Although the clinical consequences of homelessness are well described, less is known about the role for health care systems in improving clinical and social outcomes for the homeless. We described the national implementation of a “homeless medical home” initiative in the Veterans Health Administration (VHA) and correlated patient health outcomes with characteristics of high-performing sites. We conducted an observational study of 33 VHA facilities with homeless medical homes and patient- aligned care teams that served more than 14,000 patients. We correlated site-specific health care performance data for the 3,543 homeless veterans enrolled in the program from October 2013 through March 2014, including those receiving ambulatory or acute health care services during the 6 months prior to enrollment in our study and 6 months post-enrollment with corresponding survey data on the Homeless Patient Aligned Care Team (H-PACT) program implementation. We defined high performance as high rates of ambulatory care and reduced use of acute care services.More than 96% of VHA patients enrolled in these programs were concurrently receiving VHA homeless services. Of the 33 sites studied, 82% provided hygiene care , 76% provided transportation, and 55% had an on-site clothes pantry; 42% had a food pantry and provided on-site meals or other food assistance. Six-month patterns of acute-care use pre-enrollment and post-enrollment for 3,543 consecutively enrolled patients showed a 19.0% reduction in emergency department use and a 34.7% reduction in hospitalizations. Three features were significantly associated with high performance: 1) higher staffing ratios than other sites, 1) integration of social supports and social services into clinical care, and 3) outreach to and integration with community agencies.Integrating social determinants of health into clinical care can be effective for high-risk homeless veterans. In 1988, the Institute of Medicine described homeless-related health problems as 3-pronged: health problems caused by homelessness, health problems that cause homelessness, and health conditions that are difficult to treat because of homelessness ,3; one cHomeless people also use high levels of health care, often in costly acute-care settings. One survey of homeless adults found that more than 40% used an emergency department (ED) at least once in the previous year ; anotherDeveloping a population-based approach and increasing health care systems’ capacity to address the health care needs of the homeless have challenges. Homeless people face multiple barriers to health care, including transportation, limited availability and fragmentation of health care services, difficulty scheduling and keeping appointments, perceived or actual stigma of homelessness, lack of trust, social isolation, and competing sustenance needs –15. HomeFor homeless people and for other socially disadvantaged populations, effective health care often lies outside the confines of a strictly medical approach  and inclThe homeless medical home initiative —known at VHA as the Homeless Patient Aligned Care Team (H-PACT) program — was launched in 2011 as part of the Ending Homelessness Among Veterans initiative . The int; 3) intensive health care management that is integrated with community agencies with an emphasis on ongoing, continuous care; 4) ongoing staff training and development of homeless care skills; and 5) data-driven, accountable care processes. Implementation fidelity among sites is addressed in 2 ways. First, during start-up, teams are provided an itemized checklist specific to the H-PACT model  enhanced, low-threshold access to care with open-access, walk-in capacity, flexible scheduling , and clinical outreach to homeless people on streets, in shelters, and in community locations ; 2) integrated services . In addition, sustenance needs  are available at the same locationCT model . Second,Monthly site-specific reports are provided to each team and consist of the following monitored performance measures across key indicators: 1) panel growth (a measurement of a site’s ability to engage and retain homeless veterans in the care model); 2) patient complexity (measured by the Diagnostic Cost Group (DCG)-Index panel complexity score, a global composite score on a scale of 0-to-5 defined by key diagnoses  and service use patterns   to ensurWe collected demographic data on all homeless veterans who were enrolled in H-PACT as of August 1, 2014. This cut-off date was selected to correlate with the annual survey data submitted by each clinic. Health services use was identified through administrative records capturing clinical encounter data for each care visit for VA-specific types of health care use  and averaged over 12 months for people continuously enrolled during that time. Because of the high numbers of administrative records on clinical encounters associated with mental health visits and homeless program participation, we examined only the proportion of patients receiving those services post-enrollment. Also, non-VHA–based care was not considered in this analysis.Analyses of pre-enrollment and post-enrollment use of health services were limited to VA-based inpatient hospitalizations and ED visits during the 6 months before enrollment in the H-PACT and the 6 months after enrollment. To provide historic context to our findings, we chose this period to be consistent with previous studies of homeless health services that used this timeframe. We included all veterans who enrolled in an H-PACT from October 2013 through March 2014, capturing data on their 6 month pre-enrollment use beginning in May 2013 (for October 2013 enrollees) and their 6 month post-enrollment use ending in August 2014 (for March 2014 enrollees). We stratified care teams into high performing, moderate performing, and low performing on the basis of the net change in their 6 month pre-enrollment–post-enrollment acute care use by patients enrolled in each site’s H-PACT program. High-performing H-PACTs were those demonstrating significant reductions in use of acute care services . Moderate performing H-PACTs had a 0% to 30% reduction in ED use or a 0% to 20% reduction in hospitalizations. Low-performing H-PACTs had an increase in ED use or hospitalizations in the 6-months post-enrollment. These criteria were selected as a surrogate measure for the ability of the H-PACT to successfully transition care from acute care settings to ambulatory care settings, presumably driven by reducing the need for acute care, having the capacity to provide on-demand outpatient care, improvements in the patient’s physical environment, or the result of case management. The stratification was limited to well-established H-PACT teams at the 33 sites studied, which had been in operation for at least 18 months and had at least 100 patients enrolled to minimize potential biases associated with start-up or extremely small enrollments.We used results from the 2014 clinic surveys to define characteristics and care elements of stratified sites: 1) access to care characteristics, 2) staffing and team member availability, 3) care management and treatment engagement approaches, 4) integration of homeless-specific interventions and monitors into clinical care, 5) incorporation of social support into care delivery, and 6) community integration elements.P ≤ .05 significant. We used STATA 8.0 (STATA Corp) for our analyses.We conducted a 2-sample proportions analysis of low-performing and high-performing H-PACTs, comparing the proportion of stratified clinics with each care element described previously. Included in this analysis were subelements specific to a particular service or offering. We reported z test statistical values for all implementation variables and considered The H-PACT program was launched in 2011 with 32 sites and expanded to 58 medical facilities and approximately 18,000 patients by 2015. The demographic and ambulatory care use data used in this analysis were for the August 2014 enrollment of 14,088 patients with corresponding characteristics of 33 established H-PACTs. The pre-enrollment and post-enrollment acute care use data were the aggregated clinical data of 3,543 veterans enrolled in an H-PACT program from October 2013 through March, 2014.The average age of participants was 53.4 years; 8.8% served in the military after September 11, 2001, 4.0% were women, and 11.0% were 65 years or older. Their DCG-Index complexity score was 0.96. These findings contrast with those for the overall population enrolled in primary care at VHA at the time: average age was 63 years and average DCG-Index complexity score was 0.66.Patients continuously enrolled in care for at least 1 year  in 2014 averaged 3.4 clinic visits with their primary care provider (PCP) and an additional 5.9 separate visits with other members of the H-PACT team  during the previous 12 months. They also averaged 1.5 visits in a specialty clinic, and 82.2% were actively receiving mental health and substance abuse services. By comparison, patients in general VHA primary care clinics averaged 1.8 PCP visits per year. More than 96% of patients enrolled in an H-PACT were concurrently receiving homeless program services, including permanent supportive housing placement and case management (a jointly run US Department of Housing and Urban Development and VHA program that uses Section 8 housing coupled with VHA case management to place homeless veterans in permanent housing with ongoing care management), transitional housing support (grant and per diem housing), outreach , justice programs  and vocational assistance .Overall, 82% of H-PACT sites provided hygiene support , 76% % provided direct assistance for transportation, 55% % had a clothes pantry on-site, and 42% % provided meals or other food assistance . Additionally, 39% of H-PACTs had peer mentors available on-site to assist with care navigation; 30% had vocational programs on-site, 27% processed benefits and disability claims on site, and 21% provided on-site legal aid.-PACT program (416–733 per month). In the 6 months before their enrollment, participating veterans had 3,022 ED visits and 812 hospitalizations. In the 6 months after enrollment, they had 2,447 ED visits (19.0% reduction) and 530 hospitalizations (34.7% reduction). Since the program’s inception (54 months previously), the overall reduction in both ED use and hospital admissions averaged 25%.From October 2013 through March 2014, 3,543 homeless veterans enrolled in the HP = .05), have more than 50% fulltime equivalent staffing of a clinic nurse  and primary care provider , to have social services and supports embedded in the clinic ; to have a clothes pantry , and to participate in community events such as health screenings  or community outreach .Overall 17 sites were found to be high performing, 9 sites were mid performing, and 7 sites were low performing. Although several core elements and features of the H-PACT model had been implemented to varying degrees throughout the sites studied, the association of these elements and features with high performance was limited . High-peIncorporating social determinants of health into clinical care is one approach to effectively engaging and managing the needs of vulnerable and disenfranchised patients . EvaluatThe pre-enrollment and post-enrollment analyses showed substantial reductions in acute care use in the 6 months after enrollment in the H-PACT program. This type of analysis is subject to potential regression-to-the-mean biases, because drops in acute care use could be explained by recovery from an acute event and health stabilization independent of the program. However, previous research of enrollment in ambulatory care models often showed at least an initial increase in acute care use post-enrollment, presumably by removing barriers to access and addressing delayed or deferred health care needs ,24–26. SIn our study patients enrolled in H-PACTs reduced their acute care use much faster than patients described in other reports. Other studies of homeless interventions found that reductions often occurred 6 to 12 months after people were enrolled in the program ,24,25. WFinally, developing and maintaining a homeless medical home model such as H-PACT presents challenges and costs. The model requires that leaders commit resources and understand that activities perceived as inefficiencies for clinics with high patient-visit rates and relatively low enrollment caps are necessary for reducing use of acute care. Sustaining the capacity to offer comprehensive care for those most in need, such as homeless veterans, also requires active panel management of those patients enrolled in the program, including the ability to advance patients to lower-intensity care settings when they have stabilized in terms of clinical, housing, and social needs.Our study has several limitations and strengths. The findings are from 4 years’ experience with a national demonstration project that consists of widely distributed care sites and settings. In contrast to single-site studies in more controlled settings, this study assumes a naturalistic, observational approach that may be more realistic when considering what is replicable and generalizable. Although using administrative data from VHA electronic medical records facilitates a comprehensive capture of demographic and health care use data, these data do not allow us to comment on care outside the VHA system. The parameters used for identifying high-performing H-PACTs were narrowly defined and do not address other equally important measures, such as housing stability, satisfaction with health care, and chronic disease management, which were considered elsewhere ,23. We aIn summary, findings from this pilot project suggest that high levels of patient engagement in health care, evidenced by enhanced use of health care and social services, were associated with a population-tailored medical home approach for homeless veterans. Critical elements associated with high-performing clinics are the robust incorporation of social determinant programs into clinical care delivery, dedicated staff time, and community integration.


