at the target level, colorectal biopsies were collected before and after the intervention. Total RNA was isolated from the biopsies to measure gene expression of 597 genes relevant for responses to xenobiotics by microarray technology, followed by confidence analyses to identify differentially expressed genes. Mainly genes related to cell cycle control and genes for oxidoreductase activities were over-represented in the list of modulated genes. Twenty genes were modulated, which are known to be related to (colon)carcinogenesis. Seven genes were similarly modulated in patients and controls, for example fos proto-oncogene and ornithine decarboxylase. Thirteen genes were modulated differently in patients compared with controls, including cyclooxygenase-2 and human mdm2-A in patients and cytochrome P45027B1, -2C19, -2D6, -2C9 and -3A4 in controls. Almost all the effects on modulating the expression of genes by altering vegetable intake can be mechanistically linked to cellular processes that explain either prevention of colorectal cancer risk by high vegetable intake or increased colorectal cancer risk by low vegetable intake. Furthermore, it seems that vegetables in patients affect genes involved in the late stage of colorectal cancer, whereas in controls genes involved in the initiation phase are modulated.

Various transplantation strategies have been designed to improve the poor prognosis of adult (ages 15 to 60 years) acute lymphoblastic leukemia (ALL). The GOELAL02 trial evaluated the impact of early allogeneic bone marrow transplantation (alloBMT) or delayed unpurged autologous stem cell transplantation (ASCT) for patients who had no human leukocyte antigen (HLA)-matched sibling donor or who were older than 50 years. Inclusion criteria included at least one of the following: age older than 35 years; non-T-ALL; leukocytosis greater than 30 x 10(9)/L; t(9;22), t(4;11), or t(1; 19); or failure to achieve complete remission (CR) after one induction course. Among 198 patients, the median age was 33 years. The CR rate was 80% with vincristine, idarubicine, L-asparaginase, and randomized intravenous injection or oral steroids (P = nonsignificant [ns]). AlloBMT was performed after 2 consolidation courses while ASCT was delayed after 1 additional reinduction. Intensified conditioning regimen before transplantation included etoposide, cyclophosphamide, and total body irradiation (TBI). Median follow-up was 5.1 years. The median overall survival (OS) was 29 months, with a 6-year OS of 41%. On an intent-to-treat analysis for patients younger than 50 years, alloBMT significantly improved the 6-year OS (75% versus 40% after ASCT; P = .0027). Randomized interferon-alpha maintenance had no effect on relapse or survival after ASCT. In conclusion, the outcome of adult ALL is better after early alloBMT than after delayed ASCT.

In general, elderly patients with aggressive non-Hodgkin's lymphoma (NHL) have a less favourable prognosis than younger patients. Established predictors of prognosis in NHL are less discriminatory in the elderly, which is why there is a need for additional markers giving guidance on treatment decisions and prediction of outcome. The expected length of life of an individual in the general population is intimately associated with that of his/her parents. The aim of this study was to test the hypothesis that parental longevity is associated with improved outcome also among elderly patients with aggressive NHL and thus serves as an easily accessible non-disease associated prognostic factor. A total of 220 patients ( > 60 years) with aggressive NHL with a median age of 71 years (range 60-86) were included. Patients were randomized to receive CHOP or CNOP (doxorubicin replaced with mitoxantrone) chemotherapy with or without the addition of granulocyte colony-stimulating factor. The median follow-up time was 56 (19-89) months. Parental data regarding age at death were available through parish offices for 425 (97%) parents. Relative risk (RR) of death (disease-specific and all-cause) associated with parental lifespan was assessed using Cox proportional hazards regression analyses, with adjustment for sex, age, prognostic index, symptoms, and calendar period of diagnosis. Maternal lifespan below (versus above) median was associated with a borderline significant reduced disease-specific (adjusted RR of death from NHL = 1.5; 95% confidence interval 1.0-2.1) and overall survival. The effect of maternal lifespan was somewhat more pronounced in patients receiving CHOP than CNOP treatment. Paternal lifespan below the median was associated with a borderline significant increased disease-specific (adjusted RR of death from NHL = 0.8 [0.5-1.0]) and overall survival. Combined, maternal, and paternal lifespan had little impact on survival. These effects were true also when CHOP and CNOP treated patients were analysed separately. Maternal and paternal lifespan may predict survival in NHL, but with opposing effects. At present parental age appears not to be a clinically useful predictor of prognosis in the elderly with aggressive NHL.

The AF1q gene, a mixed-lineage leukemia fusion partner, is highly expressed in hematopoietic progenitor cells but has low expression in differentiated cells. We determined the expression of the AF1q gene by reverse transcriptase-polymerase chain reaction in 64 pediatric acute myeloid leukemia (AML) patients treated on Children's Cancer Group clinical trial CCG-2891 and correlated its expression level to clinical characteristics and outcome. AF1q expression in patients varied from 0- to 154-fold compared with normal marrow, and increasing expression level was associated with worsening survival, with a hazard ratio of 1.02 per fold increase in AF1q expression (P = .032). We divided patients into tertile groups based on AF1q expression level. Patients with high AF1q expression (top tertile) had a higher predominance of French-American-British M1 compared to patients with lower 2 tertiles of AF1q expression (43% vs 9%, P = .003). High AF1q expression was associated with poor survival in univariate and multivariate models. Overall survival at 8 years for patients with the high AF1q expression was 19% versus 50% in patients with low AF1q expression, (P = .01). AF1q expression may correlate with clinical outcome in pediatric AML, although it is not clear if AF1q is simply a marker of a more primitive phenotype or contributes directly to leukemogenesis.

Identification of factors that assist prediction of tumor response to radiotherapy may aid in refining treatment strategies and improving outcome. Possible association of molecular marker expression profiles with locoregional control of head and neck squamous cell carcinoma was investigated in a randomized trial of conventional versus continuous hyperfractionated accelerated radiotherapy (CHART).

