De novo variants in ATP2B1 lead to neurodevelopmental delay.

Calcium (Ca2+) is a universal second messenger involved in synaptogenesis and cell survival; consequently, its regulation is important for neurons. ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) belongs to the family of ATP-driven calmodulin-dependent Ca2+ pumps that participate in the regulation of intracellular free Ca2+. Here, we clinically describe a cohort of 12 unrelated individuals with variants in ATP2B1 and an overlapping phenotype of mild to moderate global development delay. Additional common symptoms include autism, seizures, and distal limb abnormalities. Nine probands harbor missense variants, seven of which were in specific functional domains, and three individuals have nonsense variants. 3D structural protein modeling suggested that the variants have a destabilizing effect on the protein. We performed Ca2+ imaging after introducing all nine missense variants in transfected HEK293 cells and showed that all variants lead to a significant decrease in Ca2+ export capacity compared with the wild-type construct, thus proving their pathogenicity. Furthermore, we observed for the same variant set an incorrect intracellular localization of ATP2B1. The genetic findings and the overlapping phenotype of the probands as well as the functional analyses imply that de novo variants in ATP2B1 lead to a monogenic form of neurodevelopmental disorder.

Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders.

BACKGROUND: Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined. METHODS: Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder. RESULTS: We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain. CONCLUSION: We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.

Conceptualizing Trust and Distrust as Alternative Stable States: Lessons from the Flint Water Crisis.

Despite the universally recognized importance of fostering trust and avoiding distrust in governance relationships, there remains considerable debate on core questions like the relation between (dis)trust and the evaluations of the characteristics that make a governance agent appear (un)worthy of trust. In particular, it remains unclear whether levels of (dis)trust simply follow levels of (dis)trustworthiness-such that building trust is primarily a question of increasing evidence of trustworthiness and avoiding evidence of distrustworthiness, or if their dynamics are more complicated. The current paper adds novel theory for thinking about the management of trust and distrust in the governance context through the application of principles borrowed from resilience theory. Specifically, we argue that trust and distrust exist as distinct, self-reinforcing (i.e., stable) states separated by a threshold. We then theorize as to the nature of the self-reinforcing processes and use qualitative data collected from and inductively coded in collaboration with Flint residents as part of a participatory process to look for evidence of our argument in a well-documented governance failure. We conclude by explaining how this novel perspective allows for clearer insight into the experience of this and other communities and speculate as to how it may help to better position governance actors to respond to future crises.

Biallelic pathogenic variants in roundabout guidance receptor 1 associate with syndromic congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses with biallelic truncating or combined missense and truncating variants in ROBO1. Kidney and genitourinary manifestation included unilateral or bilateral kidney agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation, and increased kidney echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects. By in silico analysis, we determined the functional significance of identified missense variants and observed absence of kidney ROBO1 expression in both human and murine mutant tissues. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of the kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. Thus, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Hence, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for kidney involvement is indicated.

TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study.

Biallelic loss-of-function variants in the thrombospondin-type laminin G domain and epilepsy-associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype-phenotype associations for TSPEAR variants, we characterized 13 individuals with biallelic TSPEAR variants. Individuals underwent either exome sequencing or panel-based genetic testing. Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether TSPEAR variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association.

Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.

Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase III, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma.

Background: Treatment options for soft tissue sarcoma (STS) patients aged ≥65 years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safety and efficacy outcomes regardless of patient age, we carried out a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial. Patients and methods: Patients were randomized 2 : 1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every-3-weeks. The primary end point was overall survival (OS); secondary end points were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup. Results: Among 131 (trabectedin = 94; dacarbazine = 37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with trabectedin versus dacarbazine (median four versus two cycles, respectively), with a significantly higher proportion receiving prolonged therapy (≥6 cycles) in the trabectedin arm (43% versus 23%, respectively; P = 0.04). Elderly patients treated with trabectedin showed significantly improved PFS [4.9 versus 1.5 months, respectively; hazard ratio (HR)=0.40; P = 0.0002] but no statistically significant improvement in OS (15.1 versus 8.0 months, respectively; HR = 0.72; P = 0.18) or ORR (9% versus 3%, respectively; P = 0.43). The safety profile for elderly trabectedin-treated patients was comparable to that of the overall trabectedin-treated study population. Conclusions: This subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with STS and good performance status can expect clinical benefit from trabectedin similar to that observed in younger patients. Trial registration: www.clinicaltrials.gov, NCT01343277.