Tuberculosis (TB) infection control measures are very important to prevent nosocomial transmission and protect healthcare workers (HCWs) in hospitals. The TB infection control situation in TB treatment institutions in southeastern China has not been studied previously. Therefore, the aim of this study was to investigate the implementation of TB infection control measures in TB-designated hospitals in Zhejiang Province, China.Cross-sectional survey using observation and interviews.All TB-designated hospitals (n=88) in Zhejiang Province, China in 2014.Managerial, administrative, environmental and personal infection control measures were assessed using descriptive analyses and univariate logistic regression analysis.The TB-designated hospitals treated a median of 3030 outpatients (IQR 764–7094) and 279 patients with confirmed TB (IQR 154–459) annually, and 160 patients with TB (IQR 79–426) were hospitalised in the TB wards. Most infection control measures were performed by the TB-designated hospitals. Measures including regular monitoring of TB infection control in high-risk areas (49%), shortening the wait times (42%), and providing a separate waiting area for patients with suspected TB (46%) were sometimes neglected. N95 respirators were available in 85 (97%) hospitals, although only 44 (50%) hospitals checked that they fit. Hospitals with more TB staff and higher admission rates of patients with TB were more likely to set a dedicated sputum collection area and to conduct annual respirator fit testing.TB infection control measures were generally implemented by the TB-designated hospitals. Measures including separation of suspected patients, regular monitoring of infection control practices, and regular fit testing of respirators should be strengthened. Infection measures for sputum collection and respirator fit testing should be improved in hospitals with lower admission rates of patients with TB. This study evaluated the implementation and practice of tuberculosis (TB) infection control measures among all TB-designated hospitals in a provincial region of China.All TB-designated hospitals (n=88) in Zhejiang Province, China were investigated in the cross-sectional survey in 2014.Our study had limitations. The survey was conducted on-site with the hospital staff; therefore, it is difficult to avoid response or observation bias. The study was limited to the Zhejiang Province of China, and it may not represent the current TB infection control situation in the central or western provinces of China. In addition, owing to the small sample size, we could not conduct multivariate analysis. Therefore, the effects of infection control measures need to be evaluated in a further study.China, the second most populated country in the world, accounted for 10% of global tuberculosis (TB) cases in 2014.TB transmission, especially of its MDR and extensively drug-resistant forms, poses a high occupational risk to healthcare workers (HCWs) at health institutions.9Recent studies performed in resource-limited countries have shown that even relatively simple control measures to prevent TB infection appear to be inadequately implemented.Before 2005, TB diagnostic and treatment services were performed in most regions in Zhejiang Province by local Centres for Disease Control and Prevention (CDCs). During the past decade, these tasks were assigned to local hospitals  by the government to provide better medical services for patients with TB. Currently, TB diagnostic and treatment services are performed by TB-designated hospitals in all regions of the province.A cross-sectional survey was conducted among TB-designated hospitals in Zhejiang Province. The province consists of 11 prefectures and 90 counties. TB services in Zhejiang Province are provided by provincial-level, prefectural-level and county-level TB-designated hospitals. These three levels were classified according to the administrative system in China. The provincial level is the highest level in the province. Provincial-level hospitals are located in the capital of the province and provide medical service mainly to patients who are critically ill with TB or with MDR-TB. The prefectural level is the second level, providing services for 4–12 counties; prefectural-level TB hospitals provide medical services to patients with MDR-TB or with TB from the administrative area. The county level is the lowest level, and county-level hospitals care for local patients with TB. Zhejiang Province has one provincial-level, 12 prefectural-level and 75 county-level TB-designated hospitals. Each prefecture-level city has a local designated hospital, except for two designated hospitals in Hangzhou, but each county does not have its own TB-designated hospital because the prefectural-level TB-designated hospitals might provide services for some of the governed counties. All of the 88 TB-designated hospitals have outpatient TB clinics. However, only 74 of the TB-designated hospitals have inpatient TB wards. All of the TB-designated hospitals were invited and agreed to participate in the survey.Data collection was conducted between September and December 2014. A facility-level survey and direct observations were conducted in the 88 TB-designated hospitals. The TB infection control questionnaire was based on the WHO TB infection control policyData analysis was performed using SPSS, V.19 . Descriptive analysis was used to summarise the characteristics of the designated hospitals and infection control implementation. Univariate logistic regression analyses were used to assess the relationships between the characteristics of the TB-designated hospitals and TB infection control practice. Three TB infection control measures which were not implemented well were selected as indicators for factor analysis: whether the hospital had a TB infection control plan, whether the hospital had a dedicated sputum collection area (a well-ventilated area), and whether the hospital conducted fit testing for N95 respirators. Crude ORs and 95% CIs were obtained for each association. A p value <0.05 was considered statistically significant. All of the investigated hospitals agreed to participate in the survey.The majority of the designated hospitals (94%) were general hospitals. The median numbers of HCWs in the designated hospitals, TB outpatient clinics and inpatient TB wards were 825, 3 and 18, respectively. Each hospital had a median of three infection control staff. The median annual numbers of outpatients and inpatients with TB in each hospital were 3030 (IQR 764–7094) and 160 , respectively. The median number of outpatients with TB treated per staff member per year in the TB clinics was 1263 (IQR 202–1985). A written TB infection control plan was available in the TB clinic/ward at 72/88 (82%) of the TB-designated hospitals, yet only 51/88 (58%) of the TB-designated hospitals had a TB infection control committee. Most  of the TB-designated hospitals reported having a regulation for prompt sputum tests for patients with TB. A referral policy for patients with suspected TB was commonly reported . Only 37/88 (42%) of the TB-designated hospitals provided an expedited priority service to shorten the stay for patients with TB, and less than half (46%) had a separate patient waiting area .Among all of the TB clinics, 68/88 (77%) had dedicated TB outpatient waiting areas. Fifty-six hospitals (64%) had a dedicated sputum collection area, while 25 hospitals (28%) collected sputum samples in the waiting area, 5 (6%) outside the hospital building and 2 (2%) in the washroom. TB infection control training was available in 81 of the TB-designated hospitals. Most  of the hospitals supplied HCWs with N95 respirators, although only 44 (50%) of the hospitals had conducted fit testing for these respirators. Of the 88 TB-designated hospitals, 81 (92%) offered training on TB infection control, 65 (74%) screened staff for TB at least annually, and 61 (69%) tested the infection control knowledge of staff every year.In the univariate analysis, no factors were associated with the availability of a TB infection control protocol. Factors associated with a dedicated sputum collection area were staff number and confirmed TB patient load in the TB outpatient clinic. Compared with hospitals with only 1 staff member in the TB outpatient department, those with 3–5 or 6–26 staff members were more likely to have dedicated sputum collection areas . Compared with hospitals that had <154 confirmed patients with TB in the TB outpatient clinic annually, those that had 279–458 or 459–6906 patients with confirmed TB annually were more likely to have a dedicated sputum collection area . Confirmed TB patient load in the TB outpatient department was associated with fit testing for N95 respirators. Compared with hospitals that had <154 patients with confirmed TB in the TB outpatient clinic annually, those with 279–458 or 459–6906 patients with confirmed TB were more likely to conduct fit testing for N95 respirators  .This study evaluated the implementation and practice of TB infection control measures among all TB-designated hospitals in a provincial region of China. According to the previous studies, the common method to assess the effect of TB infection control measures is to investigate the prevalence of LTBI in HCWs.Managerial and administrative control measures are the first and most important level of control to reduce the exposure of HCWs and other patients to TB.Environmental control is the second step in reducing the concentration of droplet nuclei in the air.Personal respiratory protection is the recommended third and final barrier to protect HCWs from inhaling infectious droplets.In resource-limited countries with a high prevalence of TB, healthcare facilities cannot effectively implement separation measures due to limited space and budget constraints.TB infection control measures were generally implemented by the TB-designated hospitals of Zhejiang Province, but the use of some measures needs to be strengthened, including the separation of patients with suspected TB, triage and priority service to shorten the stay of patients with TB, and regularly monitoring infection control and annual fit testing of respirators. Hospitals with lower admission rates of patients with TB should also place more importance on infection control measures such as sputum collection and appropriate respirator usage. Further research methods such as quantitatively measuring the adequacy of ventilation, investigating the prevalence of LTBI in HCWs, and in-depth interview with HCWs could be conducted to assess the effectiveness of TB infection control measures.


