Citations

Osteosarcoma is a bone tumor that affects children and young adults. 2‐Methoxyestradiol (2‐ME), a naturally occurring estrogen metabolite, kills osteosarcoma cells, but does not affect normal osteoblasts. In order to effectively target osteosarcoma and improve the therapeutic index of the drug 2‐ME, we have encapsulated 2‐ME in a composite of oligo‐(polyethylene glycol) fumarate (OPF) hydrogel and poly (lactic‐co‐glycolic acid) (PLGA) microspheres and investigated the effect of polymer composition on 2‐ME release kinetics and osteosarcoma cell survival. The in vitro study shows that 2‐ME can be released in a controlled manner over 21‐days. The initial burst releases observed on day 1 were 50% and 32% for OPF and OPF/PLGA composites, respectively. The extended release kinetics show that 100% of the encapsulated 2‐ME is released by day 12 from OPF, whereas the OPF/PLGA composites showed a release of 85% on day 21. 2‐ME released from the polymers was biologically active and blocked osteosarcoma cell proliferation in vitro. Also, comparison of 2‐ME delivery in osteosarcoma cells in culture, shows that direct treatment has no effect after 3 days, whereas polymer‐mediated delivery produces anti‐tumor effects that could be sustained for 21 days. These findings show that the OPF and PLGA polymeric system may prove to be useful in controlled and sustained delivery of 2‐ME and could be further explored in the treatment of osteosarcoma. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 2491–2499, 2013.

Abstract The determination of HER2 amplification is critical to selecting appropriate patients for HER2 targeted therapy in breast cancer. Dual in situ hybridization (DISH), an alternative to fluorescence in situ hybridization (FISH) and immunohistochemistry, is now available. To compare the FISH and DISH methods, we tested 251 samples enriched for common or difficult-to-assess HER2 anomalies. Seven samples failed DISH testing. There was a 64% (156/244) concordance between FISH and DISH by anomaly (κ = 0.58, 95% confidence interval, 0.51-0.65; P < .0001) and an 83% (203/244) concordance by amplification status (κ = 0.58; 95% confidence interval, 0.47-0.69; P < .0001). DISH resulted in lower estimates of HER2/ centromere 17 ratios than FISH, and many cases that were equivocal with FISH were normal with DISH. DISH did not detect any case with coamplification of HER2 and centromere 17. Using a cohort of difficult specimens, we observed less than 95% concordance between FISH and DISH. DISH may underestimate the HER2/chromosome 17 ratio, or FISH may overestimate this ratio.

Hypophosphatemia with osteomalacia may be due to a neoplasm that produces fibroblast growth factor 23 (FGF-23), which inhibits phosphate reabsorption in the kidneys. Most of these tumors occur in bone or soft tissue and occasionally in the head, although intracranial occurrence is very rare. This report describes a tumor that caused hypophosphatemia and osteomalacia and was located entirely in the right anterior cranial fossa. Radiologically, the tumor resembled a meningioma; histologically, it was a low-grade phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). After gross-total resection, the patient's symptoms abated and laboratory values normalized. The authors also studied another PMTMCT initially diagnosed as a hemangiopericytoma that involved the left anterior cranial fossa and ethmoid sinus, and reviewed reports of 6 other intracranial tumors that induced osteomalacia, 3 entirely in the anterior cranial fossa, 2 involving the anterior cranial fossa and ethmoid sinus, and 1 in the cavernous sinus. In older children or adults who have hypophosphatemia with osteomalacia and no personal or family history of metabolic, renal, or malabsorptive disease, a neoplasm should be suspected and an imaging workup that includes the brain is warranted, with particular attention to the anterior cranial fossa. Additionally, because there are some overlapping histological features between PMTMCTs and hemangiopericytomas, it may be helpful to assess tumoral FGF-23 expression by reverse transcriptase polymerase chain reaction or immunohistochemical analysis in patients with oncogenic osteomalacia from an intracranial tumor diagnosed as, or resembling, hemangiopericytoma.

Chromosomal microarray analysis (CMA) is standard of care, first‐tier clinical testing for detection of genomic copy number variation among patients with developmental disabilities. Although diagnostic yield is higher than traditional cytogenetic testing, management impact has not been well studied. We surveyed genetic services providers regarding CMA ordering practices and perceptions about reimbursement. Lack of insurance coverage because of perceived lack of clinical utility was cited among the most frequent reasons why CMA was not ordered when warranted. We compiled a list of genomic regions where haploinsufficiency or triplosensitivity cause genetic conditions with documented management recommendations, estimating that at least 146 conditions potentially diagnosable by CMA testing have published literature supporting specific clinical management implications. Comparison with an existing clinical CMA database to determine the proportion of cases involving these regions showed that CMA diagnoses associated with such recommendations are found in approximately 7% of all cases (n = 28,526). We conclude that CMA impacts clinical management at a rate similar to other genetic tests for which insurance coverage is more readily approved. The information presented here can be used to address barriers that continue to contribute to inequities in patient access and care in regard to CMA testing.

Spillover of lipoprotein lipase-generated fatty acids from chylomicrons into the plasma free fatty acid (FFA) pool is an important source of FFA and reflects inefficiency in dietary fat storage. We measured spillover in 13 people with type 2 diabetes using infusions of a [3H]triolein-labeled lipid emulsion and [U-13C]oleate during continuous feeding, before and after weight loss. Body fat was measured with dual energy X-ray absorptiometry and computed tomography. Participants lost ∼14% of body weight. There was an ∼38% decrease in meal-suppressed FFA concentration (P < 0.0001) and an ∼23% decrease in oleate flux (P = 0.007). Fractional spillover did not change (P = NS). At baseline, there was a strong negative correlation between spillover and leg fat (r = −0.79, P = 0.001) and a positive correlation with the trunk-to-leg fat ratio (R = 0.56, P = 0.047). These correlations disappeared after weight loss. Baseline leg fat (R = −0.61, P = 0.027) but not trunk fat (R = −0.27, P = 0.38) negatively predicted decreases in spillover with weight loss. These results indicate that spillover, a measure of inefficiency in dietary fat storage, is inversely associated with lower body fat in type 2 diabetes.