Biotinylation: a novel posttranslational modification linking cell autonomous circadian clocks with metabolism.

Circadian clocks are critical modulators of metabolism. However, mechanistic links between cell autonomous clocks and metabolic processes remain largely unknown. Here, we report that expression of the biotin transporter slc5a6 gene is decreased in hearts of two distinct genetic mouse models of cardiomyocyte-specific circadian clock disruption [i.e., cardiomyocyte-specific CLOCK mutant (CCM) and cardiomyocyte-specific BMAL1 knockout (CBK) mice]. Biotinylation is an obligate posttranslational modification for five mammalian carboxylases: acetyl-CoA carboxylase α (ACCα), ACCß, pyruvate carboxylase (PC), methylcrotonyl-CoA carboxylase (MCC), and propionyl-CoA carboxylase (PCC). We therefore hypothesized that the cardiomyocyte circadian clock impacts metabolism through biotinylation. Consistent with decreased slc5a6 expression, biotinylation of all carboxylases is significantly decreased (10-46%) in CCM and CBK hearts. In association with decreased biotinylated ACC, oleate oxidation rates are increased in both CCM and CBK hearts. Consistent with decreased biotinylated MCC, leucine oxidation rates are significantly decreased in both CCM and CBK hearts, whereas rates of protein synthesis are increased. Importantly, feeding CBK mice with a biotin-enriched diet for 6 wk normalized myocardial 1) ACC biotinylation and oleate oxidation rates; 2) PCC/MCC biotinylation (and partially restored leucine oxidation rates); and 3) net protein synthesis rates. Furthermore, data suggest that the RRAGD/mTOR/4E-BP1 signaling axis is chronically activated in CBK and CCM hearts. Finally we report that the hepatocyte circadian clock also regulates both slc5a6 expression and protein biotinylation in the liver. Collectively, these findings suggest that biotinylation is a novel mechanism by which cell autonomous circadian clocks influence metabolic pathways.

Cancer incidence among HIV-positive women in British Columbia, Canada: Heightened risk of virus-related malignancies.

OBJECTIVES: We used population-based data to identify incident cancer cases and correlates of cancer among women living with HIV/AIDS in British Columbia (BC), Canada between 1994 and 2008. METHODS: Data were obtained from a retrospective population-based cohort created from linkage of two province-wide databases: (1) the database of the BC Cancer Agency, a province-wide population-based cancer registry, and (2) a database managed by the BC Centre for Excellence in HIV/AIDS, which contains data on all persons treated with antiretroviral therapy in BC. This analysis included women (≥ 19 years old) living with HIV in BC, Canada. Incident cancer diagnoses that occurred after highly active antiretroviral therapy (HAART) initiation were included. We obtained a general population comparison of cancer incidence among women from the BC Cancer Agency. Bivariate analysis (Pearson χ(2) , Fisher's exact or Wilcoxon rank-sum test) compared women with and without incident cancer across relevant clinical and sociodemographic variables. Standardized incidence ratios (SIRs) were calculated for selected cancers compared with the general population sample. RESULTS: We identified 2211 women with 12 529 person-years (PY) of follow-up who were at risk of developing cancer after HAART initiation. A total of 77 incident cancers (615/100 000 PY) were identified between 1994 and 2008. HIV-positive women with cancer, in comparison to the general population sample, were more likely to be diagnosed with invasive cervical cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma and Kaposi's sarcoma and less likely to be diagnosed with cancers of the digestive system. CONCLUSIONS: This study observed elevated rates of cancer among HIV-positive women compared to a general population sample. HIV-positive women may have an increased risk for cancers of viral-related pathogenesis.

Surgeon Volume, Patient Age, and Tumor-Related Factors Influence the Need for Re-Excision After Breast-Conserving Surgery.

BACKGROUND: Breast-conserving surgery (BCS) is the preferred surgical approach for the majority of patients with early-stage breast cancer. There are frequent issues regarding pathologic margin status, requiring margin re-excision, and, in the literature, there is significant variability in re-excision rates, suggesting this is a potential quality-of-care issue. Understanding the patient-, disease-, and physician-related factors influencing reoperation rates is of importance in an effort to minimize this occurrence. METHODS: A retrospective analysis of all patients referred to our cancer center over a 3-year period (1 January 2011-31 December 2013) was performed. Surgeon volume, and patient- and tumor-related factors were assessed for their impact on re-excision rates. Multivariate logistic regression analysis was performed to identify variables of significance influencing reoperation rates after attempted BCS. RESULTS: Overall, 594 patients underwent initial BCS, with 159 (26.8%) patients requiring at least one re-excision to ensure negative pathologic margins. On multivariate analysis, low surgeon case volume, patient age (under 46 years of age), tumor size (>2 cm), and lobular carcinoma were associated with an increased re-excision rate. CONCLUSION: Re-excisions are frequent after BCS and are influenced by surgeon volume, patient age, and tumor-related factors. These factors should be considered when counseling patients considering BCS, and also for quality assurance.

