Citations

In conventional shear wave elastography materials are assumed to be linear, elastic, homogeneous, and isotropic. These assumptions are important to account for in certain tissues because they are not always appropriate. Many tissues such as skeletal muscle, the kidney, and the myocardium are anisotropic. Shear waves can be used to investigate the directionally dependent mechanical properties of anisotropic media. To study these tissues in a systematic way and to account for the effects of the anisotropic architecture, laboratory-based phantoms are desirable. We will report on several phantom-based approaches for studying shear wave anisotropy, assuming that these materials are transversely isotropic. Phantoms with embedded fibers were used to mimic anisotropic tissues. Homogeneous phantoms were compressed to induce transverse isotropy according to the acoustoelastic phenomenon, which is related to nonlinear behavior of the materials. The fractional anisotropy of these phantoms was quantified to compare with measurements made in soft tissues. In addition, soft tissues are also viscoelastic, and we have developed a method to model viscoelastic transversely isotropic materials with the finite element method (FEM). The viscoelastic property estimation from phantom experiments and FEM simulations will also be discussed.

Significance The major portion of hereditary breast cancer still remains unexplained, and many susceptibility loci are yet to be found. Exome sequencing of 24 high-risk familial BRCA1/2 -negative breast cancer patients and further genotyping of a large sample set of breast/ovarian cancer cases and controls was used to discover previously unidentified susceptibility alleles and genes. A significant association of a FANCM nonsense mutation with breast cancer, especially triple-negative breast cancer, identifies FANCM as a breast cancer susceptibility gene. Identification of such risk alleles is expected to improve cancer risk assessment for breast cancer patients and families, and may lead to improvements in the prevention, early diagnosis, and treatment of cancer.

AbstractThe GM2 gangliosidoses are a group of autosomal recessive lysosomal storage disorders caused by defective β‐hexosaminidase. There are three clinical conditions in this group: Tay‐Sachs disease (TSD), Sandhoff disease (SD), and hexosaminidase activator deficiency. The three conditions are clinically indistinguishable. TSD and SD have been identified with infantile, juvenile, and adult onset forms. The activator deficiency is only known to present with infantile onset. Diagnosis of TSD and SD is based on decreased hexosaminidase activity and a change in the percentage of activity between isoforms. There are no biochemical tests currently available for activator deficiency. This unit provides a detailed procedure for identifying TSD and SD in affected individuals and carriers from leukocyte samples, the most robust sample type available. Curr. Protoc. Hum. Genet. 83:17.16.1‐17.16.8. © 2014 by John Wiley & Sons, Inc.

Abstract Background: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is the most common adult leukemia in the United States. Prior studies in Olmsted County, Minnesota, showed a CLL age and sex adjusted incidence rate of 6.6 per 100,000 during 1985-89. Subsequently, the definition of CLL is now based on the 2008 International Workshop on CLL (IWCLL) Guidelines. Individuals having a CLL immunophenotype by flow cytometry are classified as CLL if the absolute B-cell count (ABC) is >5 x 109/L or classified as monoclonal B-cell lymphocytosis (MBL) if ABC is <5 x 109/L. To assess the impact of these changes on the incidence of CLL and clinically discovered MBL, we conducted an incidence study in Olmsted County for the years 2000-2010. Methods Using diagnostic indexes available through the Rochester Epidemiology Project and the Mayo CLL database, we identified all CLL and clinically identified MBL cases from 2000-2010. Incidence rates and demographics were compared between the older National Cancer Institute-Working Groups 1996 guidelines (NCI-WG 96) defined as absolute lymphocyte count (ALC)> 5 x 109/L and the IWCLL 2008 guidelines defined as ABC > 5 x 109/L. Incidence rates were age and sex adjusted using the 2010 US white population. Time to treatment (TTT) survival analyses was from time of diagnosis to date of first treatment or last follow-up and Cox regression analysis was used. Results Using the NCI-WG 96 classification, there were 8 MBL cases and 115 CLLs in whom 61% were Rai stage 0, 34% were Rai stage 1-2, and 5% were Rai stage 3-4. Using the IWCLL 2008 classification, there were 44 MBL cases and 79 CLLs in whom 43% Rai stage 0, 49% were Rai stage 1-2 and 8% Rai stage 3-4. Median ALC at diagnosis was 8.1 x 109/L for CLL and 5.9 x 109/L for MBL. Median ABC count at diagnosis was 7.1 x 109/L for CLL and 2.8 x 109/L for MBL. The age and sex adjusted incidence rate (per 100,000) for CLL for 2000-2010 was 10.0 using NCI-WG 96 and 6.8 using IWCLL 2008. Rates for MBL were 0.66 using NCI-WG 96 and 3.5 using IWCLL 2008. The median TTT for CLL was 9.2 years using NCI-WG 96 and 6.5 years by IWCLL 2008. Discussion This study demonstrates that reclassification of CLL using the IWCLL 2008 guidelines decreases CLL incidence relative to the NCI-WG 96 criteria. For the first time, this population based study also establishes an incidence rate for clinically identified MBL. Approximately 50% of previously labeled Rai 0 CLL are now reclassified as MBL. Re-classification increases the percent of Rai stage 1-2 and decreases the percent of Rai 0 cases at diagnosis. Reclassification also substantially shortens the median TTT for newly diagnosed CLL cases classified by the 2008 criteria relative to the NCI-WG 96 criteria. In summary, the IWCLL 2008 reclassification has significant implications for incidence studies, staging, and prognosis of CLL and MBL. Citation Format: Aaron D. Norman, Timothy G. Call, Curtis A. Hanson, Neil E. Kay, Clive S. Zent, Wei Ding, James R. Cerhan, Sara J. Achenbach, Kari G. Rabe, Celine M. Vachon, Emily J. Hallberg, Tait D. Shanafelt, Susan L. Slager. Incidence of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis in Olmsted county, 2000-2010: impact of the 2008 International Workshop on CLL Guidelines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2287. doi:10.1158/1538-7445.AM2013-2287

