Time Pattern of Presentation of Victims of High-Speed Passenger Ferry Mass Casualty Incidents to the Emergency Department.

OBJECTIVE: Mass Casualty Incidents (MCIs) involving high-speed passenger ferries (HSPFs) may result in the dual-wave phenomenon, in which the emergency department (ED) is overwhelmed by an initial wave of minor injuries, followed by a second wave of more seriously injured victims. This study aimed to characterize the time pattern of ED presentation of victims in such accidents in Hong Kong. METHODS: All HSPF MCIs from 2005 to 2015 were reviewed retrospectively, with the time interval from accident to ED registration determined for each victim. Multivariable linear regression was used to identify independent factors associated with the time of ED presentation after the accidents. RESULTS: Eight MCIs involving 492 victims were identified. Victims with an Injury Severity Score (ISS) ≥ 9 had a significantly shorter median time interval compared to those with minor injuries. An ISS ≥ 9 and evacuation by emergency service vessels were associated with a shorter delay in ED arrival, whereas ship sinking, accident at nighttime, and a longer linear distance between the accident and receiving ED were associated with a longer delay. CONCLUSION: The dual-wave phenomenon was not present in HSPF MCIs. Early communication is the key to ensure early resource mobilisation and a well-timed response.

Facilitating Safe Discharge Through Predicting Disease Progression in Moderate Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study to Develop and Validate a Clinical Prediction Model in Resource-Limited Settings.

BACKGROUND: In locations where few people have received coronavirus disease 2019 (COVID-19) vaccines, health systems remain vulnerable to surges in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Tools to identify patients suitable for community-based management are urgently needed. METHODS: We prospectively recruited adults presenting to 2 hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 to develop and validate a clinical prediction model to rule out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 < 94%; respiratory rate > 30 BPM; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex, and SpO2) and 1 of 7 shortlisted biochemical biomarkers measurable using commercially available rapid tests (C-reactive protein [CRP], D-dimer, interleukin 6 [IL-6], neutrophil-to-lymphocyte ratio [NLR], procalcitonin [PCT], soluble triggering receptor expressed on myeloid cell-1 [sTREM-1], or soluble urokinase plasminogen activator receptor [suPAR]), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration, and clinical utility of the models in a held-out temporal external validation cohort. RESULTS: In total, 426 participants were recruited, of whom 89 (21.0%) met the primary outcome; 257 participants comprised the development cohort, and 166 comprised the validation cohort. The 3 models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72-0.74) and calibration (calibration slopes: 1.01-1.05) in the validation cohort and provided greater utility than a model containing the clinical parameters alone. CONCLUSIONS: We present 3 clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources.

The limited value of triage vital signs in predicting influenza infection in children aged 5 years and under in the emergency department: A single-center retrospective cross-sectional study.

ABSTRACT: Diagnosing influenza in children aged 5 years and under can be challenging because of their difficulty in verbalizing symptoms. This study aimed to explore the value of the triage heart rate (HR), respiratory rate (RR), and temperature, either alone or when combined with individual symptoms and signs, in predicting influenza infection in this age group.This was a retrospective study covering 4 influenza seasons from 2017 to 2019 in an emergency department (ED) in Hong Kong. We recruited patients ≤5 years of age who had an reverse transcription polymerase chain reaction influenza test within 48 hours of ED presentation. The diagnostic performance of the triage HR, RR, and temperature was evaluated as dichotomized or categorized values with diagnostic odds ratios (DORs) calculated based on different age-appropriate thresholds. Linear discriminant analysis was performed to assess the combined discriminatory effect of age, HR, RR, and temperature as continuous variables.Of 322 patients (median age 26 months), 99 had influenza A and 13 had influenza B infection. For HR and RR dichotomized based on age-appropriate thresholds, the DORs ranged from 1.16 to 1.54 and 0.78 to 1.53, respectively. A triage temperature ≥39.0 °C had the highest DOR (3.32) among different degrees of elevation of temperature. The diagnostic criteria that were based on the presence of fever and cough and/or rhinitis symptoms had a higher DOR compared with the Centers for Disease Control and Prevention influenza-like illness criteria (4.42 vs 2.41). However, combining HR, RR, or temperature with such diagnostic criteria added very little to the diagnostic performance. The linear discriminant analysis model had a high specificity of 92.5%, but the sensitivity (18.3%) was too low for clinical use.Triage HR, RR, and temperature had limited value in the diagnosis of influenza in children ≤5 years of age in the ED. Fever and cough and/or rhinitis symptoms had a better diagnostic performance than the Centers for Disease Control and Prevention influenza-like illness criteria in predicting influenza in this age group.

Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles.

OBJECTIVE: Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs. DESIGN: We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed. RESULTS: We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time. CONCLUSIONS: These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.

Functional characterization of a candidate tumor suppressor gene, Mirror Image Polydactyly 1, in nasopharyngeal carcinoma.

Mirror Image Polydactyly 1 (MIPOL1) is generally associated with congenital anomalies. However, its role in cancer development is poorly understood. Previously, by utilizing the functional complementation approach, microcell-mediated chromosome transfer (MMCT), a tumor suppressor gene, MIPOL1, was identified. MIPOL1 was confirmed to be downregulated in nasopharyngeal carcinoma (NPC) cells and tumor tissues, and re-expression of MIPOL1 induced tumor suppression. The aim of the current study is to further elucidate the functional tumor suppressive role of MIPOL1. In our study, with an expanded sample size of different clinical stages of NPC tumor tissues, we further confirmed the downregulation of MIPOL1 in different cancer stages. MIPOL1 re-expression down-regulated angiogenic factors and reduced phosphorylation of metastasis-associated proteins including AKT, p65, and FAK. In addition, MIPOL1 was confirmed to interact with a tumor suppressor, RhoB, and re-expression of MIPOL1 enhanced RhoB activity. The functional role of MIPOL1 was further validated by utilizing a panel of wild-type (WT) and truncated MIPOL1 expression constructs. The MIPOL1 tumor-suppressive effect can only be observed in the WT MIPOL1-expressing cells. In vitro and nude mice in vivo functional studies further confirmed the critical role of WT MIPOL1 in inhibiting migration, invasion and metastasis in NPC. Overall, our study provides strong evidence about the tumor-suppressive role of MIPOL1 in inhibiting angiogenesis and metastasis in NPC.

Injury patterns of mass casualty incidents involving high-speed passenger ferries presenting to accident and emergency departments in Hong Kong: a retrospective review.

BACKGROUND: Accidents involving high-speed passenger ferries have the potential to cause mass-casualty incidents (MCIs), yet there is a lack of relevant studies available to inform hospital disaster preparedness planning. OBJECTIVE: The objective was to study the injury patterns and outcomes of MCI victims involved in high-speed passenger ferry accidents in Hong Kong waters. METHODS: A retrospective study was conducted from 1 January 2005 to 31 December 2015. All MCIs involving high-speed passenger ferries were captured from the Marine Department of Hong Kong. Victims of all age who were sent to the accident and emergency departments (A&Es) of seven public hospitals around Victoria Harbour, including three trauma centres, were identified from electronic disaster registries of the study hospitals. Data on injury patterns and outcomes were extracted from medical records with the Injury Severity Score (ISS) calculated for each victim. The Kruskal-Wallis test was used to compare medians of the ISS across different mechanisms of injury. Multivariable logistic regression was performed to identify independent predictors for major trauma (ISS≥16). RESULTS: During the study period, eight MCIs involving high-speed passenger ferries were reported and 512 victims (median age: 44 years, age range: 2-85 years) were sent to the study hospitals. The A&E triage categories were Cat 1, 3.1%; Cat 2, 4.3%; Cat 3, 19.3%; Cat 4, 72.9%; and Cat 5, 0.4%, respectively. The median ISS was 1.0 (interquartile range: 1.0-2.0). Fourteen victims (2.7%) had an ISS≥16 and age was the only independent predictor for major trauma (OR 1.06, p = 0.025, 95% CI 1.01-1.11). Trauma call was activated at A&E for 11 victims. In total, 100 victims (19.5%) were admitted to the study hospitals, including 19 (3.5%) and 15 (2.9%) who required surgery and intensive care unit stay, respectively. Eleven victims (2.1%) died, mostly due to drowning. CONCLUSION: MCIs involving high-speed passenger ferries can result in a sudden surge in demand for both A&E and in-patient care, though the majority of victims may have minor injuries. Better access to lifejackets and mandatory seatbelt use may help to reduce injuries and deaths.

EBV infection is associated with histone bivalent switch modifications in squamous epithelial cells.