Partial trisomy 21: a fifty-year follow-up visit.

We describe a clinical encounter with family members that carry a balanced translocation involving chromosomes 15 and 21 roughly 50 years after the proband was diagnosed with partial trisomy 21 due to an unbalanced translocation. We discuss how these chromosomal rearrangements have impacted the lives of these individuals, and how they responded to revisiting their diagnoses after using updated cytogenetic techniques including high resolution chromosome banding and array comparative genomic hybridization.

Incidental detection of cancer predisposition gene copy number variations by array comparative genomic hybridization.

We describe 2 pediatric patients who presented to medical genetics clinic for evaluation and were incidentally found via array comparative genomic hybridization to have pathogenic copy number variations of cancer predisposition genes. We subsequently reviewed 3554 previous array comparative genomic hybridization results to estimate the frequency of similar incidental findings.

Frequency of deployed emergency donor panel use prior to implementation of the low titre group O whole blood program.

INTRODUCTION: The US military has frequently used a 'walking blood bank', formally known as an 'emergency donor panel' (EDP) to obtain warm fresh whole blood (WFWB) which is then immediately transfused into the casualty. We describe the frequency of EDP activation by the US military. METHODS: We analysed data from 2007 to 2015 within the Department of Defense Trauma Registry for US, Coalition and US contractor casualties that received at least 1 unit of blood product within the first 24 hours and described the frequency of WFWB use. RESULTS: There were 3474 casualties that met inclusion, of which, 290 casualties (8%) required activation of the EDP. The highest proportion of EDP events was in 2014, whereas the highest number of EDP events was in 2011. Median injury severity scores were higher in the recipients, compared with non-EDP recipients (29 vs 20), as were proportions with serious injuries to the abdomen (43% vs 19%) and extremities (77% vs 65%). The median number of units of all blood products, except for packed red blood cells, was higher for WFWB recipients. Of the WFWB recipients, the median was 5 units (IQR 2-10) with a maximum documented 144 units. There were four documented cases of EDP recipients receiving >100 units of WFWB with only one surviving to hospital discharge. During the study period, there were a total of 3102 (3%) units of WFWB transfused among a total of 104 288 total units. CONCLUSIONS: We found nearly 1 in 11 casualties who received blood required activation of the EDP. Blood from the EDP accounted for 3% of all units transfused. These findings will enable future mission planning and medical training, especially for units with smaller, limited blood supplies. The lessons learned here can also enable mass casualty planning in civilian settings.

Clinical outcomes and safety with trabectedin therapy in patients with advanced soft tissue sarcomas following failure of prior chemotherapy: results of a worldwide expanded access program study.

BACKGROUND: This expanded access program (EAP) was designed to provide trabectedin access for patients with incurable soft tissue sarcoma (STS) following progression of disease with standard therapy. The outcomes of trial participants accrued over approximately 5 years are reported. PATIENTS AND METHODS: Adult patients with advanced STS of multiple histologies, including leiomyosarcoma and liposarcoma (L-sarcomas), following relapse or disease progression following standard-of-care chemotherapy, were enrolled. Trabectedin treatment cycles (1.5 mg/m(2), intravenously over 24 h) were repeated q21 days. Objective response, overall survival (OS), and safety were evaluated. RESULTS: Of 1895 patients enrolled, 807 (43%) had evaluable objective response data, with stable disease reported in 343 (43%) as best response. L-sarcoma patients exhibited longer, OS compared with other histologies [16.2 months (95% confidence interval (CI) 14.1-19.5) versus 8.4 months (95% CI 7.1-10.7)], and a slightly higher objective response rate [6.9% (95% CI 4.8-9.6) versus 4.0% (95% CI 2.1-6.8)]. The median treatment duration was 70 days representing a median of three treatment cycles; 30% of patients received ≥ 6 cycles. Safety and tolerability in this EAP were consistent with prior clinical trial data. CONCLUSION: Results of this EAP are consistent with previous reports of trabectedin, demonstrating disease control despite a low incidence of objective responses in advanced STS patients after failure of standard chemotherapy. CLINICALTRIALS.GOV: NCT00210665.