Abstract Background: Our group and others have identified a subset of ER/PR(−) breast cancers characterized by expression of the androgen receptor (AR) and androgen-dependent growth (Doane 2006). We conducted a proof-of-concept multicenter phase II study to test the efficacy of the AR-antagonist, bicalutamide for the treatment of AR(+) ER/PR(−) MBC (NCT00468715). Results of the primary endpoint, clinical benefit rate (CBR), were presented at ASCO (Gucalp 2012). Data for the impact of bicalutamide on circulating hormone levels in women are limited. Elevations in serum testosterone (T) and estradiol (E) have been observed for men treated with bicalutamide. We hypothesized comparable patterns of change in circulating endocrine markers in response to bicalutamide for women with MBC. Methods: Patients (pts) with AR(+) (IHC ≥10%), ER/PR(−) (IHC <10%) MBC were eligible for treatment (tx) if ECOG performance status ≤2 and normal organ function regardless of menopausal status. There was no limit to prior tx except prior trastuzumab required if HER2(+). Tx consisted of bicalutamide 150mg orally daily in 28-day cycles (C). Toxicity assessed q4 weeks, response q12wks. Primary endpoint was CBR. Peripheral blood was collected for total and free T, E and sex hormone binding globulin (SHBG) at baseline, start of C2 (C2) and at end of study (EOS). Standard institutional assays were used. A Wilcoxon signed-rank test was done to compare baseline to C2 and EOS values. Results: 26 patients with AR(+) ER/PR(−) MBC were treated on study. Evaluable number (n) of pts at baseline, C2 and EOS are 26, 26 and 19 respectively. Two pts remain on study. Menopausal status: pre=2, post=24. Baseline median total and free T and estradiol were consistent with expected norms, however a wide range was observed (Table). There were no significant differences observed for median free T, total T, E or SHBG between baseline and C2 or baseline and EOS. Changes in hormone levels could not be stratified by menopausal status or response to bicalutamide given small sample size. Given the wide range of baseline values, we examined the percent change for each endocrine biomarker from baseline to C2 and EOS. As shown in the Table, there was no difference in median percent change observed across time points for each biomarker. Conclusions: No discernible patterns of change in T, E or SHBG were observed in response to bicalutamide therapy when given to women for the treatment of AR(+), ER/PR(−) MBC. These circulating hormones require further evaluation for use as a pharmacodynamic marker. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-02.

ScopeWe reevaluated previously reported associations between variants in pathways of one‐carbon (1‐C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10−5) and rs828054 (OR = 1.06; p = 1 × 10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1‐C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03–0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP‐by‐folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.