Challenges in ductal carcinoma in situ risk communication and decision-making: report from an American Cancer Society and National Cancer Institute workshop

In September 2010, the American Cancer Society and National Cancer Institute convened a conference to review current issues in ductal carcinoma in situ (DCIS) risk communication and decision-making and to identify directions for future research. Specific topics included patient and health care provider knowledge and attitudes about DCIS and its treatment, how to explain DCIS to patients given the heterogeneity of the disease, consideration of nomenclature changes, and the usefulness of decision tools/aids. This report describes the proceedings of the workshop in the context of the current literature and discusses future directions. Evidence suggests that there is a lack of clarity about the implications and risks of a diagnosis of DCIS among patients, providers, and researchers. Research is needed to understand better the biology and mechanisms of the progression of DCIS to invasive breast cancer and the factors that predict those subtypes of DCIS that do not progress, as well as efforts to improve the communication and informed decision-making surrounding DCIS.     

Application of magnetic resonance imaging in developmental neurotoxicity testing: a pilot study

In a pilot developmental neurotoxicity study, a protocol was designed to utilize three-dimensional magnetic resonance (MR) images for linear and volumetric measurements of the developing rat brain. MR imaging, because of its non-destructive nature, provides a complement to traditional optical microscopy. Sprague-Dawley dams received 0, 1.25, 4.0 or 7.5mg/kg methylazoxymethanol acetate (MAM) by intraperitoneal injection during gestation days 13-15. At postnatal days (PND) 23 and 60, brains from representative male and female rats from two dams in each dose group were fixed with 10% neutral buffered formalin by transcardial perfusion for in situ MR imaging. A 7T small animal magnet system was used to obtain isotropic images at 100 microm resolution for PND 23 and 150 microm resolution for PND 60. Data from a rapid screening method based on midpoint MR slices of whole brain, cerebrum, cerebellum, and hippocampus showed a dose-related decreased volume of whole brain, cerebrum, and hippocampus in treated rats. Subsequent volumetric estimates using the Cavalieri method confirmed these findings. The brains were subsequently removed and processed for conventional histologic examination of hematoxylin and eosin-stained sections. It is concluded that MR imaging in rat developmental neurotoxicity studies offers the advantages of in situ volumetric measurements of brain structures while preserving the samples for conventional optical microscopy.     

CD34 expression by hair follicle stem cells is required for skin tumor development in mice

The cell surface marker CD34 marks mouse hair follicle bulge cells, which have attributes of stem cells, including quiescence and multipotency. Using a CD34 knockout (KO) mouse, we tested the hypothesis that CD34 may participate in tumor development in mice because hair follicle stem cells are thought to be a major target of carcinogens in the two-stage model of mouse skin carcinogenesis. Following initiation with 200 nmol 7,12-dimethylbenz(a)anthracene (DMBA), mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. Under these conditions, CD34KO mice failed to develop papillomas. Increasing the initiating dose of DMBA to 400 nmol resulted in tumor development in the CD34KO mice, albeit with an increased latency and lower tumor yield compared with the wild-type (WT) strain. DNA adduct analysis of keratinocytes from DMBA-initiated CD34KO mice revealed that DMBA was metabolically activated into carcinogenic diol epoxides at both 200 and 400 nmol. Chronic exposure to TPA revealed that CD34KO skin developed and sustained epidermal hyperplasia. However, CD34KO hair follicles typically remained in telogen rather than transitioning into anagen growth, confirmed by retention of bromodeoxyuridine-labeled bulge stem cells within the hair follicle. Unique localization of the hair follicle progenitor cell marker MTS24 was found in interfollicular basal cells in TPA-treated WT mice, whereas staining remained restricted to the hair follicles of CD34KO mice, suggesting that progenitor cells migrate into epidermis differently between strains. These data show that CD34 is required for TPA-induced hair follicle stem cell activation and tumor formation in mice.     

Laparoscopic Rectal Resection for Cancer: Effects of Conversion on Short-Term Outcome and Survival