Active nanoplasmonic metamaterials.

Optical metamaterials and nanoplasmonics bridge the gap between conventional optics and the nanoworld. Exciting and technologically important capabilities range from subwavelength focusing and stopped light to invisibility cloaking, with applications across science and engineering from biophotonics to nanocircuitry. A problem that has hampered practical implementations have been dissipative metal losses, but the efficient use of optical gain has been shown to compensate these and to allow for loss-free operation, amplification and nanoscopic lasing. Here, we review recent and ongoing progress in the realm of active, gain-enhanced nanoplasmonic metamaterials. On introducing and expounding the underlying theoretical concepts of the complex interaction between plasmons and gain media, we examine the experimental efforts in areas such as nanoplasmonic and metamaterial lasers. We underscore important current trends that may lead to improved active imaging, ultrafast nonlinearities on the nanoscale or cavity-free lasing in the stopped-light regime.

Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I.

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.

Metabolic tumour volume is prognostic in patients with non-small-cell lung cancer treated with stereotactic ablative radiotherapy.

Introduction: Stereotactic ablative radiotherapy (sabr) is a relatively new technique for the curative-intent treatment of patients with inoperable early-stage non-small-cell lung cancer (nsclc). Previous studies have demonstrated a prognostic value for positron emission tomography-computed tomography (pet/ct) parameters, including maximal standardized uptake value (suvmax), metabolic tumour volume (mtv), and total lesion glycolysis (tlg) in lung cancer patients. We aimed to determine which pet/ct parameter is most prognostic of local control (lc) and overall survival (os) in patients treated with sabr for nsclc. Methods: We conducted a retrospective review of patients treated with sabr for stage I inoperable nsclc at BC Cancer between 2009 and 2013. The Akaike information criterion was used to compare the prognostic value of the various pet/ct parameters. Results: The study included 134 patients with a median age of 76 years. Median tumour diameter was 2.2 cm, gross tumour volume was 8.1 mL, suvmax was 7.9, mtv was 2.4 mL, and tlg was 10.9 suv·mL. The 2-year lc was 92%, and os was 66%. On univariate and multivariate analysis, imaging variables including tumour size, gross tumour volume, suvmax, mtv, and tlg were all associated with worse lc. Tumour size was not associated with significantly worse os, but other imaging variables were. The pet/ct parameter most prognostic of lc was mtv. Compared with suvmax, tlg and mtv were more prognostic of os. Conclusions: In patients with early-stage nsclc treated with sabr, mtv appears to be prognostic of lc and os.

Stereotactic Body Radiotherapy for Small Unresectable Hepatocellular Carcinomas.

AIMS: Stereotactic body radiotherapy (SBRT) is an option for the treatment of hepatocellular carcinoma (HCC) in patients ineligible for standard local therapies. This study reports on the safety and efficacy of SBRT in small HCC tumours (≤5 cm) in the province of British Columbia. MATERIALS AND METHODS: Between March 2011 and July 2015, 31 patients with Child-Pugh Class A or B, with small HCCs measuring ≤5 cm were treated with SBRT at our institution. Primary end points were local control, progression-free survival, overall survival and toxicity. RESULTS: Thirty-four hepatomas (median size 3.3 cm, range 1.3-5.0 cm) were treated. The median follow-up was 18.3 months. Twenty-six patients (84%) had received previous liver-directed treatments. Most patients (88%) were treated with 45 Gy in three or five fractions. Six patients (19%) had worsened Child-Pugh score by two or more points during follow-up; overall 32% of patients experienced ≥ grade 3 + toxicities. One-year local control and overall survival were 94 and 84%, respectively. One-year progression-free survival was 49%; 81% of patients with disease progression received further HCC therapy. On univariate analysis, small tumour size predicted for improved overall survival (P = 0.01) whereas prescription biological equivalent dose (BED10) ≥100Gy10 approached significance (P = 0.06). CONCLUSION: SBRT provides high local control to small inoperable HCC. SBRT can be delivered safely even after previous liver-directed therapies and further liver therapies can follow treatment with SBRT. Although overall 32% of patients experienced ≥ grade 3 + toxicities, and 19% had a deterioration in Child-Pugh score of two or more points, these changes were mainly transient with minimal clinical impact. Despite excellent local control, disease progression outside of the irradiated site remains prominent. Further studies are warranted to examine combined therapy approaches to maximise disease control.