Although adjunctive educational and psychosocial programs are now being developed for BRCA1 and BRCA2 (BRCA1/2) mutation carriers, limited information is available about whether mutation carriers will want to receive such programs or about the characteristics of individuals who participate. The goals of the present study were to describe rates of completing a psychosocial telephone counseling (PTC) intervention that was offered to female BRCA1/2 mutation carriers and to identify sociodemographic and psychological factors associated with decisions to complete the intervention. Subjects were 66 BRCA1/2 mutation carriers who were randomized to receive a PTC intervention following receipt of genetic test results. Sociodemographic and psychological factors were evaluated before notification of assignment to the PTC intervention. Completion of the intervention was determined from study records. Overall, 75.8% of subjects completed the PTC intervention. Compared to unaffected subjects, those affected with breast and/or ovarian cancer were 76% less likely to complete the intervention [odds ratio (OR) = 0.24, 95% confidence interval (CI) = 0.06, 0.98, P = 0.05]. In addition, subjects with higher levels of cancer-specific distress [OR = 4.74, 95% CI = 1.02, 22.03, P = 0.05] and those with greater perceptions of social support [OR = 5.81, 95% CI = 1.29, 26.16, P = 0.02] were also most likely to complete the intervention. The results of this study suggest that while most BRCA1/2 mutation carriers are likely to complete an adjunctive psycho-educational program, personal history of cancer, cancer-specific distress, and perceptions of social support are likely to influence participation.

Antioestrogen treatment by tamoxifen is a well-established adjuvant therapy for oestrogen receptor-alpha (ERalpha) positive breast cancer. Despite ERalpha expression some tumours do not respond to tamoxifen and we therefore delineated the potential link between the cell cycle regulator and ERalpha co-factor, cyclin D1, and tamoxifen response in a material of 167 postmenopausal breast cancers arranged in a tissue array. The patients had been randomised to 2 years of tamoxifen treatment or no treatment and the median follow-up time was 18 years. Interestingly in the 55 strongly ERalpha positive samples with moderate or low cyclin D1 levels, patients responded to tamoxifen treatment whereas the 46 patients with highly ERalpha positive and cyclin D1 overexpressing tumours did not show any difference in survival between tamoxifen and no treatment. Survival in untreated patients with cyclin D1 high tumours was slightly better than for patients with cyclin D1 low/moderate tumours. However, there was a clearly increased risk of death in the cyclin D1 high group compared to an age-matched control population. Our results suggest that cyclin D1 overexpression predicts for tamoxifen treatment resistance in breast cancer, which is line with recent experimental data using breast cancer cell lines and overexpression systems.

Advances in genetics are allowing a greater number of clinical genetics services to be offered to individuals with family histories of particular diseases. It is important that such services are not allowed to proliferate before they have been properly evaluated in terms of both their clinical and cost-effectiveness. A randomised controlled study of a new clinical genetics service in Wales for women with a family history of breast cancer has been undertaken. The health service costs from initial consultation and counselling through to mutation testing within families were assessed, along with patient travel costs. The extra cost of specialist genetics assessment (intervention) was pound 16.36 higher per woman than assessment by a breast surgeon at a District General Hospital (control). A further cost of pound 46.42 per initially presenting woman was also generated as a result of further counselling within the families of 48, and testing within the families of 36 of the 412 original presenting women. An explanation is given here of the costing methodology as an illustration of what is involved in such an exercise.

To determine whether, after very intensive induction and consolidation therapy in childhood AML, further maintenance therapy (MT) confers any advantage.

Acute myeloid leukemia (AML) is a heterogeneous composition of biologically defined subgroups. Modern trials aim at developing subgroup-specific therapies. The German AML Cooperative Group 1999 trial asks three questions in a randomized factorial design: high-dose vs. standard-dose AraC during induction therapy; G-CSF priming vs. no G-CSF priming; and autologous stem cell transplantation vs. maintenance therapy. An interim analysis with 938 patients reveals subgroup-specific differences in treatment efficacies. Thus, the application of high-dose AraC during induction results in a superior outcome as compared to standard-dose AraC in patients with unfavorable prognosis but not in other patients. These results underline the need for large comprehensive trials to allow the detection of therapy effects in biologically defined subgroups of AML.

Staging systems and laboratory features help predict survival in chronic lymphocytic leukaemia but they do not distinguish patients who will progress from those whose disease will remain indolent. CD38 expression has emerged as an independent prognostic factor, yet there is debate as to what level of CD38 affects prognosis. We plotted the hazard ratios for the treatment-free interval (TFI) between the higher and lower groups defined by CD38 cut-offs from 0 to 100%. The maximum hazard ratio was achieved for a cut-off of 7%. We examined by triple colour analysis the values for CD38 in 289 untreated patients using both >or=30 and >or=7% as thresholds for prognosis. Using a >or=7% threshold (but not >or=30%), we showed a significant correlation with advanced stage and male sex. The interval from diagnosis to first therapy or TFI was longer (median 36 months) in patients with <7% CD38 positive cells than those with >or= 30% (8.7 months) or with intermediate values between 7 and 29% (P<0.00005). The <7% threshold also identified patients in stage A with a long TFI (P=0.0001). Multivariate analysis showed that CD38 has independent prognostic value for TFI in all patients. In 135 patients tested for deletions of p53, 13q14 and 11q23 and for trisomy 12, we showed a correlation between 13q14 deletion and <30%/<7% CD38 positive cells and a tendency for trisomy 12 to be associated with >or=30%/>or=7% CD38 positive cells. We conclude that 7% may be a more useful threshold for disease progression than higher values of CD38.