The quality of care delivered and clinical outcomes of care are of paramount importance. Wide variations in the outcome of emergency care have been suggested, but the scale of variation, and the way in which outcomes are inter-related are poorly defined and are critical to understand how best to improve services. This study quantifies the scale of variation in three outcomes for a contemporary cohort of patients undergoing emergency medical and surgical admissions. The way in which the outcomes of different diagnoses relate to each other is investigated.A retrospective study using the English Hospital Episode Statistics 2005–2010 with one-year follow-up for all patients with one of 20 of the commonest and highest-risk emergency medical or surgical conditions. The primary outcome was in-hospital all-cause risk-standardised mortality rate (in-RSMR). Secondary outcomes were 1-year all-cause risk-standardised mortality rate (1 yr-RSMR) and 28-day all-cause emergency readmission rate (RSRR).2,406,709 adult patients underwent emergency medical or surgical admissions in the groups of interest. Clinically and statistically significant variations in outcome were observed between providers for all three outcomes (p < 0.001). For some diagnoses including heart failure, acute myocardial infarction, stroke and fractured neck of femur, more than 20% of hospitals lay above the upper 95% control limit and were statistical outliers. The risk-standardised outcomes within a given hospital for an individual diagnostic group were significantly associated with the aggregated outcome of the other clinical groups.Hospital-level risk-standardised outcomes for emergency admissions across a range of specialties vary considerably and cross traditional speciality boundaries. This suggests that global institutional infra-structure and processes of care influence outcomes. The implications are far reaching, both in terms of investigating performance at individual hospitals and in understanding how hospitals can learn from the best performers to improve outcomes. Wide variations in clinical outcomes between hospitals have been described for a number of conditions. In addition, a number of high-profile failures of healthcare have been reported ,2. One cThe feasibility of a single rating being able to achieve all these aims has been questioned by commentators, including a report by the Nuffield Trust ,4. In paThe objectives of this study were to determine whether the risk-standardised clinical outcomes for emergency admissions varied significantly between providers, and whether outcomes were inter-related between different diagnoses at a hospital level.st April 2005 to 31st March 2010. The HES detail every admission into the NHS and allow patients to be tracked between NHS hospitals and across years through the use of a unique pseudo-anonymised identifier. The dataset can be considered an inclusive record of National Health Service (NHS) hospital activity in England as there is a requirement for every hospital to submit a “minimum dataset” to the Department of Health. Each hospital submits data from its own Patient Administration System (PAS) to the centralised HES data warehouse which is then validated and cleaned by the NHS Information Centre according to a pre-specified list of rules. HES contains publicly available admitted patient care data from 1989 onwards, with more than 12 million new records added each year. Each HES record contains a significant amount of information about the associated admission including patient demographics, the treating hospital, diagnostic and procedural coding, length of stay, discharge status and destination. Emergency and elective admissions can be differentiated by specific combinations of codes relating to type of admission and diagnostic/procedural code sub-groups. As a result, it is possible to identify patient cohorts with specific characteristics with a high degree of accuracy [The data source for this retrospective study was the national administrative dataset, the Hospital Episode Statistics (HES) data, for the period 1accuracy .A five-year study period was chosen to achieve a pragmatic balance between sample size and the cohort reflecting contemporary practice. The HES were linked with the Office of National Statistics (ONS) Registry data to provide longer-term and out-of-hospital mortality data. Clinical coding in the HES is through the OPCS-4 procedural coding system and ICD-10 diagnostic codes .Twenty patient groups were used that covered the breadth of hospital emergency admissions in adults (>17years of age) to acute NHS (public) hospitals. The groups were chosen a-priori by quantifying the commonest emergency admission diagnoses with the highest numbers of deaths to all acute NHS hospitals using a sample of HES data (2010/2011)  and secondary outcomes were one-year all-cause risk-standardised mortality rate (1yr-RSMR) and 28-day all-cause emergency readmission rate (RSRR) . In-hospEstablished methods were used to extract and clean the data, and entries with missing key fields, such as operation dates, were excluded from analyses (representing 1.15% of the dataset) . Each paThe confounding effect of inter-hospital transfers on in-RSMR and RSRR was accounted for as patients can be tracked between hospitals within the HES. Previous studies have shown that linking concurrent admissions together and assigning the ultimate outcome to the index hospital (super-spells) provides the most accurate reflection of in-hospital death rates .The analyses had two distinct stages: first, to quantify the extent of variations in outcome within each clinical group; and second, to determine whether the outcomes of a specific clinical group were associated with the collective outcomes of the other clinical groups within the same hospital. Statistical analysis was performed using SAS version 9.2 .Risk-standardisation was performed using hierarchical logistic regression models. Patient age, sex, RCS  Charlson score, social deprivation index and year of admission formed first-level predictors . Co-morbThe second level of the RSMR and RSRR models permitted hospital-level random intercepts to vary in order to identify hospital-specific random effects and account for the clustering of patients within the same hospital . This alVariations in outcome for each metric were assessed for each clinical group. Risk estimates from individual patient data were used to calculate the expected number of deaths for each condition at each hospital. For each clinical group, the discrepancy between the observed and expected mortality in each hospital was quantified. A statistically significant divergence was reported when it exceeded the 95% confidence interval of the Poisson distribution. Visually these were represented with risk-standardised funnel plots.The risk-standardised outcome for each of the twenty clinical groups was compared against the risk-standardised aggregate outcome for the other clinical groups excluding the procedure/condition of interest  using published methodology ,14.Hospitals were placed into quintiles containing equal numbers of patients based on their aggregate events rates. This was achieved by ranking hospitals according to their aggregate “other” event rate into five groups (quintiles) such that hospitals with the highest observed event rate relative to expectation  were in the highest numbered group (quintile 5) and those with the lowest observed event rate relative to expected were in quintile 1. Hospitals with very high event rates relative to expected would not necessarily be allocated to the highest quintile if the case load was small. Aggregation was performed using the provider’s mean Studentised residual aggregated across the remaining patient groups such that conditions with high event rates did not dominate the aggregation. Hospitals were assigned such that there were roughly equal numbers of patients in each quintile. Having assigned quintiles of aggregate “other” event rates, the combined event rate for the procedure/condition of interest was calculated for each quintile . Results were expressed as a bar plot. The relationship between the outcome for each clinical group and the amalgamated outcome quintiles was tested using logistic regression.Reporting of the study complied with the STROBE guidelines .The Wandsworth research ethics committee (WanREC) confirmed that no ethical approval was required for this study.2,406,709 admissions were included across 20 emergency groups in the five-year period. Summary demographic and outcome data for each group are provided Table .Clinically important, and statistically significant, variations in outcome were seen across the range of medical and surgical conditions for in-RSMR, 1 yr-RSMR and RSRR Table .For in-RSMR, the clinical groups with the greatest proportion of hospitals lying outside statistical control limits were medical diagnoses, including acute myocardial infarction, heart failure, stroke, pneumonia and sepsis. For each of these, more than 20% of hospitals lay above the 95% confidence limit. This was in addition to wide variations in the actual in-RSMR for each diagnosis, with many diagnoses demonstrating more than doubling of mortality rates between hospitals. An illustrative funnel plot for fractured neck of femur is given in Figure Within surgical diagnoses, significant variations in mortality were seen for fractured neck of femur, emergency colorectal laparotomy, ruptured abdominal aortic aneurysm repair, and emergency urological interventions. Of particular note, for fractured neck of femur, 19.4% of hospitals lay above the upper 95% confidence limit for in-RSMR.A number of medical conditions displayed wide variations in 1 yr-RSMR. For acute myocardial infarction, heart failure, stroke, pneumonia