Citations

Abstract Background: Single nucleotide polymorphisms (SNP) in microRNA-related genes have been associated with epithelial ovarian cancer (EOC) risk in two reports, yet associated alleles may be inconsistent across studies. Methods: We conducted a pooled analysis of previously identified SNPs by combining genotype data from 3,973 invasive EOC cases and 3,276 controls from the Ovarian Cancer Association Consortium. We also conducted imputation to obtain dense coverage of genes and comparable genotype data for all studies. In total, 226 SNPs within 15 kb of 4 miRNA biogenesis genes (DDX20, DROSHA, GEMIN4, and XPO5) and 23 SNPs located within putative miRNA binding sites of 6 genes (CAV1, COL18A1, E2F2, IL1R1, KRAS, and UGT2A3) were genotyped or imputed and analyzed in the entire dataset. Results: After adjustment for European ancestry, no overall association was observed between any of the analyzed SNPs and EOC risk. Conclusions: Common variants in these evaluated genes do not seem to be strongly associated with EOC risk. Impact: This analysis suggests earlier associations between EOC risk and SNPs in these genes may have been chance findings, possibly confounded by population admixture. To more adequately evaluate the relationship between genetic variants and cancer risk, large sample sizes are needed, adjustment for population stratification should be carried out, and use of imputed SNP data should be considered. Cancer Epidemiol Biomarkers Prev; 20(8); 1793–7. ©2011 AACR.

Object The authors describe the unique occurrence of nodular enhancement within the fundus of the internal auditory canal (IAC) lateral to the preoperative radiological tumor margin following gross-total vestibular schwannoma (VS) resection. Methods The nature of the study was a retrospective chart review of records. The authors reviewed the cases of all patients who underwent microsurgical resection of a VS between January 2000 and January 2010 at a single tertiary referral center. Patients with incomplete resection, neurofibromatosis Type 2, and those with fewer than 2 postoperative MR images available for review were excluded. Postsurgical patients with IAC enhancement located lateral to the preoperative imaging–delineated tumor margin were identified. Lesion morphology was characterized on serial MR imaging studies. Clinical follow-up and outcomes were recorded. Results Over the past decade, 350 patients underwent microsurgical VS resection. Of these, 16 patients met study criteria and were found to have postsurgical enhancement in the distal aspect of the IAC lateral to the imaging limits of the preoperative tumor margin on the first postoperative MR imaging study (37.5% women, median age 45 years). Initial MR imaging was performed at a mean of 3.1 months following surgery, and the mean radiological follow-up duration was 39.8 months (range 16.4–101.9 months). None of the 16 patients developed recurrence during the follow-up course. Conclusions In contrast to previous publications that have reported a high rate of recurrence in cases involving nodular enhancement within the original tumor bed, postoperative enhancement in the IAC lateral to the original tumor margin appears to carry much less risk for tumor recurrence. These findings may be helpful when counseling patients on the recommended frequency of postoperative follow-up imaging.

Abstract Eight surgical and one autopsy specimen of pituitary adenomas (six cases of Cushing's disease, two of Nelson's syndrome. and one of hypopituitarism) were studied by histochemical, immunohistocytological, and ultrastructural methods. Eight tumors showed the characteristic histochemical profile of corticotroph adenoma—amphophilic to basophilic, and periodic acid-Schiff-positive to some extent. In all tumors, immunohistochemical studies revealed adrenocorticotropic hormone (ACTH) and à-subunit in the cytoplasm of some adenoma cells. By electron microscopy, seven tumors were found to be monomorphous; six were typical corticotroph adenomas and one was a subtype II silent corticotroph adenoma. One unique lesion was bimorphous—i.e., composed of corticotrophs as well as cells resembling glycoprotein cells. Immunoelectron microscopy by the double-labeling immunogold technique, performed on one corticotroph adenoma, demonstrated the presence of ACTH and à-subunit not only within the same adenoma cells but also within the same secretory granules. The cytogenesis of ACTH à-subunit tumors, a rare form of plurihormonal adenoma. remains to be elucidated. The duration of disease associated with these tumors exceeded the duration in patients with ordinary corticotroph adenomas. Given the low frequency with which increases in serum à-subunit are detectable in patients with such tumors—13% in this series—hormone production is not recognized at preoperative evaluation.

Abstract Defective microRNA (miRNA) biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNP) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P < 0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), an SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR = 0.90, 95% CI: 0.82–0.98; P = 0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B overexpression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be because of reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility. Cancer Res; 71(11); 3896–903. ©2011 AACR.

There is a growing emphasis on delivering services for persons with early-stage dementia (ie, ‘‘persons with memory loss,’’ or PWMLs) and their family members (care partners). The goal of this evaluation was to determine whether participation in the Memory Club, a 10- to 13-session joint support group, would result in decreased distress, enhanced preparation for care, and improved feelings of confidence managing the challenges of early-stage dementia. The single group, pre-/post-test evaluation included 63 PWMLs and 61 care partners who participated in three Memory Club sites in Minnesota. Paired T-test results found that care partners reported significant (P < .05) increases in preparation activities, feelings of preparation, and confidence in managing memory loss. The results suggest that the Memory Club can fill an important gap in early-stage dementia care by offering care partners the opportunity to plan, prepare, and increase coping skills in the face of early dementia progression.