Epstein-Barr virus (EBV) induces histone modifications to regulate signaling pathways involved in EBV-driven tumorigenesis. To date, the regulatory mechanisms involved are poorly understood. In this study, we show that EBV infection of epithelial cells is associated with aberrant histone modification; specifically, aberrant histone bivalent switches by reducing the transcriptional activation histone mark (H3K4me3) and enhancing the suppressive mark (H3K27me3) at the promoter regions of a panel of DNA damage repair members in immortalized nasopharyngeal epithelial (NPE) cells. Sixteen DNA damage repair family members in base excision repair (BER), homologous recombination, nonhomologous end-joining, and mismatch repair (MMR) pathways showed aberrant histone bivalent switches. Among this panel of DNA repair members, MLH1, involved in MMR, was significantly down-regulated in EBV-infected NPE cells through aberrant histone bivalent switches in a promoter hypermethylation-independent manner. Functionally, expression of MLH1 correlated closely with cisplatin sensitivity both in vitro and in vivo. Moreover, seven BER members with aberrant histone bivalent switches in the EBV-positive NPE cell lines were significantly enriched in pathway analysis in a promoter hypermethylation-independent manner. This observation is further validated by their down-regulation in EBV-infected NPE cells. The in vitro comet and apurinic/apyrimidinic site assays further confirmed that EBV-infected NPE cells showed reduced DNA damage repair responsiveness. These findings suggest the importance of EBV-associated aberrant histone bivalent switch in host cells in subsequent suppression of DNA damage repair genes in a methylation-independent manner.

Global governance and the broader determinants of health: A comparative case study of UNDP's and WTO's engagement with global health.

This comparative case study investigated how two intergovernmental organisations without formal health mandates - the United Nations Development Programme (UNDP) and the World Trade Organization (WTO) - have engaged with global health issues. Triangulating insights from key institutional documents, ten semi-structured interviews with senior officials, and scholarly books tracing the history of both organisations, the study identified an evolving and broadened engagement with global health issues in UNDP and WTO. Within WTO, the dominant view was that enhancing international trade is instrumental to improving global health, although the need to resolve tensions between public health objectives and WTO agreements was recognised. For UNDP, interviewees reported that the agency gained prominence in global health for its response to HIV/AIDS in the 1990s and early 2000s. Learning from that experience, the agency has evolved and expanded its role in two respects: it has increasingly facilitated processes to provide global normative direction for global health issues such as HIV/AIDS and access to medicines, and it has expanded its focus beyond HIV/AIDS. Overall, the study findings suggest the need for seeking greater integration among international institutions, closing key global institutional gaps, and establishing a shared global institutional space for promoting action on the broader determinants of health.

A comparison of shoulder muscular performance and lean mass between elite and recreational swimmers: Implications for talent identification and development.

This study compared the shoulder muscular performance and lean mass between elite and recreational swimmers.Thirty elite swimmers (mean age ±â€Šstandard deviation = 23.1 ±â€Š3.5 years) and 21 recreational swimmers (mean age ±â€Šstandard deviation = 20.8 ±â€Š2.1 years) participated in the study. Maximum muscle strength and time to maximum muscle strength of shoulder flexor, extensor, abductor, and adductor muscles were measured using a handheld dynamometer. Lean mass of the arms and body (excluding the head) were measured using dual-energy x-ray absorptiometry (DXA).Results revealed that compared with recreational swimmers, elite swimmers had higher maximum muscle strength of the shoulder flexor, extensor, abductor, and adductor muscles (all P < .001). The time to reach maximum muscle strength of all shoulder muscles showed no significant difference between the 2 groups (P > .05). The lean mass values in the left arm (P = .037), right arm (P < .001), and whole body (P = .014) were higher in elite swimmers than recreational swimmers.Elite swimmers had greater shoulder maximum muscle strength compared with recreational swimmers though the time taken to reach maximum muscle strength was similar between the 2 groups. Elite swimmers also showed a higher lean mass in both arms and their entire body when compared with recreational swimmers. The results may be useful for recreational swimmers who intend to advance to professional level, and for talent identification and early development of elite swimmers.

Elevated levels of serum nidogen-2 in esophageal squamous cell carcinoma.

