Citations

In 2012, the Norwegian newborn screening program (NBS) was expanded (eNBS) from screening for two diseases to that for 23 diseases (20 inborn errors of metabolism, IEMs) and again in 2018, to include a total of 25 conditions (21 IEMs). Between 1 March 2012 and 29 February 2020, 461,369 newborns were screened for 20 IEMs in addition to phenylketonuria (PKU). Excluding PKU, there were 75 true-positive (TP) (1:6151) and 107 (1:4311) false-positive IEM cases. Twenty-one percent of the TP cases were symptomatic at the time of the NBS results, but in two-thirds, the screening result directed the exact diagnosis. Eighty-two percent of the TP cases had good health outcomes, evaluated in 2020. The yearly positive predictive value was increased from 26% to 54% by the use of the Region 4 Stork post-analytical interpretive tool (R4S)/Collaborative Laboratory Integrated Reports 2.0 (CLIR), second-tier biochemical testing and genetic confirmation using DNA extracted from the original dried blood spots. The incidence of IEMs increased by 46% after eNBS was introduced, predominantly due to the finding of attenuated phenotypes. The next step is defining which newborns would truly benefit from screening at the milder end of the disease spectrum. This will require coordinated international collaboration, including proper case definitions and outcome studies.

ABSTRACTIntroduction: Rotator cuff (RC) tears result in muscle atrophy and fat infiltration within the RC muscles. An estimation of muscle quality and deformation, or extensibility, is useful in selecting the most appropriate surgical procedure. We determined if noninvasive quantitative assessment of intramuscular fat using MRI could be used to predict extensibility of the supraspinatus muscle. Methods: Seventeen cadaveric shoulders were imaged to assess intramuscular fat infiltration. Extensibility and histological evaluations were then performed. Results: Quantitative fat infiltration positively correlated with histological findings and presented a positive correlation with muscle extensibility (r = 0.69; P = 0.002). Extensibility was not significantly different between shoulders graded with a higher fat content versus those with low fat when implementing qualitative methods. Discussion: A noninvasive prediction of whole‐muscle extensibility may directly guide pre‐operative planning to determine if the torn edge could efficiently cover the original footprint while aiding in postoperative evaluation of RC repair. Muscle Nerve 57: 129–135, 2018

Abstract Background: First in human studies of Z-endoxifen hydrochloride (E), the active metabolite of tamoxifen (T), are underway in metastatic breast cancer (BC). Previous data have demonstrated the superiority of aromatase inhibitors (AI's) over T in estrogen receptor (ER) + BC. Using an in vivo aromatase expressing model (MCF7/AC1), we compared the antitumor activity of E with T and Letrozole (L), as well as the antitumor activity and global gene expression changes of E with T in an L-resistant model. Methods: MCF7/AC1 tumors were stimulated with androstenedione. Once tumor size reached 300 mm3, mice (30/group) were randomly assigned to one of five treatment groups: control (daily, po), T (500 μg/day, sc), endoxifen 25 mg/kg/day p.o.(LDE) endoxifen 75 mg/kg/day p.o. (HDE) or letrozole, 10 μg/day s.c for 4 weeks. Tumors were harvested from control, T, and E groups while the L group continued treatment until the development of resistance defined as an increase in tumor volume of at least 300% from day 1. Mice with L-resistant tumors were randomly assigned to T (n=4) or E (n=5) for 4 weeks and then sacrificed. Gene expression in L-resistant tumors was quantified using Affymetrix U133+2 and changes in gene expression profiles [comparing T and E with L-resistant (n=3)] were analyzed. Genes identified as significantly different were confirmed by real-time RT-PCR assays. Results: At the 4 week time point, both doses of E and L resulted in greater anti-tumor activity than control (Wilcoxon rank sum test: all p < 0.0001); however, tumor burden did not differ between T and control (p=0.095). HDE resulted in significantly less tumor burden than T (p=0.002) but was similar to L. In mice that continued on L, resistance developed at 24 weeks in 9/25 mice. These mice were randomly assigned to either T (n=4) or E (n=5) for 4 weeks. Tumor volume (expressed as a% of its size prior to randomization) was significantly different comparing E (73.3%; range: 69.3 to 80.75%) versus T (148.39%; range: 114.07 to 165.99%) (Wilcoxon rank sum test p=0.016). Compared to control, microarray studies identified 1518 unique probe sets regulated by E (p<0.001) compared to 441 for T including estrogen-regulated genes such as progesterone receptor (PGR) and amphiregulin (AREG) that were significantly down-regulated in the E group [PGR (−6.2 fold, p=0.000008) and AREG (−3.2 fold, p=.0006) but unchanged or up-regulated in the T group (PGR unchanged and AREG +9.2 fold p=0.00002). These findings were confirmed by RT-PCR. Conclusions: Using the MCF7/AC1 model previously used to show the superiority of AI's over T, HDE demonstrated similar antitumor activity to L and was superior to T. In cells resistant to L, E was superior to T and gene expression changes demonstrate that E down-regulates while T activates estrogen regulated genes. These findings support the ongoing development of E for the treatment of ER+ BC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-06.