Abstract Background: Endoxifen, the active metabolite of tamoxifen (Tam), is currently being developed as a drug for the treatment of estrogen receptor (ER) + breast cancer (BC). HER2 expression in ER+ BC is associated with Tam resistance, and in vivo Tam administration to mice bearing ER+/HER2+ xenografts stimulates BC growth (Shou, JNCI 2004). In humans, endoxifen is the most important Tam metabolite responsible for inhibiting estrogen induced BC growth (Wu, Cancer Research 2009). CYP2D6 metabolism affects the concentrations (conc) of endoxifen (Stearns, JNCI, 2003) and associated with worse disease free survival (DFS) in Tam treated BC (Goetz, JCO, 2005). We sought to determine the activity of Tam and its metabolites in ER+/HER2+ BC cell lines and to evaluate the role of CYP2D6 metabolism in Tam-treated patients (pts) with ER+/HER2+ BC. Additionally, we sought to determine endoxifen conc in mice administered oral Tam.Methods: MCF7 (parental and HER2-expressing) and BT474 (ER+/HER2+) cells were used to compare the activity of Tam, 4HT, and endoxifen on estrogen- stimulated growth. Oral tam PK were characterized in mice treated with standard dose of Tam (4 mg/kg; 100 μg). Clinical data were obtained via a retrospective analysis of Tam-treated pts with ER+/ HER2+ BC randomized to receive 5 years of Tam (NCCTG 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6 genotype (*3, 4, 6, 10, 17, 41) and co-administration of a CYP2D6 inhibitor (yes/no). HER2 was determined by immunohistochemistry (IHC) or FISH (tumors 0, 1, or 2+ by IHC). The association between CYP2D6 and DFS was assessed using the log-rank test and proportional hazards modeling.Results: Compared to Tam, endoxifen potently inhibited the growth of estrogen- stimulated BT474 cells. In MCF7 cells, expression of HER2 shifted the conc of endoxifen required for 50% inhibition of growth (IC50) from 54 nM (parental) to 131 nM (HER2 expressing). Using the range of conc of Tam and its metabolites observed in humans (Tam, 300-500 nM; 4HT, 5-10 nM; and endoxifen, 10-200 nM), only endoxifen potently inhibited estrogen- stimulated growth of MCF7HER2+ cells and only at conc achievable in CYP2D6 extensive metabolizers (&gt;50nM). In mice, conc of 4HT and endoxifen were below 15 nM following an oral dose of 4 mg/kg. In NCCTG 89-30-52, both CYP2D6 phenotype and HER2 status was determined in 201/256 randomized pts. HER2 was expressed in 23/215 (11%) but not associated with DFS overall (p=0.62). In the HER2+ subset, pts with decreased CYP2D6 metabolism (n=10) had significantly shorter DFS compared to extensive metabolizers (n=9) (HR 9.5, p=0.03; 95% CI 1.16-76.9).Conclusions: Our in vitro and clinical data provide a simple pharmacological model for understanding HER2 resistance in Tam-treated breast cancer. Mice, which lack the CYP2D6 enzyme, may not be an appropriate model for understanding tam resistance given low conc of both 4HT and endoxifen. Given that the in vitro conc of endoxifen needed to inhibit the growth of ER+/HER-2+ BC are achievable in only a subset of humans (CYP2D6 extensive metabolizers), the primary administration of endoxifen could overcome de novo Tam resistance in ER+/HER2+ BC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2006.

Background— Health status is a key outcome for comparing treatments, particularly when mortality does not differ significantly. Methods and Results— Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomized 2368 patients with type 2 diabetes mellitus and stable ischemic heart disease to (1) prompt revascularization versus medical therapy and (2) insulin sensitization versus insulin provision. Randomization was stratified by the intended method of revascularization, coronary artery bypass graft surgery or percutaneous coronary intervention. The Duke Activity Status Index and RAND Energy, Health Distress, and Self-Rated Health scales were assessed at study entry and annually thereafter; linear mixed models were used to evaluate the effect of randomized treatment on these measures. Health status improved significantly from baseline to 1 year ( P <0.001) in each randomized treatment group. Compared with medical therapy, prompt revascularization was associated with significantly greater improvements in Duke Activity Status Index (1.32 points; P <0.001), Energy (1.36 points; P =0.02), and Self-rated Health (1.77 points; P =0.007) but not Health Distress (−0.47; P =0.46). These treatment effects were largely maintained over 4 years of follow-up. The effect of revascularization on the Duke Activity Status Index was significantly larger in the subgroup of patients intended for coronary artery bypass graft surgery compared with the subgroup intended for percutaneous coronary intervention. Health status did not differ significantly on any of the 4 measures between the insulin provision and insulin sensitization strategies. Conclusions— Prompt coronary revascularization was associated with small yet statistically significant improvements in health status compared with initial medical therapy among patients with diabetes mellitus and stable ischemic heart disease. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00006305.

Abstract Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for hetero geneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies. Cancer Epidemiol Biomarkers Prev; 19(2); 600–4

Abstract We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat containing, nuclear envelope 1 (SYNE1), which is involved in nuclear organization and structural integrity, function of the Golgi apparatus, and cytokinesis. An isoform encoded by SYNE1 has been reported to be downregulated in ovarian and other cancers. rs2295190 was genotyped in an additional 12 studies through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190 was not associated with risk. These data provide suggestive evidence that the rs2295190 T allele, or another allele in linkage disequilibrium with it, may be associated with increased risk of invasive ovarian cancer. Cancer Epidemiol Biomarkers Prev; 19(1); 244–50