Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodically exuberant heterotopic ossification (HO), whereby skeletal muscle is abnormally converted into misplaced, but histologically normal bone. This HO leads to progressive immobility with catastrophic consequences, including death by asphyxiation. FOP results from mutations in the intracellular domain of the type I BMP (bone morphogenetic protein) receptor ACVR1; the most common mutation alters arginine 206 to histidine (ACVR1R206H) and has been thought to drive inappropriate bone formation as a result of receptor hyperactivity. We unexpectedly found that this mutation rendered ACVR1 responsive to the activin family of ligands, which generally antagonize BMP signaling through ACVR1 but cannot normally induce bone formation. To test the implications of this finding in vivo, we engineered mice to carry the Acvr1R206H mutation. Because mice that constitutively express Acvr1[R206H] die perinatally, we generated a genetically humanized conditional-on knock-in model for this mutation. When Acvr1[R206H] expression was induced, mice developed HO resembling that of FOP; HO could also be triggered by activin A administration in this mouse model of FOP but not in wild-type controls. Finally, HO was blocked by broad-acting BMP blockers, as well as by a fully human antibody specific to activin A. Our results suggest that ACVR1R206H causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, demonstrating that this ligand is necessary and sufficient for driving HO in a genetically accurate model of FOP; hence, our human antibody to activin A represents a potential therapeutic approach for FOP.

We assessed gene expression profiles in 2,752 twins, using a classic twin design to quantify expression heritability and quantitative trait loci (eQTL) in peripheral blood. The most highly heritable genes (~777) were grouped into distinct expression clusters, enriched in gene-poor regions, associated with specific gene function/ontology classes, and strongly associated with disease designation. The design enabled a comparison of twin-based heritability to estimates based on dizygotic IBD sharing and distant genetic relatedness. Consideration of sampling variation suggests that previous heritability estimates have been upwardly biased. Genotyping of 2,494 twins enabled powerful identification of eQTLs, which were further examined in a replication set of 1,895 unrelated subjects. A large number of local eQTLs (6,988) met replication criteria, while a relatively small number of distant eQTLs (165) met quality control and replication standards. Our results provide an important new resource toward understanding the genetic control of transcription.

BackgroundStereotactic body radiotherapy (SBRT) is an emerging treatment option for liver metastases in patients unsuitable for surgery. We investigated factors associated with clinical outcomes for liver metastases treated with SBRT from a multi-center, international patient registry.MethodsPatients with liver metastases treated with SBRT were identified in the RSSearch® Patient Registry. Patient, tumor and treatment characteristics associated with treatment outcomes were assessed. Dose fractionations were normalized to BED10. Overall survival (OS) and local control (LC) were evaluated using Kaplan Meier analysis and log-rank test.ResultsThe study included 427 patients with 568 liver metastases from 25 academic and community-based centers. Median age was 67 years (31–91 years). Colorectal adenocarcinoma (CRC) was the most common primary cancer. 73% of patients received prior chemotherapy. Median tumor volume was 40 cm3 (1.6–877 cm3), median SBRT dose was 45 Gy (12–60 Gy) delivered in a median of 3 fractions [1–5]. At a median follow-up of 14 months (1–91 months) the median overall survival (OS) was 22 months. Median OS was greater for patients with CRC (27 mo), breast (21 mo) and gynecological (25 mo) metastases compared to lung (10 mo), other gastro-intestinal (GI) (18 mo) and pancreatic (6 mo) primaries (p < 0.0001). Smaller tumor volumes (< 40 cm3) correlated with improved OS (25 months vs 15 months p = 0.0014). BED10 ≥ 100 Gy was also associated with improved OS (27 months vs 15 months p < 0.0001). Local control (LC) was evaluable in 430 liver metastases from 324 patients. Two-year LC rates was better for BED10 ≥ 100 Gy (77.2% vs 59.6%) and the median LC was better for tumors < 40 cm3 (52 vs 39 months). There was no difference in LC based on histology of the primary tumor.ConclusionsIn a large, multi-institutional series of patients with liver metastasis treated with SBRT, reasonable LC and OS was observed. OS and LC depended on dose and tumor volume, while OS varied by primary tumor. Future prospective trials on the role of SBRT for liver metastasis from different primaries in the setting of multidisciplinary management including systemic therapy, is warranted.Trial registrationClinicaltrials.gov: NCT01885299.

ObjectivesTo report overall survival and local control for patients identified in the RSSearch® Patient Registry with metastatic cancer to the lung treated with SBRT.MethodsSeven hundred two patients were identified with lung metastases in the RSSearch® Registry. Of these patients, 577 patients had SBRT dose and fractionation information available. Patients were excluded if they received prior surgery, radiation, or radiofrequency ablation to the SBRT treated area. Between April 2004-July 2015, 447 patients treated with SBRT at 30 academic and community-based centers were evaluable for overall survival (OS). Three hundred four patients with 327 lesions were evaluable for local control (LC). All doses were converted to Monte Carlo equivalents and subsequent BED Gy10 for dose response analysis.ResultsMedian age was 69 years (range, 18–93 years). Median Karnofsky performance status (KPS) was 90 (range 25/75% 80–100). 49.2% of patients had prior systemic therapy. Median metastasis volume was 10.58 cc (range 25/75% 3.7–25.54 cc). Site of primary tumor included colorectal (25.7%), lung (16.6%), head and neck (11.4%), breast (9.2%), kidney (8.1%), skin (6.5%) and other (22.1%). Median dose was 50 Gy (range 25/75% 48–54) delivered in 3 fractions (range 25/75% 3–5) with a median BED of 100Gy10 (range 25/75% 81–136).Median OS for the entire group was 26 months, with actuarial 1-, 3-, and 5-year OS of 74.1%, 33.3, and 21.8%, respectively. Patients with head and neck and breast cancers had longer median OS of 37 and 32 months respectively, compared to colorectal (30 months) and lung (26 months) which corresponded to 3-year actuarial OS of 51.8 and 47.9% for head and neck and breast respectively, compared to 35.8% for colorectal and 31.2% for lung.The median LC for all patients was 53 months, with actuarial 1-, 3-, and 5-year LC rates of 80.4, 58.9, and 46.3%, respectively. There was no difference in LC by primary histologic type (p = 0.49). Improved LC was observed for lung metastases that received SBRT doses of BED ≥100Gy10 with 3-year LC rate of 77.1% compared to 45% for lung metastases treated with BED < 100Gy10 (p = 0.01). Smaller tumor volumes (<11 cc) had improved LC compared to tumor volumes > 11 cc. (p = 0.005) Two-year LC rates for tumor volumes < 11 cc, 11–27 cc and > 27 cc were 72.9, 64.2 and 45.6%, respectively. This correlated with improved OS with 2-year OS rates of 62.4, 60.9 and 46.2% for tumor volumes < 11 cc, 11–27 cc and > 27 cc, respectively (p = 0.0023). In a subset of patients who received BED ≥100Gy10, 2-year LC rates for tumor volumes < 11 cc, 11–27 cc and > 27 cc were 82.8, 58.9 and 68.6%, respectively (p = 0.0244), and 2-year OS rates were 66.0, 58.8 and 28.5%, respectively (p = 0.0081).ConclusionExcellent OS and LC is achievable with SBRT utilizing BED ≥100Gy10 for lung metastases according to the RSSearch® Registry data. Patients with small lung metastases (volumes < 11 cc) had better LC and OS when using SBRT doses of BED ≥100Gy10. Further studies to evaluate a difference, if any, between various...