Clinical Outcomes After Stereotactic Body Radiation Therapy for Nonspinal Bone Metastases: A Systematic Review and Meta-analysis.

There are limited data available on clinical outcomes after stereotactic body radiation therapy (SBRT) for nonspinal bone metastases. We performed a systematic review and meta-analysis to characterize local control (LC), overall survival (OS), pain response rates, and toxicity after SBRT. The primary outcomes were 1-year LC, incidence of acute and late grade 3 to 5 toxicities, and overall pain response rate at 3 months. The secondary outcome was 1-year OS. The Newcastle-Ottawa scale was used for assessment of study bias, with a median score of 5 for included studies (range, 4-8). Weighted random-effects meta-analyses were conducted to estimate effect sizes. We identified 528 patients with 597 nonspinal bone lesions in 9 studies (1 prospective study and 8 retrospective observational studies) treated with SBRT. The estimated 1-year LC rate was 94.6% (95% CI, 87.0%-99.0%). The estimated 3-month combined partial and complete pain response rate after SBRT was 87.7% (95% CI, 55.1%-100.0%). The estimated combined acute and late grade 3 to 5 toxicity rate was 0.5% (95% CI, 0%-5.0%), with an estimated pathologic fracture rate of 3.1% (95% CI, 0.2%-9.1%). The estimated 1-year OS rate was 71.0% (95% CI, 51.7%-87.0%). SBRT results in excellent LC and palliation of symptoms with minimal related toxicity. Prospective investigations are warranted to further characterize long-term outcomes of SBRT for patients with nonspinal bone metastases.

mTOR Regulation of N-Myc Downstream Regulated 1 (NDRG1) Phosphorylation in Clear Cell Renal Cell Carcinoma.

The mechanistic target of rapamycin (mTOR) kinase is a component of two signaling complexes that are known as mTOR complex 1 (mTORC1) and mTORC2. We sought to identify mTOR-phosphorylated proteins that are differently expressed in clinically resected clear cell renal cell carcinoma (ccRCC) relative to pair-matched normal renal tissue. Using a proteomic array, we found N-Myc Downstream Regulated 1 (NDRG1) showed the greatest increase (3.3-fold) in phosphorylation (on Thr346) in ccRCC. This was associated with an increase in total NDRG1. RICTOR is a required subunit in mTORC2, and its knockdown decreased total and phospho-NDRG1 (Thr346) but not NDRG1 mRNA. The dual mTORC1/2 inhibitor, Torin 2, significantly reduced (by ~100%) phospho-NDRG1 (Thr346). Rapamycin is a selective mTORC1 inhibitor that had no effect on the levels of total NDRG1 or phospho-NDRG1 (Thr346). The reduction in phospho-NDRG1 (Thr346) due to the inhibition of mTORC2 corresponded with a decrease in the percentage of live cells, which was correlated with an increase in apoptosis. Rapamycin had no effect on ccRCC cell viability. Collectively, these data show that mTORC2 mediates the phosphorylation of NDRG1 (Thr346) in ccRCC. We hypothesize that RICTOR and mTORC2-mediated phosphorylation of NDRG1 (Thr346) promotes the viability of ccRCC cells.

Osteoregenerative Potential of 3D-Printed Poly ε-Caprolactone Tissue Scaffolds In Vitro Using Minimally Manipulative Expansion of Primary Human Bone Marrow Stem Cells.

The repair of orthopedic and maxillofacial defects in modern medicine currently relies heavily on the use of autograft, allograft, void fillers, or other structural material composites. This study examines the in vitro osteo regenerative potential of polycaprolactone (PCL) tissue scaffolding, fabricated via a three-dimensional (3D) additive manufacturing technology, i.e., a pneumatic micro extrusion (PME) process. The objectives of this study were: (i) To examine the innate osteoinductive and osteoconductive potential of 3D-printed PCL tissue scaffolding and (ii) To perform a direct in vitro comparison of 3D-printed PCL scaffolding with allograft Allowash® cancellous bone cubes with regards to cell-scaffold interactions and biocompatibility with three primary human bone marrow (hBM) stem cell lines. This study specifically examined cell survival, cell integration, intra-scaffold cell proliferation, and differentiation of progenitor cells to investigate the potential of 3D-printed PCL scaffolds as an alternative to allograft bone material for the repair of orthopedic injuries. We found that mechanically robust PCL bone scaffolds can be fabricated via the PME process and the resulting material did not elicit detectable cytotoxicity. When the widely used osteogenic model SAOS-2 was cultured in PCL extract medium, no detectable effect was observed on cell viability or proliferation with multiple test groups showing viability ranges of 92.2% to 100% relative to a control group with a standard deviation of ±10%. In addition, we found that the honeycomb infill pattern of the 3D-printed PCL scaffold allowed for superior mesenchymal stem-cell integration, proliferation, and biomass increase. When healthy and active primary hBM cell lines, having documented in vitro growth rates with doubling times of 23.9, 24.67, and 30.94 h, were cultured directly into 3D-printed PCL scaffolds, impressive biomass increase values were observed. It was found that the PCL scaffolding material allowed for biomass increase values of 17.17%, 17.14%, and 18.18%, compared to values of 4.29% for allograph material cultured under identical parameters. It was also found that the honeycomb scaffold infill pattern was superior to the cubic and rectangular matrix structures, and provided a superior microenvironment for osteogenic and hematopoietic progenitor cell activity and auto-differentiation of primary hBM stem cells. Histological and immunohistochemical studies performed in this work confirmed the regenerative potential of PCL matrices in the orthopedic setting by displaying the integration, self-organization, and auto-differentiation of hBM progenitor cells within the matrix. Differentiation products including mineralization, self-organizing "proto-osteon" structures, and in vitro erythropoiesis were observed in conjunction with the documented expression of expected bone marrow differentiative markers including CD-99 (>70%), CD-71 (>60%), and CD-61 (>5%). All of the studies were conducted without the addition of any exogenous chemical or hormonal stimulation and exclusively utilized the abiotic and inert material polycaprolactone; setting this work apart from the vast majority of contemporary investigations into synthetic bone scaffold fabrication In summary, this study demonstrates the unique clinical potential of 3D-printed PCL scaffolds for stem cell expansion and incorporation into advanced microstructures created via PME manufacturing to generate a physiologically inert temporary bony defect graft with significant autograft features for enhanced end-stage healing.