Background  Laparoscopic rectal resection (LRR) is an oncologically safe procedure. The impact of conversion to open surgery on outcomes has not been fully elucidated. The aim of the study is to compare short- and long-term outcomes of converted (CR) and not converted (NCR) patients undergoing LRR. Methods  Data were drawn from a prospective database of LRR performed between 1999 and 2008. Statistical analysis employed the chi-squared or Wilcoxon test and Kaplan–Meier estimation. Results  Of 173 patients undergoing LRR, 26 (15%) required conversion. No differences in age, gender, American Society of Anesthesiologists (ASA) score, and T and N stages were observed between CR and NCR patients. Conversion was associated with higher body mass index (BMI) (27.3 versus 24.9 kg/m², P < 0.001) and American Joint Committee on Cancer (AJCC) stage IV (26.9% versus 4.8%, P < 0.001), and resulted in longer operative time (342 versus 285 min, P = 0.006) and increased intraoperative complication rate (31% versus 5%, P < 0.001). No differences were observed in postoperative outcome between CR and NCR patients. After a mean follow-up of 46 and 36 months, 5-year disease-free survival was 55.7% in CR group and 79.2% in NCR group (P = 0.007). After exclusion of stage IV patients from the analysis, 5-year disease-free survival was 71.1% in CR group and 85.3% in NCR group (P = 0.17), while the overall recurrence rate was 26.3% in CR patients and 11.4% in NCR patients (P = 0.07). Conclusions  Our study suggests that conversion to open surgery does not affect postoperative outcome, but could have a negative impact on long-term overall recurrence rate. LRR should be performed by experienced surgeons in selected patients. This study was partially presented at the 49th Annual Meeting of the Society for Surgery of the Alimentary Tract, on May 20, 2008 in San Diego, CA.     

Demystifying the NIH Grant Application Process

The process of applying to the National Institutes of Health (NIH) for grant funding can be daunting. The objective of this article is to help investigators successfully navigate the NIH grant application process. We focus on the practical aspects of this process, which are commonly learned through trial and error. Our target audience is generalist faculty and fellows who are applying for NIH funding to support their career development or a clinical research project.     

Development and characteristics of a human cell assay for screening agents for melanoma prevention

This paper describes the development and initial evaluation of a human cell assay to identify potentially efficacious agents for preventing melanoma. Four human cell lines were used: normal melanocytes, a radial growth-phase-like melanoma cell line (WM3211), a vertical growth-phase-like melanoma cell line (Lu1205), and 83-2c, a cell strain cloned from metastatic melanoma. Four endpoints were evaluated in ultraviolet B-treated cells: annexin V, human leukocyte antigen-DR; E-cadherin, and N-cadherin. Annexin V was induced by nimesulide, 4-hydroxyphenylretinamide, and difluoromethylornithine in ultraviolet-B-treated radial growth-phase-like melanoma cells. None of the agents inhibited human leukocyte antigen-DR expression in ultraviolet-B-treated radial growth-phase-like melanoma cells, the only cells that strongly expressed human leukocyte antigen-DR. E-cadherin was overexpressed only in radial growth-phase-like melanoma cells relative to melanocytes, and ultraviolet B exposure dramatically reduced this expression. E-cadherin was only induced by difluoromethylornithine in ultraviolet-B-treated radial growth-phase-like melanoma cells. N-cadherin was over- expressed in all melanoma cell lines relative to melanocytes. In this study, all candidate preventive agents inhibited N-cadherin in ultraviolet B-treated radial growth-phase-like melanoma cells. Four agents inhibited N-cadherin in ultraviolet B-treated vertical growth-phase-like melanoma cells. The mean ratios of N-cadherin to E-cadherin levels and specific endpoint responses for both the radial growth-phase-like melanoma and vertical growth-phase-like melanoma cells were used to rank the agents. Agents were evaluated at clinically relevant concentrations. The rankings were difluoromethylornithine>4-hydroxyphenylretinamide>nimesulide>9-cis-retinoic acid>polyphenon E. Diphenylhydramine, D-mannitol, and nordihydroguaiaretic acid were inactive. The results of these initial studies suggest that ultraviolet-B-treated radial growth-phase-like melanoma cells are the most responsive to chemopreventive agents, and may be the cell line of choice for screening melanoma prevention agents.     

Development and characterization of 23 microsatellite loci for scaled quail (Callipepla squamata)

The scaled quail (Callipepla squamata) is a common but declining game bird found throughout large portions of the arid southwest region of the United States. Range-wide population declines have been linked to long term drought and land use changes and have led to a resurgance in research investigating various aspects of scaled quail ecology. In order to facilitate future research on scaled quail, we have developed and characterized 23 polymorphic microsatellite loci. Among 16 individuals from populations located throughout scaled quail range, the number of alleles per locus ranged from 3 to 14 with an average of 7. Polymorphic information content ranged from 0.210 to 0.899 with an average of 0.654, indicating that these loci have high applicability for future scaled quail genetic studies.     

Psychotropic medication control of non-paraphilic sexual addiction in a female

We present a 47y/o swf treated with venlafaxine, sodium valproate, and risperdone, which normalized her capacity for sexual relations and orgasm. Paroxetine also diminished her sexual drive. She found that she could regulate the intensity of her sexual urges by decreasing her risperdone.