and urinary tract infection more than 15% of hospitals lay above the upper 95% confidence limit. An illustrative funnel plot for acute myocardial infarction is given in Figure Mortality variations after emergency surgery were less pronounced for 1 yr-RSMR than for in-RSMR. Significant variations were still observed, most notably, for fractured neck of femur where 14.4% of hospitals lay above the upper 95% confidence limit for 1 yr-RSMR.The widest variations in RSRR were for appendicectomy, fractured neck of femur, urinary tract infections, pneumonia, stroke and acute myocardial infarction with over 10% of hospitals lying above the upper 95% confidence limit. An illustrative funnel plot for pneumonia is given in Figure First, significant differences were observed between aggregated outcome quintiles when considering all 20 groups together for in-RSMR, 1 yr-RSMR and RSRR (p < 0.0001 for each). This confirmed hospital-wide variations in the overall outcomes delivered by individual hospitals for acute medical and surgical admissions.Second, the outcomes for specific patient groups within a hospital were strongly associated with the aggregate outcome of the other clinical groups within the same hospital . At one-year, the 1 yr-RSMR was 27.0% for quintile 1 and increased across quintiles to 31.0% for quintile 5 (p < 0.001).Diagnoses such as sepsis showed similar results with the best outcomes being in quintile 1 for in-RSMR 24.3% rising to 32.4% in quintile 5. This 33.3% risk increase was incremental across quintiles, and demonstrated a strong association with the sepsis-specific outcome (p < 0.001). Similarly, the 1 yr-RSMR for sepsis was 41.1% for quintile 1 rising to 48.7% for quintile 5 (p < 0.001).Even for surgical procedures with low event rates the relationships were notable. For example, a doubling of in-RSMR was observed for appendicectomy between quintile 1 (0.119%) and quintile 5 (0.252%), but the aggregate outcome was associated with the appendicectomy-specific outcome for in-RSMR (p = 0.02) and 1 yr-RSMR .When considering RSRR, the aggregated readmission rate was associated with the diagnosis-specific readmission rates in many cases. For example, the RSRR after fractured neck of femur was 9.80% in quintile 1 rising to 13.0% for quintile 5 (Figure This study analysed nearly 2.5 million emergency admissions to acute English NHS Trusts over a contemporary five-year period, with one year follow-up. The risk-standardised analyses covered the commonest acute medical and acute surgical diagnoses and procedures using granular, and clinically meaningful subgroups.The key finding of this study was to demonstrate significant variations between hospitals in terms of the in-hospital mortality rates, one-year mortality rates and 28-day emergency readmission rates that followed non-elective medical or surgical admissions. Furthermore, highly relevant within-provider inter-relationships were seen such that the outcome of a particular condition in one hospital was strongly associated with the aggregated outcome of the other conditions in that hospital.These data are suggestive of the presence of hospital-level factors that determine the outcomes of a variety of disparate emergency conditions ,26. In sOn the basis of these results, the development of an outcomes rating system could be cautiously supported, as this work has shown that there is a need for improved outcomes and reduced variations in outcome in emergency care -41. HoweClinical outcomes in this study were limited to validated hard endpoints. As a contemporary five-year cohort was used, concerns about the quality of coding in administrative data are mitigated as systematic reviews have found acceptable coding accuracy rates within the HES data, with data quality improving in more recent years ,46. UniqAnother strength of the study lies in case selection that focussed on a group of commonly encountered medical and surgical pathologies and ensured a plausible link between mortality and quality by including patients with conditions amenable to salvage . Using tFinally, the use of a super-spell definition of in-hospital mortality and the inclusion of 1-year mortality and 28-day emergency readmissions as secondary outcome measures demonstrated that the findings were consistent and mitigated criticisms of in-hospital mortality as an outcome measure, namely that it can be confounded by institutional, social and financial factors favouring rapid discharge ,52. DespLimitations of this study include the possibility of inter-hospital coding variability inherent to the use of retrospective administrative data and it is acknowledged that there remains no universal consensus on risk adjustment methodology with the consequence that different models can yield conflicting results ,47. WhilThe RCS Charlson score has been specifically modified and validated against the HES data . NonetheThe use of mortality as a metric for assessing the quality of care has been criticised although it remains a commonly used measure in health outcomes research and is particularly relevant in the context of emergency admissions ,14,42.It is acknowledged that the study does not address which critical structural and process measures account for the observed inter-relationships and that the results are not necessarily generalisable to paediatric populations, elective care admissions or to healthcare systems outside the United Kingdom. Determination of the underlying structures and processes of care remains the focus of ongoing research.For emergency medical and surgical admissions in England, wide variations in outcome exist between providers. In addition, strong associations in outcome were found between disparate clinical groups within individual providers that suggested the presence of underlying global structure and process factors underpinning clinical outcomes. These results have implications for the way in which care is delivered and provides potential targets for global quality improvement.The authors declare that they have no competing interest.PJEH: conception, design, analysis, drafting and critical revision. SS: conception, design, analysis, drafting and critical revision. BAO: design and drafting. AK: drafting and critical revision. JDP: design, analysis, drafting and critical revision. MMT: drafting, critical revision and guarantor. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/14/270/prepubTable S2. Highest numbers of deaths by OPCS-4, ICD-10 and HRG codes providing the basis for the selection of the 20 emergency groups. Table S3. Results from the inter-relationship quintile analysis for in-hospital all-cause risk-stratified mortality. Table S4. Results from the inter-relationship quintile analysis for 1-year all-cause risk-stratified mortality. Table S5. Results from the inter-relationship quintile analysis for all-cause risk-stratified 28-day emergency readmissions. Figure S1. Figures from the inter-relationship quintile analysis for in-hospital all-cause risk-stratified mortality. Figure S2. Figures from the inter-relationship quintile analysis for 1-year all-cause risk-stratified mortality. Figure S3. Figures from the inter-relationship quintile analysis for all-cause risk-stratified 28-day emergency readmissions.Clinical group descriptors by diagnostic and procedural codes. Click here for file


Artemisinin-based combination therapies (ACTs) are the cornerstone for the treatment of malaria. However, confirmed resistance to artemisinins in South-East Asia, and reports of reduced efficacy of ACTs raise major concerns for malaria treatment and control. Without new drugs to replace artemisinins, it is essential to define dosing strategies that maximize therapeutic efficacy, limit the spread of resistance, and preserve the clinical value of ACTs. It is important to determine the extent to which reduced efficacy of ACTs reflects true resistance versus sub-optimal dosing, and quantify other factors that determine treatment failure. Pooled analyses of individual patient data from multiple clinical trials, by investigators in the Worldwide Antimalarial Resistance Network, have shown high overall efficacy for three widely used ACTs, artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine. Analyses also highlight that suboptimal dosing leads to increased risk of treatment failure, especially among children. In the most recent study, an analysis of clinical trials of artesunate-amodiaquine, widely used among children in Africa, revealed a superior efficacy for fixed-dose combination tablets compared to loose non-fixed dose combinations. This highlights the benefits of fixed-dose combinations as a practical strategy for ensuring optimal antimalarial dosing and maximizing efficacy.http://www.biomedcentral.com/1741-7015/13/66Please see related article:  P. falciparum malaria in all areas in which malaria is endemic [Artemisinin-based combination therapies (ACTs) have made a major contribution to the reduction in global malaria morbidity and mortality since their use became widespread approximately 10 years ago. ACTs are recommended by the WHO as the first-line treatment of uncomplicated and severe  endemic . Drugs o endemic . Artesunkelch13 gene (gene ID PF3D7_1343700) [Unfortunately, the early signs of artemisinin resistance have emerged in South-East Asia threatening recent gains and milestones in the treatment and control of malaria ,5. Resis1343700) -8, and t1343700) . Emergin1343700) -15. It iA new study from the Worldwide Antimalarial Resistance Network (WWARN) investigated risk factors for treatment failure with AS-AQ therapy . ReducedAS-AQ is available in three different body-weight-adjusted drug formulations: fixed-dose combinations, loose non-fixed dose combinations, and co-blistered non-fixed-dose combinations. All of these combinations