BACKGROUND: Nidogen-2 (NID2), a secretory basement membrane protein, has been implicated as a potential biomarker in ovarian cancer and hepatocellular carcinoma. OBJECTIVE: In this study, we aimed to investigate the utility of detecting serum NID2 levels for identification of esophageal squamous cell carcinoma (ESCC) patients and prediction of poor survival outcome. METHODS: Using an in-house NID2 enzyme-linked immunosorbent assay (ELISA), serum samples from 101 ESCC patients and 50 healthy controls were screened for their NID2 levels. RESULTS: The serum NID2 levels in ESCC patients (median 24.4 µg/L) are significantly higher (p= 4.3e-09) than that of the healthy controls (median 15.85 µg/L). The receiver operating characteristic (ROC) curve demonstrated an area under the curve of 0.756. At the threshold of 17.95 µg/L, the sensitivity and specificity achieved are 0.76 and 0.63, respectively. Kaplan-Meier survival analysis revealed that patients with high serum NID2 levels (⩾ 32.6 µg/L) have significantly higher risk of death (HR = 1.984, 95% CI: 1.175-3.349; log-rank p-value = 0.012) compared to those with low serum NID2 levels (< 20.0 µg/L). CONCLUSIONS: In conclusion, we show that detecting the elevation of serum NID2 levels has potential diagnostic and prognostic value for ESCC patients.

Visual Outcomes and Local Control After Fractionated Stereotactic Radiotherapy for Optic Nerve Sheath Meningioma.

PURPOSE: To review the outcomes of patients with optic nerve sheath meningiomas (ONSM) treated with fractionated stereotactic radiotherapy. METHODS: Patient characteristics, treatment, and outcomes were analyzed for all patients with primary and secondary ONSM treated from 2001 to 2012. Clinically significant visual acuity change was defined as a 2-line change on the Snellen eye chart from pre-fractionated stereotactic radiotherapy. RESULTS: Forty-one patients were treated: 23 patients with primary ONSM and 18 patients with secondary ONSM. The median age at diagnosis was 56 years. The median visual follow up was 3.8 years and the median radiologic follow up was 4.4 years. At diagnosis, 36% had normal vision (20/20-20/40), 10% had mild impairment (<20/40-20/60), 20% had moderate visual impairment (<20/60-20/200), 27% had severe impairment (<20/200), and 7% had no light perception. Common acute side effects were headache (32%) and nausea (15%); 15% of patients required corticosteroids during stereotactic radiotherapy. Chronic toxicities included retinopathy (7%), pituitary dysfunction (13%), chronic ocular pain (5%), and cataracts (2%). Visual acuity was stable in 65%, improved in 27%, and decreased in 8% of patients. Visual fields were stable in 70%, improved in 21%, and reduced in 9%. Actuarial 5-year local control rates were 100% for primary ONSM and 88% for secondary ONSM. Actuarial 5-year visual preservation rates were 100% for primary ONSM and 86% for secondary ONSM. CONCLUSIONS: Fractionated stereotactic radiotherapy for primary and secondary ONSM was well tolerated and provides excellent local control and visual preservation. Longer follow up is required to determine the risk of late ocular and pituitary sequelae.

Metastasis-suppressing NID2, an epigenetically-silenced gene, in the pathogenesis of nasopharyngeal carcinoma and esophageal squamous cell carcinoma.

Nidogen-2 (NID2) is a key component of the basement membrane that stabilizes the extracellular matrix (ECM) network. The aim of the study is to analyze the functional roles of NID2 in the pathogenesis of nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC). We performed genome-wide methylation profiling of NPC and ESCC and validated our findings using the methylation-sensitive high-resolution melting (MS-HRM) assay. Results showed that promoter methylation of NID2 was significantly higher in NPC and ESCC samples than in their adjacent non-cancer counterparts. Consistently, down-regulation of NID2 was observed in the clinical samples and cell lines of both NPC and ESCC. Re-expression of NID2 suppresses clonogenic survival and migration abilities of transduced NPC and ESCC cells. We showed that NID2 significantly inhibits liver metastasis. Mechanistic studies of signaling pathways also confirm that NID2 suppresses the EGFR/Akt and integrin/FAK/PLCγ metastasis-related pathways. This study provides novel insights into the crucial tumor metastasis suppression roles of NID2 in cancers.

Whole-exome sequencing identifies multiple loss-of-function mutations of NF-κB pathway regulators in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3 Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-κB activity, which is critical for NPC tumorigenesis. In addition, somatic mutations were found in several cancer-relevant pathways, including cell cycle-phase transition, cell death, EBV infection, and viral carcinogenesis. These data provide an enhanced road map for understanding the molecular basis underlying NPC.

