Improved local control following dose-escalated stereotactic ablative radiation therapy (SABR) for metastatic sarcomas: An international multi-institutional experience.

BACKGROUND: We aimed to characterize local control (LC) and overall survival (OS) following stereotactic ablative radiation therapy (SABR) for extracranial sarcoma metastases. METHODS: A prospectively-maintained institutional registry was queried for patients with metastases from sarcoma primaries managed with SABR. Kaplan-Meier analysis was utilized for univariate analyses to assess potential prognostic factors regarding LC and OS. A Cox proportional hazards multivariate (MVA) model was employed to further assess initially identified independent variables. RESULTS: A total of 94 patients with 118 lesions with LC information were identified. Common metastatic sites treated were lung (77), non-spinal bone (15), and spine (10). The median biologically effective dose (BED4) was 175 Gy4 (range56.3 Gy4-360 Gy4) with a median dose/fractionation schedule of 50 Gy/5 fractions. One- and 2-year OS rates were 81.3 % (95 % CI: 71.2-88.1 %6) and 50.5 % (95 % CI: 38.6-61.3 %, respectively. On Cox MVA, advanced age and non-lung metastases were associated with inferior OS (p < 0.03) with patients with 0-2 of these risk factors having estimated 2-year OS of 65.1 %, 38.9 %, and N/A, respectively. One- and 2-year LC rates were 85.3 % (95 % CI: 77.7-90.9 %) and 78.2 % (95 % CI: 67.9-85.6 %), respectively. On MVA, only BED4 < 175 Gy was associated with inferior LC (hazard ratio (HR) = 3.33; p = 0.01). Ten of 118 treated lesions had treatment-related toxicities (all Grade 1-2). CONCLUSION: Age and lung vs. non-lung metastases were prognostic of OS and should be considered in patient selection for SABR. Dose escalation when feasible with BED4 ≥ 175 Gy is recommended given durable LC achieved without a subsequent increase in toxicity.

A Review of miRNAs as Biomarkers and Effect of Dietary Modulation in Obesity Associated Cognitive Decline and Neurodegenerative Disorders.

There has been a progressive increase in the prevalence of obesity and its comorbidities such as type 2 diabetes and cardiovascular diseases worldwide. Recent studies have suggested that the crosstalk between adipose tissue and central nervous system (CNS), through cellular mediators and signaling pathways, may causally link obesity with cognitive decline and give rise to neurodegenerative disorders. Several mechanisms have been proposed in obesity, including inflammation, oxidative stress, insulin resistance, altered lipid and cholesterol homeostasis, which may result in neuroinflammation, altered brain insulin signaling, amyloid-beta (Aß) deposition and neuronal cell death. Since obesity is associated with functional and morphological alterations in the adipose tissues, the resulting peripheral immune response augments the development and progression of cognitive decline and increases susceptibility of neurodegenerative disorders, such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Studies have also elucidated an important role of high fat diet in the exacerbation of these clinical conditions. However, the underlying factors that propel and sustain this obesity associated cognitive decline and neurodegeneration, remains highly elusive. Moreover, the mechanisms linking these phenomena are not well-understood. The cumulative line of evidence have demonstrated an important role of microRNAs (miRNAs), a class of small non-coding RNAs that regulate gene expression and transcriptional changes, as biomarkers of pathophysiological conditions. Despite the lack of utility in current clinical practices, miRNAs have been shown to be highly specific and sensitive to the clinical condition being studied. Based on these observations, this review aims to assess the role of several miRNAs and aim to elucidate underlying mechanisms that link obesity with cognitive decline and neurodegenerative disorders. Furthermore, this review will also provide evidence for the effect of dietary modulation which can potentially ameliorate cognitive decline and neurodegenerative diseases associated with obesity.