aim at delivering 12 mg/kg of AS over 3 days, but the total target dose of AQ ranges from 25 to 30 mg/kg for loose non-fixed dose combinations and is 30 mg/kg for co-blistered non-fixed-dose combinations and fixed-dose combinations. The WWARN study included 43 trials , of which 39 trials (95% of subjects) were conducted in Africa, as well as 3 in Asia and 1 in South America, and the great majority were children (87.5% were <12 years old) . The autP. falciparum malaria using fixed-dose AS-AQ formulations should be promoted for national treatment guidelines.Arguably, the most important finding was that fixed-dose combinations were associated with the highest AS-AQ treatment efficacy in all age groups, including in children less than 5 years of age, independently of high baseline parasitemia and young age. The fixed dose combination of AS-AQ was developed using weight-for-age values from malaria endemic countries, to ensure optimal dosing ,22. LoosP. falciparum resistance to AQ could not be evaluated in this study and further studies incorporating molecular markers of AQ resistance are warranted. Resistance to AQ is associated with mutations in the pfcrt and pfmdr genes [The study also found that the risk of recrudescence after AS-AQ treatment was higher among young children (<12 years old), those with a high baseline parasitemia, and in Asian studies compared to African. This may be reflective of the overall higher level of AQ resistance in Asia; however, given the small number of subjects from Asian trials, further studies are needed to examine this. The potentially crucial impact of dr genes ,24, whicdr genes . It willThere have been two related studies performed by WWARN investigators on the efficacy of other ACTs, highlighting the importance of optimal dosing. Dihydroartemisinin-piperaquine is another widely used ACT, and risk factors for recrudescence after treatment were examined in a pooled analysis of individual patient data from 26 efficacy studies  ; overallIn an era of emerging artemisinin resistance, and the push for malaria elimination in many regions, studies such as that of the WWARN collaboration provide important data to inform policymakers and clinicians to optimise antimalarial therapies to maximize efficacy and help reduce the evolution of resistance (see Box 1 for a summary of key points). These findings provide further support for international collaborative networks and data sharing arrangements to address major challenges in global health, and the approach used for malaria has strong relevance to antimicrobial therapy and resistance more broadly. Individual patient meta-analyses of therapeutic efficacy studies are considered the strongest form of clinical evidence, and are essential to inform antimalarial policy and clinical treatment guidelines to ensure the rapid and effective treatment of malaria cases.The WHO recommends artemisinin combination therapies (ACT) as the first-line treatment of malaria1Around 390 million courses of ACTs procured annually Emerging resistance to ACTs: Resistance confirmed in five countries in the Greater Mekong sub-regionSuspected artemisinin resistance is defined as failure to clear parasitemia within 3 days of commencing treatment, or a parasite clearance half-life of ≥5 hourskelch13 geneResistance to ACTs is associated with mutations in Resistance to other antimalarials is widespread pfcrt and pfmdr1 genesResistance to amodiaquine and chloroquine is associated with mutations in the Ensuring effective dosing is crucial to maximize efficacy and to protect against the further development and spread of resistanceAS-AQ is widely used in Africa, and is the second most widely used ACTAS-AQ Previously shown to have high efficacy when administered correctlyWWARN study performed an individual patient meta-analysis using data from 43 studies (39 studies in Africa) with over 9,000 treatments, predominantly in childrenStudy evaluated the impact of different dosing strategies on therapeutic efficacyFixed-dose and co-blistered non-fixed dose combinations had high efficacy (98%)Use of loose tablets at non-fixed dose had significantly lower efficacy (up to 3.5-fold higher risk of treatment failure)Findings highlight the benefit of fixed dose combinations and support this strategy in the treatment and control of malariaIncreased risk of recrudescence among young children, those with high baseline parasitemia, and among trials conducted in AsiaBased on WHO figures from 2013.See reference


This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children’s Cancer Research Institute in Vienna, Austria on September 24–25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas. The 3rd European bone sarcoma networking meeting was held at the Children’s Cancer Research Institute in Vienna, Austria on September 24–25, 2015. It was organized by Stefan Bielack, Stuttgart, and Leo Kager, Vienna, and supported by the European Network for Cancer research in Children and Adolescents Work Package 7 , the EUROpean Clinical Trials in Rare SARComas initiative , the European Ewing Consortium , the PROspective VAlidation of Biomarkers in Ewing Sarcoma network , and the European branch of the EURopean and AMerican Osteosarcoma Study Group .High-grade osteosarcomas (HGOS) have complex karyotypes showing abundant structural and numerical aberrations. Michaela Nathrath, Kassel, presented data from the Cooperative Osteosarcoma Biology Study Group. Exomes of 31 HGOS were sequenced and their evolutionary landscape was deciphered by inferring clonality of the individual mutation events. Exome findings were interpreted in the context of mutation and single-nucleotide polymorphism (SNP) array data from a replication set of 92 tumours. 14 genes were identified as the main drivers, some of which were formerly unknown in the context of HGOS. Tumour protein 53 (TP53) and molecular pathways functionally similar to TP53 seem to drive genomic instability in HGOS. More than 80 % of HGOSs exhibited a specific combination of single base substitutions, loss of heterozygosity (LOH), or large-scale genome instability signatures characteristic of breast cancer 1/2, and early onset (BRCA1/2)-deficient tumours. The findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited.http://NoSarC.org), a national collaboration collecting samples from all sarcoma patients in Norway for next generation sequencing (NGS)-based analysis and the search for new therapies, was introduced by Ola Myklebost, Oslo. He presented preclinical studies of a panel of osteosarcoma cell lines using NGS of DNA and RNA . They found hundreds of fusion transcripts, of which only a small fraction corresponded to fusion genes, suggesting a phenotype of trans-splicing, by which transcripts from different genes are joined during splicing. They did, however, find a recurrent fusion gene involving PMP22  and ELOVL5 (which encodes ELOVL fatty acid elongase 5). Whereas only a few of the genomic fusions produced fusion transcripts, the trans-spliced mRNAs should yield large numbers of neoantigens that could support immune checkpoint therapies. Furthermore, all cell lines had completely abrogated the p53 response, largely caused by copy number-neutral fusions and aberrations of TP53. The group will perform the NGS analysis of the SARC028 trial of Pembrolizumab in sarcoma.The Norwegian Sarcoma Consortium  screen, the aven-ATM serine/threonine kinase-checkpoint kinase 1 (ATM-CHEK1) pathway was identified as a target to sensitize osteosarcoma cells to conventional chemotherapeutic agents. Modulation of Aven-ATM-CHEK1 may also provide a novel strategy towards improving HGOS therapy.Aurélie Dutour, Lyon, demonstrated that chemotherapeutic treatments trigger an increase of netrin-1 (NTN1) expression, accompanied by an increase in netrin-1 dependence receptors DCC and UNC5H, and that combining chemotherapeutic agents and netrin-1 interference potentiates cancer cell death. The effect of anti-Ntn1 antibody combined with doxorubicin was investigated in an orthotopic metastatic rat model of osteosarcoma. The combination slows down osteosarcoma progression, significantly prolongs animal survival and prevents metastatic dissemination. Therefore, combining conventional drugs with Ntn-1 interference could lead to superior efficacy as well as lower chemotherapy doses for HGOS treatment.18F-fluorothymidine positron emission tomography/computed tomography (18F-FLT-PET/CT) analyses of tumour response indicated that tumour volumes underestimated treatment efficacy, and that 18F-FLT-PET/CT can potentially be used to measure response in the early phases of treatment. These findings suggest the need for further exploration of temsirolimus combined with either cisplatin or bevacizumab for HGOS, with the incorporation of 18F-FLT-PET scans.Blocking mammalian target of rapamycin (mTOR) activity is a promising approach to the treatment of patients with HGOS, although mTOR monotherapy has met with mixed results. Winette van der Graaf, London, suggested that combination therapy might be the key to success. Using two in vivo osteosarcoma models, she and her colleagues demonstrated that the activity of the mTOR-inhibitor temsirolimus is significantly enhanced by the addition of either cisplatin or bevacizumab. Moreover, extensive immunohistochemical and 3′-deoxy-3′-Stefano Ferrari, Bologna, pointed out that novel approaches to the treatment of HGOS should include patient risk stratification. For example, over-expression of the ATP-binding cassette transporter B1 (ABCB1) at diagnosis is involved in the processes of resistance to classic antineoplastic drugs, identifying patients with a poor prognosis in Italian sarcoma group (ISG) studies. The ISG and Spanish sarcoma group are presently carrying out a trial  in which patients are stratified into different regimens based on ABCB1 expression. Besides ABCB1, overexpression of the DNA excision repair protein ‘excision repair cross-complementation group 1’ (ERCC1) was found to be associated with a high relapse rate and poor EFS and OS. The co-evaluation of ERCC1 and ABCB1 protein expression showed that patients positive for both markers had a significantly worse prognosis.Pharmacogenomics, which aims to tailor drug therapy based on the genomic ‘make-up’ of normal host cells and cancer cells, can help to improve drug therapy. Accordingly, there has been an increase in pharmacogenomic investigations in patients with HGOS. Dr. Ferrari pointed out that a special effort should be made to prospectively undertake pharmacogenetic profiling of patients entering clinical trials.The beneficial effect of combining chemotherapy with the bisphosphonate zoledronate in syngenic models of rat osteosarcoma constituted the rationale for the French OS2006 trial (NCT00470223). Laurence Brugières, Villejuif, reported on the final results of the OS2006 trial conducted in France between 2007 and 2014. 