K. Shiue

Cellular Epigenetic Modifications of Neural Stem Cell Differentiation

Emerging information indicates that epigenetic modification (i.e., histone code and DNA methylation) may be integral to the maintenance and differentiation of neural stem cells (NSCs), but their actual involvement has not yet been illustrated. In this study, we demonstrated the dynamic nature of epigenetic marks during the differentiation of quiescent adult rat NSCs in neurospheres. A subpopulation of OCT4+ NSCs in the neurosphere contained histone marks, trimethylated histone 3 on lysine 27 (3me-H3K27), 2me-H3K4, and acetylated H4 (Ac-H4). A major decrease of these marks was found prior to or during differentiation, and was further diminished or reprogrammed in diverse subpopulations of migrated NSCs expressing nestin or β-III-tubulin. The DNA methylation mark 5-methyl-cytosine (5-MeC), and DNA methyltransferase (DNMT) 1 and 3a expression also correlated to the state of differentiation; they were highly present in undifferentiated NSCs but downregulated in migrated populations. In contrast, DNA methyl-CpG-binding protein (MBD1) was low in undifferentiated NSCs in neurospheres, but highly appeared in differentiating NSCs. Furthermore, we found an outward translocation of DNA methylation marker 5-MeC, DNMT1, DNMT3a, and MBD1 in NSCs as differentiation began and proceeded; 5-MeC from homogeneous nucleus to peripheral nucleus, and DMNT1a and 3a from nuclear to cytoplasm, indicating chromatin remodeling. Treatment with DNA methylation inhibitor, 5-aza-cytidine, altered DNA methylation and disrupted migration as indicated by a reduction of migrated neurons and differentiation. These results indicate that chromatin is dynamically remodeled when NSCs transform from the quiescent state to active growth, and that DNA methylation modification is essential for neural stem cell differentiation.

Histology, Tumor Volume, and Radiation Dose Predict Outcomes in NSCLC Patients After Stereotactic Ablative Radiotherapy

Introduction: It remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy dose prescriptions for NSCLC. Methods: The study population included 508 patients with 561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early‐stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in‐field tumor control censored by either death or progression. Involved lobe control was also assessed. Results: At 6.7 years median follow‐up, 3‐year in‐field control, involved lobe control, overall survival, and progression‐free survival rates were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV) (hazard ratio [HR] = 1.01 per mL, p = 0.0044) and histology (p = 0.0225) were independently associated with involved lobe failure. GTV (HR = 1.013, p = 0.001) and GTV dose (cutoff of 110 Gy, biologically effective dose with &agr;/&bgr; = 10 [BED10], HR = 2.380, p = 0.0084) were independently associated with in‐field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in‐field control (12 Gy × 4 or 10 Gy × 5 versus 18 Gy or 20 Gy × 3: HR = 3.530, p = 0.0447, confirmed by propensity score matching) and was independent of GTV (HR = 1.014 per mL, 95% confidence interval: 1.005–1.022, p = 0.0012). For adenocarcinomas, there were no differences in in‐field control observed using the above dose groupings (p = 0.12 and p = 0.31, respectively). Conclusions: In the absence of level I data, GTV and histology should be considered to personalize radiation dose for stereotactic ablative body radiotherapy. We suggest lower prescription doses (i.e., 12 Gy × 4 or 10 G × 5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.

Brainstem metastases treated with Gamma Knife stereotactic radiosurgery: the Indiana University Health experience

Brainstem metastases offer a unique challenge in cancer treatment, yet stereotactic radiosurgery (SRS) has proven to be an effective modality in treating these tumors. This report discusses the clinical outcomes of patients with brainstem metastases treated at Indiana University with Gamma Knife (GK) radiosurgery from 2008 to 2016. 19 brainstem metastases from 14 patients who had follow-up brain imaging were identified. Median tumor volume was 0.04 cc (range: 0.01–2.0 cc). Median prescribed dose was 17.5 Gy to the 50% isodose line (range: 14–22 Gy). Median survival after GK SRS treatment to brainstem lesion was 17.2 months (range: 2.8–45.6 months). The experience at Indiana University confirms the safety and efficacy of range of GK SRS prescription doses (14–22 Gy) to brainstem metastases.