Efficacy and Safety of Stereotactic Body Radiation Therapy for Pediatric Malignancies: The LITE-SABR Systematic Review and Meta-Analysis.

Purpose: Limited data are currently available on clinical outcomes after stereotactic body radiation therapy (SBRT) for pediatric and adolescent and young adult (AYA) patients with cancer. We aimed to perform a systematic review and study-level meta-analysis to characterize associated local control (LC), progression-free survival (PFS), overall survival, and toxicity after SBRT. Methods and Materials: Relevant studies were queried using a Population, Intervention, Control, Outcomes, Study Design (PICOS)/Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)/Meta-analysis of Observational Studies in Epidemiology (MOOSE) selection criteria. Primary outcomes were 1-year and 2-year LC as well as incidence of acute and late grade 3 to 5 toxicities, with secondary outcomes of 1-year overall survival and 1-year PFS. Outcome effect sizes were estimated with weighted random effects meta-analyses. Mixed-effects weighted regression models were performed to examine potential correlations between biologically effective dose (BED10), LC, and toxicity incidence. Results: Across 9 published studies, we identified 142 pediatric and AYA patients with 217 lesions that were treated with SBRT. Estimated 1-year and 2-year LC rates were 83.5% (95% confidence interval, 70.9%-96.2%) and 74.0% (95% CI, 64.6%-83.4%), respectively, with an estimated acute and late grade 3 to 5 toxicity rate of 2.9% (95% CI, 0.4%-5.4%; all grade 3). The estimated 1-year OS and PFS rates were 75.4% (95% CI, 54.5%-96.3%) and 27.1% (95% CI, 17.3%-37.0%), respectively. On meta-regression, higher BED10 was correlated with improved 2-year LC with every 10 Gy10 increase in BED10 associated with a 5% improvement in 2-year LC (P = .02) in sarcoma-predominant cohorts. Conclusions: SBRT provided durable LC for pediatric and AYA patients with cancer with minimal severe toxicities. Dose escalation may result in improved LC for sarcoma-predominant cohorts without a subsequent increase in toxicity. However, further investigations with patient-level data and prospective inquiries are indicated to better define the role of SBRT based on patient and tumor-specific characteristics.

Stereotactic Body Radiation Therapy (SBRT) for Spinal Metastases: Real-world Outcomes From an International Multi-institutional SBRT Registry.

OBJECTIVE: The objective of this study was to compare clinical outcomes following single fraction versus fractionated stereotactic body radiotherapy (SBRT) for spinal metastases. MATERIALS AND METHODS: A multi-institutional registry was queried for patients with spinal metastases treated with single-fraction or fractionated SBRT. Potential predictive factors of local control (LC) and overall survival were evaluated. Pretreatment and posttreatment Visual Analog Scale scores were analyzed to examine initial and durable pain responses and complete response (CR) rates. Logistic regression was utilized to assess potential correlations between pain response, biologically effective dose (BED), and fractionation. RESULTS: Four hundred sixty-six patients with 514 lesions treated with SBRT were identified; 209 and 104 lesions had information on LC and pain, respectively. The median pain score of patients with symptoms was 6 (range: 3 to 10). The median follow-up was 8.9 months (range: 0.4 to 125.5 mo). Utilizing Karnofsky Performance Score, age, and primary site (lung and/or nonbreast), 1-year overall survival rates were 76.1%, 59.1%, 54.9%, 37.2%, and 23.5% for patients with 0 to 4 of these factors, respectively (P<0.0001). One- and 2-year LC rates were 79.9% and 73.6%, respectively. Eighty-six patients (82.7%) had an initial pain response with a median decline of 3.5 and a CR rate of 47.1%. Sixty-five patients (62.5%) had a durable pain response with a median decline of 2 and a CR rate of 20.2%. Higher initial CR rates were observed with BED10 ≥51 Gy10 (58.7% vs. 37.9%; P=0.04). CONCLUSIONS: Following SBRT, encouraging palliative responses with >80% and 60% of patients having initial and durable pain responses, respectively. Dose escalation may result in improved initial CR rates. Performance status, age, and primary histology are factors to consider in the absence of pain.