315 patients with HGOS  were randomised to receive or not 10 injections of zoledronate in addition to chemotherapy. The final analysis of this trial showed that the addition of zoledronate to pre- and post-operative chemotherapy did not improve event-free and overall survival of patients with previously untreated osteosarcoma. This analysis also showed a slight excess of events and deaths in patients treated with zoledronate as compared to patients without zoledronate, leading to a non-significant difference in EFS and OS.Françoise Rédini, Nantes, provided information on how the French group will explore the biological background for the unexpected results of the OS2006 trial. Several hypotheses have been raised which include involvement of infiltrating macrophages, receptor activator of nuclear factor-kappa B (RANK)-expressing osteosarcoma cells, tartrate-resistant acid phosphatase (TRAP) expressing cells in the tumour bone niche, and the impact of the hormone microenvironment. The objective of ancillary studies performed on OS2006 biological samples is to determine whether the results are linked to the disease itself (HGOS), to the bone microenvironment, or to the age of the patients.David Thomas, Darlinghurst, provided an overview of immunotherapeutic approaches, which hold great promise for cancer treatment. HGOS is noted to be an immunologically interesting disease, for multiple reasons. For example, HGOS is assumed to derive from osteoblasts, a unique cell type that, together with the osteoclast, plays an important role in bone development and physiology. Dr. Thomas reviewed the complex signalling molecules and interdependencies that link the osteoblast and osteoclast, and their overlap with the immune system. There is an association between mutational load and tumour neo-antigens, apparently important to the effectiveness of a new generation of immunotherapies . In addition, HGOSs are noted to be genotypically complex and unstable, potentially making them good targets for immunotherapies. There is a long history of immunological approaches to HGOS , which reinforces optimism about their susceptibility to new developments in immune therapies.Piotr Rutkowski, Warsaw, showed that overexpression of programmed cell-death ligand 1 (PD-L1) on tumour cells, which interact with PD-1 on cytotoxic T-lymphocytes, impedes antitumour immunity and results in immune evasion. Interruption of the PD-L1/PD-1 pathway therefore represents an attractive therapeutic strategy to reinvigorate tumour-specific T cell immunity. He reported that PD-L1 had been observed to be significantly expressed in different subtypes of sarcomas including osteosarcoma (36 %), leiomyosarcoma (97 %) and Ewing sarcoma (39 %), while Kim et al. detected PD-L1 expression in 70 % of leiomyosarcomas, 67 % of Ewing sarcomas and 75 % of synovial sarcomas. These levels of expression, together with the poorer outcome of sarcoma patients with PD-L1 positivity, justify further exploration of the role of PD-L1 antibody in the treatment of sarcomas. Currently, the Soft Tissue and Bone Sarcoma Group of the European Organisation for Research and Treatment of Cancer (EORTC) and several pharmaceutical companies are planning phase II studies of anti-PD-L1 antibodies in advanced sarcomas, including HGOS.The focus of the immunoSARC project, presented by Javier Martin-Broto, Sevilla, is to explore immunomodulation as a therapeutic approach in sarcomas. The perspective is not only to investigate the impact of immune target drugs , but also to focus on the role of immunomodulation via combinations of these drugs with anti-angiogenic agents. Whereas the link between angiogenesis of tumours and immune evasion  is well known, this connection has been poorly studied in sarcomas even though some tumours are highly vascularised. A “pick the winner” randomized phase II trial has been designed, comparing the anti-PD-1 antibody nivolumab alone versus the combination of nivolumab plus pazopanib (a multi-targeted tyrosine kinase inhibitor that blocks angiogenesis) in cohorts of patients with bone sarcomas and soft tissue sarcomas. This investigation aims to explore whether combination arms prove to be synergistic in efficacy in selected sarcoma subtypes and if some immune targets  could be predictive at least in some sarcoma subtypes.Franca Fagioli, Torino, provided preclinical data on two different adoptive immunotherapy strategies for the treatment of sarcomas, including HGOS, namely human leukocyte antigen (HLA)-unrestricted and HLA-restricted strategies, with cytokine-induced killer (CIK) cells and sarcoma-specific cytotoxic T-lymphocytes (CTLs), respectively. The results of her investigations have provided preclinical proof-of-concept for an effective strategy to attack sarcomas with CIKs. A Phase I study with CIKs for patients with high-risk sarcomas, including HGOS, is being prepared.http://www.oncology.ox.ac.uk/trial/memos) of the EuroSARC group (http://eurosarc.eu/). The primary objective of this EuroSARC funded investigator initiated trial is to analyze biological effects of mifamurtide, and so requires tumour biopsies. A number of centres in UK, Norway, Italy and the Netherlands have begun recruiting patients.Bass Hassan, Oxford, reviewed current knowledge on the macrophage activating drug mifamurtide in the context of osteosarcoma and provided an overview on the MEMOS (‘A mechanistic study of mifamurtide in patients with metastatic and/or recurrent osteosarcoma’) trial  in chondrocytes, additional alterations affecting either the TP53 or cyclin-dependent kinase inhibitor 2A (CDKN2A) cause malignant transformation towards secondary peripheral chondrosarcoma. It was shown that mutations in isocitrate dehydrogenase (IDH1 or -2) are an early event for central tumours: the oncometabolite D-2-hydroxyglutarate induced by the mutation inhibits osteogenic differentiation and promotes chondrogenic differentiation, causing enchondromas of bone. In central chondrosarcomas, the IDH mutation is, however, no longer a driver mutation, as inhibition of the mutant protein has no effect on the tumourigenic properties of chondrosarcoma cell lines. Other additional genetic alterations are instead involved, affecting amongst others the TP53 and retinoblastoma (Rb) pathways, as well as collagen, type II, alpha 1 (COL2A1), neuroblastoma RAS viral oncogene homolog (NRAS), and other signalling pathways .Judith Bovée, Leiden, provided an update on the biology of chondrosarcoma (CS). A novel mouse model for peripheral CS has emphasized that, in addition to biallelic inactivation of exostosin glycosyltransferase (HEY1 and the nuclear receptor coactivator 2 (NCOA2). It mostly affects young adults and can arise at multiple anatomical sites, either in soft tissue or bone. A recent publication by Frezza et al. of a case series derived from the experience of European centres of excellence, has supported the prognostic significance of metastatic disease and proposed a survival advantage for the use of adjuvant chemotherapy. A second recent publication by Xu et al. using data extracted from subsets of patients reported in multiple retrospective series, drew opposite conclusions. Examples of where observational data had influenced clinical practice, but were refuted by data from randomised trials, were used to emphasize the importance of randomised studies, even in very rare sarcoma subtypes. The challenges of undertaking a randomised study of chemotherapy in mesenchymal chondrosarcoma were described using a recently published typology for access to trials and were concluded to be too formidable.Jeremy Whelan, London, discussed treatment of mesenchymal CS, which is a very rare subtype accounting for approximately 5 % of chondrosarcoma. The diagnosis is supported by identification of a translocation involving the transcription factor Hans Gelderblom, Leiden, reported on the COSYMO Study (EudraCT No: 2013-005155-32) in which three cohorts of patients  are treated with a combination of mTOR inhibition and cyclophosphamide. The rationale to use this drug combination in patients with CS and MLS derives from preclinical and clinical investigations.Piero Picci, Bologna, stressed the importance of a more accurate classification for spindle/pleomorphic bone sarcomas, as recently drawn up for soft tissue sarcomas. This would permit more specific chemotherapy regimens for the different entities within collaborative studies, made necessary by the rarity of these sarcomas.EWS-FLI1 affects a number of nicotinamide adenine dinucleotide (NAD) metabolizing enzymes, resulting in reduction of NAD levels in EwS cells. Drugs, which interact with the NAD metabolome  may be considered for preclinical