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.

Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages.

Sphingolipids represent a class of diverse bioactive lipid molecules that are increasingly appreciated as key modulators of diverse physiologic and pathophysiologic processes that include cell growth, cell death, autophagy, angiogenesis, and stress and inflammatory responses. Sphingomyelinases and ceramidases are key enzymes of sphingolipid metabolism that regulate the formation and degradation of ceramide, one of the most intensely studied classes of sphingolipids. Improved understanding of these enzymes that control not only the levels of ceramide but also the complex interconversion of sphingolipid metabolites has provided the foundation for the functional analysis of the roles of sphingolipids. Our current understanding of the roles of various sphingolipids in the regulation of different cellular processes has come from loss-of-function/gain-of-function studies utilizing genetic deletion/downregulation/overexpression of enzymes of sphingolipid metabolism (e.g. knockout animals, RNA interference) and from the use of pharmacologic inhibitors of these same enzymes. While genetic approaches to evaluate the functional roles of sphingolipid enzymes have been instrumental in advancing the field, the use of pharmacologic inhibitors has been equally important in identifying new roles for sphingolipids in important cellular processes.The latter also promises the development of novel therapeutic targets with implications for cancer therapy, inflammation, diabetes, and neurodegeneration. In this review, we focus on the status and use of pharmacologic compounds that inhibit sphingomyelinases and ceramidases, and we will review the history, current uses and future directions for various small molecule inhibitors, and will highlight studies in which inhibitors of sphingolipid metabolizing enzymes have been used to effectively treat models of human disease.

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...

The acid sphingomyelinase (aSMase) gene gives rise to two distinct enzymes, lysosomal sphingomyelinase (L-SMase) and secretory sphingomyelinase (S-SMase), via differential trafficking of a common protein precursor. However, the regulation of S-SMase and its role in cytokine-induced ceramide formation remain ill defined. To determine the role of S-SMase in cellular sphingolipid metabolism, MCF7 breast carcinoma cells stably transfected with V5-aSMase WT were treated with inflammatory cytokines. Interleukin-1␤ and tumor necrosis factor-␣ induced a time-and dose-dependent increase in S-SMase secretion and activity, coincident with selective elevations in cellular C 16 -ceramide. To establish a role for S-SMase, we utilized a mutant of aSMase (S508A) that is shown to retain L-SMase activity, but is defective in secretion. MCF7 expressing V5-aSMase WT exhibited increased S-SMase and L-SMase activity, as well as elevated cellular levels of specific long-chain and very long-chain ceramide species relative to vector control MCF7. Interestingly, elevated levels of only certain very long-chain ceramides were evident in V5-aSMase S508A MCF7. Secretion of the S508A mutant was also defective in response to IL-1␤, as was the regulated generation of C 16 -ceramide. Taken together, these data support a crucial role for Ser 508 in the regulation of S-SMase secretion, and they suggest distinct metabolic roles for S-SMase and L-SMase.