Risk perception and concern among brothers of men with prostate carcinoma

BACKGROUND: It is important for clinicians, researchers, and others who shape public health policy to understand the demographic correlates and psychologic factors that drive health behaviors, such as screening for early detection of cancer, particularly among individuals at high risk for developing the disease. METHODS: One-hundred eleven men whose brothers were diagnosed with prostate carcinoma completed a computer-assisted telephone interview aimed to assess their perception of absolute risk and concern about developing prostate carcinoma over the next 10 years and across their lifetime. Comparisons were made between selected demographic, behavioral, family pedigree characteristics, and measures of perceived risk and concern. RESULTS: The majority of men perceived their personal risk of developing prostate carcinoma to be > or =50%. Men who at the time of the interview were younger than their affected brother were significantly more concerned about prostate carcinoma and perceived their risk to be higher than men who were older than their brother. Estimates of personal risk and concern were also uniformly higher among men with more than one first-degree relative affected with prostate carcinoma compared to men with only one affected first-degree relative. Risk perception and concern about an impending prostate carcinoma diagnosis were associated with the use of supplements marketed for prostate health. CONCLUSIONS: The findings indicated that birth order in relation to a brother diagnosed with prostate carcinoma is significantly associated with risk perception and concern in unaffected family members. These results highlight the need for further study of the familial dynamics and characteristics that drive health behaviors and stress importance of public health education to inform men of personal risk assessment as well as the risks and benefits of screening. These studies ultimately can contribute to the success of strategies for the primary prevention and early detection of cancer.     

Feasibility and utility of using chromosomal aneusomy to further define the cytologic categories in nipple aspirate fluid specimens: a preliminary study

BACKGROUND: There is renewed interest in using the cytologic changes in the epithelial cells obtained from specimens such as nipple aspiration fluid (NAF) and ductal lavage for risk stratification of women at increased risk for developing breast carcinoma. METHODS: Molecular tests such as fluorescence in situ hybridization (FISH) have the potential to be used as adjuncts to conventional cytology for more accurately categorizing cells in these types of specimens. The current study investigated the feasibility and utility of FISH analysis of aneusomy in chromosomes 1, 8, 11 and 17 as an adjunct to conventional cytology in the classification of NAF specimens. RESULTS: The authors found chromosomal aneusomy for at least one chromosome in all three malignant and both markedly atypical cases. Of the five cases classified as being mildy atypical on cytology, four were disomic, and only one showed aneusomy in chromosomes 8 and 11. CONCLUSIONS: The current study established the possibilities, limitations, and feasibility of using FISH in conjunction with routine cytology for a more accurate classification of ductal epithelial cells in NAF specimens. FISH-based detection of chromosomal aneusomy helped to define mild atypia, thereby aiding in the selection of the truly atypical cases for appropriate therapeutic intervention. In addition, FISH-based detection of chromosomal aneusomy can also be a valuable adjunct to conventional cytology in selected cases for confirming a benign, suspicious, or malignant diagnosis.     

A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors

KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T-->C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT.     

High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells

Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate a systemic antitumor immune response. Although the minimal required GM-CSF dose produced by modified tumor cells to achieve a measurable antitumor effect is well known, no data examined whether an upper therapeutic limit may exist for this vaccination strategy. Because recent data demonstrate an immunosuppressive effect of GM-CSF produced by growing tumors, we thus sought to determine whether high GM-CSF doses administered in a vaccine formulation could impair antitumor immunity. Using a vaccine strategy involving a GM-CSF-producing bystander cell line (B78H1-GM) admixed with autologous tumor, we assessed the impact of varying doses of GM-CSF while maintaining a constant antigen dose. Our results defined a threshold above which a GM-CSF-based vaccine not only lost its efficacy, but more importantly for its clinical implications resulted in substantial immunosuppression in vivo. Above this threshold, GM-CSF induced Gr1+/CD11b+ myeloid suppressor cells that substantially impaired antigen-specific T-cell responses and adversely affected antitumor immune responses in vivo. The dual effects of GM-CSF are mediated by the systemic and not local concentration of this cytokine. Myeloid suppressor cell-induced immunosuppression is mediated by nitric oxide production via inducible nitric oxide synthase (iNOS) because the specific iNOS inhibitor, l-NMMA, restored antigen-specific T-cell responsiveness in vitro. Taken together, our data demonstrated the negative impact of supra-therapeutic vaccine doses of GM-CSF and underscored the importance of identifying these critical variables in an effort to increase the therapeutic efficacy of tumor vaccines.     

Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis

Purpose To test the anticancer properties of a nonhydrolyzable ether-linked acetic acid analogue of vitamin E, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid (-TEA), and a derivative of camptothecin, 9-nitrocamptothecin (9-NC) singly and in combination against mouse mammary tumor cells (line 66 clone 4 stably transfected with green fluorescent protein; 66c1-4-GFP) cultured in vitro or transplanted subcutaneously into the inguinal region of female BALB/c mice to form established tumors.Methods Following in vitro treatment of 66cl-4-GFP cells with -TEA and suboptimal concentrations of 9-NC, singly or in combination, apoptosis was measured by morphological evaluation of nuclei stained with 4,6-diamidino-2-phenylindole (DAPI), and DNA synthesis arrest was measured by tritiated thymidine uptake. For in vivo analyses -TEA and 9-NC, both water-insoluble compounds, were formulated into liposomes using dilauroylphosphatidylcholine and administered by aerosol to deliver doses calculated to be 36 and 0.4 g/mouse per day, respectively, (singly or each separately for combined treatments) 7 days per week.Results Treatment of 66cl-4-GFP cells in culture for 3 days with a combination of -TEA (10 g/ml; singly produces 38% apoptosis), and suboptimal concentrations of 9-NC (15.6, 31.3, 62.5, or 125 ng/ml; singly produce 2–7% apoptosis), produced 47%, 58%, 64%, and 69% apoptosis. Likewise, combinations of -TEA + 9-NC inhibited DNA synthesis more than either agent administered singly. A significant reduction (P<0.001) in growth of subcutaneous transplanted tumors was observed with liposome-formulated and aerosolized delivery of -TEA + 9-NC to BALB/c mice. The incidence of macroscopic lung metastasis was 83% in control vs 8% in -TEA-, 9-NC-, or combination-treated mice. Fluorescence microscopic examination of lungs and axillary and brachial lymph nodes showed a statistically significant decrease in metastasis observed in -TEA-, 9-NC-, and combination- vs control-treated animals. Analyses of primary tumor tissue for proliferation and apoptosis showed treatment groups to have lower Ki-67 and higher terminal deoxynucleotidyl transferase-mediated nick end labeling, respectively. Treatments showed no measurable effects on two angiogenesis parameters, namely intratumoral blood volume as assessed by hemoglobin content and intratumoral blood vessel density as assessed with CD31 staining.Conclusions Combination treatments enhanced antiproliferative and proapoptotic activities in cell culture, and when formulated in liposomes and delivered via aerosolization to treat an aggressive and metastatic syngeneic murine mammary tumor, the combination treatment showed a significant reduction in tumor volume in comparison to either treatment alone. Mechanistically, it appears that neither enhanced apoptosis, reduced cell proliferation, nor reduced blood vessel density can fully account for the enhanced effects of the combination treatment.Abbreviations -TEA 2,5,7,8-Tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid - 9-NC 9-Nitro-camptothecin - 66cl-4-GFP BALB/c mouse mammary tumor line 66 clone 4 stably transfected with GFP - DAPI 4,6-Diamidino-2-phenylindole - DMSO Dimethylsulfoxide - GFP Green fluorescent protein - PECAM-1 Platelet-endothelial cell adhesion molecule - THF Tetrahydrofuran - TUNEL Terminal deoxynucleotidyl transferase-mediated nick end labeling     

The role of industry in improving quality of life for persons with an ostomy: a Canadian consensus

Financial and clinical resources (which include 260 enterostomal therapy nurses nationwide) to provide clinical and rehabilitative expertise to the estimated 50,000 to 60,000 Canadians living with an ostomy are limited. Hence, many persons with an ostomy fall through the cracks in the early pre- and postoperative period or are lost to follow-up afterdischarge. Problems and issues related to ostomy management continue to surface throughout their lives. As a result,the time required for rehabilitation is often lengthy, affecting the person's quality of life. The First Canadian Enterostomal Therapy Nurses' Advisory Council consisting of 10 Canadian enterostomal therapy nurses met in February 2004 to identify key issues and concerns for Canadians living the ostomy experience and to identify gaps in information and services available before surgery, during the immediate postoperative period, and as the time from surgery lengthened and patients moved through age-related life issues. The two most important gaps identified were the development of quality, pertinent resources and the dissemination of those resources. The Council also identified potential strategies to bridge these gaps, including utilizing the resources of manufacturer Customer Service departments to follow a communications protocol to provide information to patients, retailers, and providers. Finally, a process map from which individual ostomy manufacturers can build programs and processes for improving patient/provider/manufacturer communication was developed.     

Risk factors for premenstrual dysphoric disorder in a community sample of young women: the role of traumatic events and posttraumatic stress disorder

BACKGROUND: There is some evidence that the onset and course of premenstrual syndrome is related to stress; however, few studies have explored the role of traumatic events and post-traumatic stress disorder (PTSD) as risk factors for the development of premenstrual dysphoric disorder (PMDD). METHOD: A community cohort of 1488 women (aged 14-24 years at baseline) were prospectively and longitudinally evaluated up to 3 times over a period of about 42 months from 1995 to 1999. The DSM-IV version of the Munich-Composite International Diagnostic Interview was used to establish PMDD and PTSD diagnostic status; stressful life events and conditions were assessed with the Munich Events List and the Daily Hassles Scale. Prevalence and incidence of either threshold or subthreshold PMDD from baseline to the second follow-up were calculated. Risk factors, including prior comorbid mental disorders and traumatic events, were examined using logistic regression analysis. RESULTS: The incidence of threshold PMDD was 3.0%. The most powerful predictors were subthreshold PMDD at baseline (OR = 11.0, 95% CI = 4.7 to 25.9). Traumatic events greatly increased the odds of developing PMDD at follow-up (OR = 4.2, 95% CI = 1.2 to 12.0). Other predictors were a history of anxiety disorder (OR = 2.5, 95% CI = 1.1 to 5.5) and elevated daily hassles scores (OR = 1.6, 95% CI = 1.1 to 2.3). Both were also associated with the risk of developing subthreshold PMDD, although the association was less robust. CONCLUSIONS: Traumatic events and pre-existing anxiety disorders are risk factors for the development of PMDD. The underlying mechanisms are unknown, making further investigation necessary.