development in EwS.Heinrich Kovar, Vienna, reported on novel players in the pathogenesis of Ewing sarcoma (EwS). David Herrero-Martin, Barcelona, provided data on non-coding RNAs in EwS. Analysis of the EwS methylome showed miR-10a (5p) hypermethylation; and miR-10a was found to be expressed at very low levels in both EwS cell lines and patient samples. Reintroduction of miR-10a in two EwS cell lines reduced migratory capacity and decreased clonogenic growth. An iTRAq (isobaric tags for relative and absolute quantification) proteomic analysis of miR-10a transfected cells allowed identification of several proteins that could be related to the described phenotype.Oscar Martinez Tirado and co-workers, Barcelona, revealed a role for ephrin A receptor 2 (EphA2) in the progression of EwS. This receptor chiefly participates in the migratory capacity of EwS cells by ligand-independent means. Work is in progress to decipher the molecular mechanisms associated with such effects.BCOR-CCNB3, CIC-DUX4, EWSR1-NFATc2 or EWSR1-PATZ1). The resemblance of these Ewing-like tumours, both to ES and among each other, was examined. It was first demonstrated that EwS presenting rare fusion variants such as FUS-ERG or FUS-FEV are transcriptionally undistinguishable from classical EWSR1-FLI1 or EWS-ERG positive tumours. Second, expression profiling and careful examination of clinical and pathological data indicated that the four Ewing-like sarcomas are far from resembling EwS and are distinct entities. Tirode et al. proposed to consider EwS as tumours carrying only fusions involving FET family proteins (EWSR1 or FUS) with ETS transcription factor genes (ERG and PEA3 types). While CIC-DUX4 and BCOR-CCNB3 are now classified as undifferentiated/unclassified sarcomas in the latest WHO sarcoma classification, said group proposed adding to this category all other types of Ewing-like translocations, as EWSR1-NFATc2 and EWSR1-PATZ1. Finally, it might even be advisable to provide a different nomenclature for Ewing-like sarcomas such as small round cell sarcoma with X-X translocation.Franck Tirode, Paris, reported that four Ewing-like sarcoma entities have been described as small round cell tumours presenting morphological characteristics of EwS but carrying a different chromosomal translocation  in EwS, reduces EWS/FLI1 expression. Treatment with bromodomain and extra-terminal motif (BET) inhibitors such as JQ1 blocks the typical expression profile of EwS. Moreover, JQ1 inhibits proliferation, induces apoptosis and reduces EwS tumour growth. When combined with phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor BEZ235, inhibition of BRD3/4 may offer new opportunities for combination therapy in EwS.Günther Richter, Munich, reported that next-generation sequencing (NGS) data confirm Emmy Fleuren, Nijmegen, focused on the topic of multi-receptor tyrosine kinase targeting in EwS. Unfortunately, inhibitors targeting a single receptor tyrosine kinase (RTK), such as insulin-like growth factor 1 receptor (IGF-1R), have been shown to be insufficient for EwS treatment in clinical practice. Since research indicates that tumours often do not rely on a single RTK and different RTKs can compensate for one another to maintain tumour growth, Fleuren et al. hypothesized that targeting multiple RTKs at once may be a more promising approach. They therefore investigated the co-expression patterns and co-targeting effects of various oncogenic RTKs implicated in EwS in 30 primary ES patient samples. Significant, strong positive correlations and co-expression patterns were observed between IGF-1R and MET, IGF-1R and AXL, and MET and AXL receptors. Co-targeting these RTKs was synergistic or at least additive in 6/6 EwS cell lines in vitro, with the most pronounced effects in IGF-1R-targeted combinations, indicating that IGF-1R deserves further investigation, particularly in combinations.’ (RON) is expressed and active in EwS, with over-expression in tumours derived from metastatic disease. Evidence of function in pro-metastatic cellular features supports RON as a potential therapeutic target. However, targeting strategies are challenged by the isoform known as short-form RON which lacks the extracellular antibody-binding domain, thereby bypassing antibody inhibition. This exemplifies that isoforms, principally described in diverse RTKs, require attention and further understanding to adapt targeting strategies.Jenny Potratz, Münster, provided data showing that the receptor tyrosine kinase (RTK) ‘recepteur d’origine nantaishttp://www.oncology.ox.ac.uk/trial/lines): a Bayesian single-arm phase II trial in which the dual anti-IGF-1R/IR drug linsitinib is investigated in patients with relapsed and/or refractory EwS. This EuroSARC biomarker directed study is currently recruiting in UK, Italy, Germany and the Netherlands, despite prolonged administrative and set up delays. The study incorporates intensive analysis including 18FDG-PET-CT and biopsies (pathway and gene expression responses including RNASeq) before and after high dose linsitinib exposure, and aims to discover potential mechanisms of dual IGF1R/IR kinase sensitivity and resistance.Bass Hassan discussed the rationale for dual inhibition of IGF-1R and insulin receptor (IR) in EwS. Moreover, he presented the LINES trial (®) and IGF-1 signalling. In EwS, trabectedin may not only inhibit but also enhance the binding of EWS-FLI1 to certain target genes, leading to upregulation of IGF1R. Combination of trabectedin and anti-IGF-1R inhibitors represents a potential therapeutic option for patients with EwS.Katia Scotlandi, Bologna, reported on the interaction between the cytotoxic drug trabectedin  project, which assesses circulating tumour DNA (ctDNA) as a response marker in EwS. EFACT is implemented as an accompanying research project to the ongoing EWING2008 trial. Extended application to relapsed EwS appears particularly informative considering that personalized treatment schedules are often necessary in this cohort. Analysis of ctDNA copy numbers is suited for integration in preclinical studies and Phase I/II trials as an additional response marker.Hans Gelderblom provided an overview on recently published clinical trials in HGOS, EwS and CS and discussed the difficulties in conducting investigator-initiated clinical trials in bone sarcomas. Collaboration, creation of centres of expertise for bone sarcomas, innovative statistical designs, lowering administrative burden, inventive funding, molecular tumour boards, etc. might help to boost investigator-initiated research in bone sarcomas.Marie-Cecile LeDeley, Villejuif, summarized results from the EURO-EWING 99 trial (NCT00020566) and discussed how to make international cooperation more efficient, based on the experience acquired in the EURO-EWING 99 trial.https://www.clinicaltrialsregister.eu/ctr-search/trial/2008-003658-13/DE) which is open in 11 countries and more than 100 centres. The trial includes three arms: standard risk, high risk and very high risk with different randomised questions. It is the first clinical trial to also include a randomised question for patients with very high risk EwS with primary disseminated disease. An interdisciplinary international tumour board is open for patients treated within the clinical trial and also for patients who do not have the chance to receive treatment within clinical trials. Part of the report focused on the administrative barriers to opening an investigator-initiated trial in Europe with national directives on top of the EU directives, and the advantages of a harmonized online registration and data entry system , now used by many European clinical trials.Uta Dirksen, Münster, provided an update on the international EWING 2008 trial  was also presented. Provabes is a joint proposal by the leading European Ewing sarcoma study groups and basic and translational researchers. Aim of the study is to validate previously described putative predictive and prognostic biomarkers. The group expects that a combination of markers rather than a single biomarker will provide the most informative prognostic algorithm for patients with EwS.The “Prospective Validation of Biomarkers in EwS for a personalized medicine” project , focusing on fertility after cancer.A short summary was provided on the long-term follow up and late effect study, PanCareLife  which has been opened and recruiting patients since December 2013 in UK, Spain and France. Thus far, 54 European centres are open with plans to set up centres in Australia and Israel in 2016. The opening of all international centres, sponsored by the Birmingham ‘Cancer Research UK Clinical Trial Unit’ (CRUK CTU), involving each country’s interpretation of EU trials regulations, has not been quick or easy. The CTU should perhaps have considered that protracted contracts with other countries would occur and have avoided the ensuing delays by addressing the problem much earlier. The presentation of data using the same investigational medical product (IMP) in another bone tumour has caused concern among investigators and may affect recruitment. Lastly the ‘R3’ cohort of EwS were not included in this trial and every effort must now be made by EEC to rectify this, considering that their prognosis remains dismal.Bernadette Brennan, Manchester, reported on the Euro Ewing 2012 trial , which aims to compare four commonly used chemotherapy regimens for efficacy and toxicity in refractory and relapsed EwS. It utilises a multi-arm, multi-stage trial design to exclude less active and/or more toxic arms at an early stage, and will therefore avoid recruitment of large numbers of patients to these less active, more toxic chemotherapy regimens. rEECur represents the most extensive collaboration yet between European Ewing sarcoma clinical trial groups. This