Genetic and epigenetic landscape of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a unique epithelial malignancy that shows a remarkable geographical and ethic distribution. Multiple factors including predisposing genetic factors, environmental carcinogens, and Epstein-Barr virus (EBV) infection contribute to the accumulation of genetic and epigenetic alterations leading to NPC development. Emerging technologies now allow us to detailedly characterize and understand cancer genomes. Genome-wide studies show that typically NPC tumors are characterized as having comparatively low mutation rates, widespread hypermethylation, and frequent copy number alterations and chromosome abnormalities. In this review, we provide an updated overview of the genetic and epigenetic aberrations that likely drive nasopharyngeal tumor development and progression. We integrate the previous knowledge and novel findings from whole-exome sequencing (WES) and methylome studies in NPC, and further discuss the potential use of these findings to identify biomarkers for NPC diagnosis and prognosis.

Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma.

Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germline variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.

Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir.

Pan-histone deacetylase (HDAC) inhibitors, which inhibit 11 HDAC isoforms, are widely used to induce Epstein-Barr virus (EBV) lytic cycle in EBV-associated cancers in vitro and in clinical trials. Here, we hypothesized that inhibition of one or several specific HDAC isoforms by selective HDAC inhibitors could potently induce EBV lytic cycle in EBV-associated malignancies such as nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). We found that inhibition of class I HDACs, particularly HDAC-1, -2 and -3, was sufficient to induce EBV lytic cycle in NPC and GC cells in vitro and in vivo. Among a panel of selective HDAC inhibitors, the FDA-approved HDAC inhibitor romidepsin was found to be the most potent lytic inducer, which could activate EBV lytic cycle at ∼0.5 to 5 nM (versus ∼800 nM achievable concentration in patients' plasma) in more than 75% of cells. Upregulation of p21(WAF1) , which is negatively regulated by class I HDACs, was observed before the induction of EBV lytic cycle. The upregulation of p21(WAF1) and induction of lytic cycle were abrogated by a specific inhibitor of PKC-δ but not the inhibitors of PI3K, MEK, p38 MAPK, JNK or ATM pathways. Interestingly, inhibition of HDAC-1, -2 and -3 by romidepsin or shRNA knockdown could confer susceptibility of EBV-positive epithelial cells to the treatment with ganciclovir (GCV). In conclusion, we demonstrated that inhibition of class I HDACs by romidepsin could potently induce EBV lytic cycle and mediate enhanced cell death with GCV, suggesting potential application of romidepsin for the treatment of EBV-associated cancers.

Volumetric Radiosurgery for 1 to 10 Brain Metastases: A Multicenter, Single-Arm, Phase 2 Study.

PURPOSE: Interest is growing in treating multiple brain metastases with radiosurgery. We report on the effectiveness and tolerability of volumetric radiosurgery (VRS). METHODS AND MATERIALS: We enrolled patients with a ≥6-month estimated life expectancy and 1 to 10 brain metastases with a diameter of ≤3 cm at 5 cancer centers. Volumetric radiosurgery was delivered in 5 fractions with 98% target coverage, prescribed as 95% of 50 Gy (47.5 Gy in 5 fractions) to the metastases with no margin and 95% of 40 Gy (38 Gy in 5 fractions) to their 2-mm planning target volumes, concurrent with 20 Gy to the whole brain planning target volume. The treatment was delivered with daily image guidance using conventional linear accelerators and volumetric modulated arc therapy. A magnetic resonance imaging scan was obtained every 3 months. The primary endpoint was the 3-month objective response in the brain according to the Response Evaluation Criteria in Solid Tumors, version 1.1. The principal secondary endpoint was 1-year actuarial control of treated metastases. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. The present study is registered with ClinicalTrials.gov (clinicaltrials.gov identifier NCT01046123). RESULTS: From July 2010 to May 2013, 60 patients underwent VRS with 47.5 Gy in 5 fractions for 12 metastases in the thalamus and basal ganglia (deep metastases) and 207 non-deep metastases. The median follow-up period was 30.5 months, and the median survival was 10.1 months. For the 43 patients assessable at 3 months, the objective response in the brain was 56%. The treated metastases were controlled in 88% of patients at 1 year and 84% at 3 years. Overall survival did not differ for patients with 4 to 10 versus 1 to 3 metastases (hazard ratio 1.18, P=.6). The crude incidence of severe radionecrosis (grade 3-5) was 25% (3 of 12) per deep metastasis, 1.9% (4 of 219) per non-deep metastasis, and 10% (6 of 60) per patient. CONCLUSIONS: For non-deep brain metastases, 47.5 Gy in 5 fractions was tolerable. Volumetric radiosurgery was effective for long-term control of treated brain metastases.