collaboration has been facilitated by the acquisition of European Commission funding. However, despite a keen willingness to collaborate and a desire to successfully answer the study questions, opening the study has been hampered by the requirement of each EU member state to individually interpret the EU Clinical Trials Directive through its Competent Authority, and to assess the ethical issues of the study. Two years into a 5-year grant, the study is open in six out of the planned thirteen countries. None of the queries raised by Competent Authorities or ethics committees have yet resulted in any changes to the design, to implementation of the study protocol or to the patient consent process, but the bureaucracy required to repeat the process in thirteen countries has contributed significantly to the time and resources needed to open the study. Major European funders should consider this time delay as an inevitable component of cross-border European clinical trials when allocating resources for running international trials.Martin McCabe, Manchester, reported on the ‘rEECur’ trial . ISG/SSG3 (1999–2006) enrolled 300 patients with non metastatic EwS, and ISG/SSG4 (1999–2008) enrolled 102 with metastatic EwS. Both protocols envisaged the use of high-dose chemotherapy (HDCHT) and peripheral blood stem cell (PBSC) support for high-risk patients (poor responders to induction chemotherapy or metastatic patients). Patients with non-metastatic EwS, responding poorly to induction treatment with the VACA-IE regimen, achieved the same probability of event-free survival as good responders, thanks to the addition of HDCHT. Surgery was the main option for local control. The use of postoperative radiotherapy should be provided in cases of inadequate surgical margins and when the histological response does not affect local control. Females and very young paediatric patients experience higher bone marrow toxicity. In patients with synchronous metastases (lung or only one bone metastasis) a 5-year overall survival rate of 50 % can be achieved with aggressive treatment with HDCHT and total lung irradiation. Complete radiological response of lung metastases is predictive of survival. Post-relapse survival is very poor in recurrent patients in spite of intensive chemotherapy treatment with high-dose ifosfamide and high-dose busulfan and melphalan. Second complete remission is the main factor predicting post relapse survival. The role of HDCHT in this subset of patients is uncertain.http://sarctrials.org/SARC025), which is a collaborative US/European phase I study of a combination of the poly(ADP-ribose) polymerase (PARP) inhibitor, Niraparib, with Temozolomide in EwS. Dr. Strauss commented on the regulatory challenges that have arisen as the sponsor of the trial (the US SARC group) is not based in the European Economic Area (EEA). Models that may help to overcome such obstacles were discussed.Sandra Strauss, London, reported on the Sarcoma Research through Collaboration SARC025/SP1 trial  consortium, discussed strategies to prioritize agents for further development in bone sarcoma. In a world where an increasing number of new drugs with increasingly varied mechanisms of action are being developed each year, international networks should think about strategies to prioritize agents for further development in bone sarcoma, along four axes. (1) To define appropriate drugable targets with relevant bone sarcoma biology at diagnosis and relapse. (2) To ensure strong preclinical evidence of drug efficacy alone and in combination in multiple bone sarcoma models, taking into account the microenvironment . (3) To promote drugs with appropriate toxicity profiles that could be compatible with relapse but mainly with first-line chemotherapy regimens. (4) To anticipate when to introduce the drug according to this mechanism of action, such as on bulky tumour or in minimal residual disease. Collaboration among clinicians and biologists but also statisticians is crucial, as the main objective remains to improve patient outcome by introducing new drugs into first-line treatment of bone sarcomas at whatever age,.http://www.sarcoma-patients.eu), discussed the efforts made over the last few years, by both the scientific and patient communities in the field of rare cancers, to allow patients access to promising new experimental drugs. Clinical studies on rare tumours, as bone sarcomas, require a significant collaborative network, resources and sufficient numbers of patients to lend statistical significance and value to study outcomes. As these tumours are, by definition, rare, the problem is the scarcity of the numbers involved. It therefore follows that as many patients as possible must be recruited. She outlined the crucial role that correct information always plays in patient recruitment. This means managing information by defining what, how, where and by whom it should be delivered to patients, in order to make them aware of the nature of clinical trials and the benefits of participating in one of them.Ornella Gonzato, Udine, a representative of SPAEN  found that only 35 % of sarcoma patients were asked by their clinician to participate in research. However, 64 % of these went on to participate, showing that patients are interested and willing to take part when invited to do so by their clinician. She provided recommendations on how to improve information on trials to patients. This included raising awareness about the importance of recommending trials to patients through a European campaign targeted at clinicians and supported by charities, patient groups and research networks. It also entailed setting up a one-stop sarcoma portal for clinical trials (in Europe), rather than having multiple places to search. Moreover, it was emphasised that clinical trials should get smarter about ‘marketing’ themselves in order to attract and retain participants, e.g., by sharing the excitement of what difference the trial could make in the future and clearly setting out the benefits to individual patients.http://unite2cure.org), calling for better treatment and better access to therapy for children and young people with cancer. The network decided to take the opportunity of Childhood Cancer Awareness month to build support for bringing about reform of Paediatric Medicines Regulations (2007). They set the target of collecting 1000 signatures for an e-petition by the end of September 2015, a goal which they easily exceeded. Amongst its supporters their website now lists many prominent professionals and numerous well-respected organisations in the field. They carried the initiative forward at meetings with the Cancer Drugs Development Forum and the European Medicines Agency.In his capacity as a consumer representative, Christopher Copland, York, presented a network of groups and individuals from across Europe , together with the Innovative Therapies for Children with Cancer Consortium (ITCC), the European Society for Paediatric Oncology (SIOPE) and the European Network for Cancer Research in Children and Adolescents (ENCCA), has created a unique Paediatric Oncology Platform, involving multiple stakeholders and the European Commission (EC), with an urgent remit to improve paediatric oncology drug development.Craig Gerrand, Newcastle upon Tyne, presented the UK ‘National Ewing’s Multidisciplinary Team’, which began as a pilot project in 2011 and serves as a forum to discuss the local treatment of patients with ES of bone. The aim was to improve the consistency of treatment decisions through discussion and peer review. In the 4 years since its establishment, over 295 patients have been discussed and the concept has been proven. More work is required to move beyond the pilot phase if the panel is to fulfil its potential, and support data collection and clinical trials in this and possibly other sarcoma types.Stephanie Klco-Brosius, and Uta Dirksen Münster, presented the international interdisciplinary virtual EwS tumour board, which has been set up in Münster as an ENCCA project. Eight European and international countries discuss their patients in the virtual tumour board. A retrospective analysis was presented of the value of a reference tumour board, implicating major advantages for patients with primary disseminated disease.http://www.expornet.eu). The main aim of ExPO-r-Net is to address and improve health inequalities for children with cancer in Europe by building a European Reference Network for Paediatric Oncology.Ruth Ladenstein, Vienna, reported on the European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment (ExPO-r-Net) (Bone sarcomas are ultra orphan-diseases with three decades of stagnation in survival. To further improve outcomes, it is essential to promote international collaboration propelled by initiatives like the European Bone Sarcoma Network. Novel insights from basic and clinical research that may help to improve sarcoma therapy were discussed during the meeting and results were presented from investigations on tumour cell genomics, epigenetics, metabolism, altered signalling pathways, sarcoma immunology as well as on pharmacodynamics, pharmacogenomics, and the measurement of circulating tumour DNA. Moreover, experiences from recent sarcoma trials were reviewed and the viewpoints of patient and parent advocates, clinical researchers, statisticians and charity representatives were summarized in order to provide knowledge that can facilitate the design of future clinical sarcoma trials. The discussions generated many novel, exciting ideas, which now need to be taken forward to proposals for innovative trials, which are urgently needed. Such proposals for collaborative research and trials should be a major focus for the next European Bone Sarcoma Networking Meeting, scheduled to take place in London in 2017.