Survival Outcome Analysis of Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) versus SBRT-Alone in Unresectable Hepatocellular Carcinoma.

Introduction: While combination of stereotactic body radiotherapy (SBRT) and immunotherapy are promising, their efficacy and safety have not been compared with SBRT-alone in patients with unresectable hepatocellular carcinoma (HCC). Methods: This retrospective study included 100 patients with nonmetastatic, unresectable HCC in two hospitals. Eligible patients had tumor nodules ≤3 and Child-Pugh liver function score of A5 to B7. Seventy patients received SBRT-alone, and 30 patients underwent combined SBRT and immunotherapy (SBRT-IO). Overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicity were analyzed. We adjusted for the potential confounding factors using propensity score matching. Results: The median tumor size was 7.3 cm (range, 2.6-18 cm). Twenty-five (25%) of patients had vascular invasion. Before propensity score matching, the 1-year and 3-year OS rate was 89.9% and 59.8% in the SBRT-IO group and 75.7% and 42.3% in SBRT-alone group (p = 0.039). After propensity score matching (1:2), 25 and 50 patients were selected from the SBRT-IO and SBRT-alone group. The 1-year and 3-year OS was 92.0% and 63.9% in the SBRT-IO group versus 74.0% and 43.3% in the SBRT-alone group (p = 0.034). The 1-year and 3-year TTP was better in SBRT-IO group (1-year: 68.9% vs. 58.9% and 3-year: 61.3% vs. 32.5%, p = 0.057). The ORR of 88% (complete response [CR]: 56%, partial response [PR]: 22%) in SBRT-IO arm was significantly better than 50% (CR: 20%, PR: 30%) in the SBRT-alone arm (p = 0.006). Three patients (12%) developed ≥grade 3 immune-related treatment adverse events (n = 2 hepatitis, n = 1 dermatitis) leading to permanent treatment discontinuation. Conclusion: Adding immunotherapy to SBRT resulted in better survival with manageable toxicities. Prospective randomized trial is warranted.

Association between health insurance cost-sharing and choice of hospital tier for cardiovascular diseases in China: a prospective cohort study.

Background: Hospitals in China are classified into tiers (1, 2 or 3), with the largest (tier 3) having more equipment and specialist staff. Differential health insurance cost-sharing by hospital tier (lower deductibles and higher reimbursement rates in lower tiers) was introduced to reduce overcrowding in higher tier hospitals, promote use of lower tier hospitals, and limit escalating healthcare costs. However, little is known about the effects of differential cost-sharing in health insurance schemes on choice of hospital tiers. Methods: In a 9-year follow-up of a prospective study of 0.5 M adults from 10 areas in China, we examined the associations between differential health insurance cost-sharing and choice of hospital tiers for patients with a first hospitalisation for stroke or ischaemic heart disease (IHD) in 2009-2017. Analyses were performed separately in urban areas (stroke: n = 20,302; IHD: n = 19,283) and rural areas (stroke: n = 21,130; IHD: n = 17,890), using conditional logit models and adjusting for individual socioeconomic and health characteristics. Findings: About 64-68% of stroke and IHD cases in urban areas and 27-29% in rural areas chose tier 3 hospitals. In urban areas, higher reimbursement rates in each tier and lower tier 3 deductibles were associated with a greater likelihood of choosing their respective hospital tiers. In rural areas, the effects of cost-sharing were modest, suggesting a greater contribution of other factors. Higher socioeconomic status and greater disease severity were associated with a greater likelihood of seeking care in higher tier hospitals in urban and rural areas. Interpretation: Patient choice of hospital tiers for treatment of stroke and IHD in China was influenced by differential cost-sharing in urban areas, but not in rural areas. Further strategies are required to incentivise appropriate health seeking behaviour and promote more efficient hospital use. Funding: Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, China Ministry of Science and Technology, and National Natural Science Foundation of China.

Efficacy and feasibility of 3D printed redesigned Venezia™ applicator for treating advanced cervix and recurrent endometrial cancer.

PURPOSE: Venezia™ is an interstitial brachytherapy applicator for treating advanced cervical and vaginal vault recurrent cancer. However, there are limitations that lead to suboptimal target coverage. 3D printing introduction allows the redesign of Venezia™ for bulky and irregular-shaped tumors. METHODS: This study first describes three new designs included: 1) add-on needles template allowed for an extra layer of straight and oblique needles, 2) redesigned vaginal cap so straight and oblique needles can be used together and 3) redesigned central tube allowed vaginal vault interstitial needle insertion. Drawbacks to original Venezia™ and rationale for using these new designs were discussed. Dosimetric analysis by comparing the original Venezia™ with new design for 10 cases in Oncentra treatment planning system v4.5 (Elekta, Stockholm, Sweden) to observe the dose differences in gross tumor volume (GTV), high risk clinical target volume (HRCTV), intermediate clinical target volume (IRCTV) and organs at risk. RESULTS: For the dosimetric comparison, there were statistically significantly increased median minimal dose to 98% (D98%) of GTV, 90% (D90%) of HRCTV, and IRCTV for the new design with p-value of 0.008, 0.005 and 0.0018, respectively. Comparing the physical dose of D98% of GTV, D90% of HRCTV, and IRCTV when using the new design, it averagely increased by 11.7%, 8.0%, 19.4%, respectively per fraction. CONCLUSIONS: Dosimetric comparison revealed the new designs increased the dose to GTV, HRCTV and IRCTV and fulfilled the dose constraints of bladder, rectum and sigmoid. The 3D printed new design is biocompatible, inexpensive and can be patient specific.

Temporal trends and rural-urban disparities in cerebrovascular risk factors, in-hospital management and outcomes in ischaemic strokes in China from 2005 to 2015: a nationwide serial cross-sectional survey.

BACKGROUND: Stroke is the leading cause of mortality in China, with limited evidence of in-hospital burden obtained from nationwide surveys. We aimed to monitor and track the temporal trends and rural-urban disparities in cerebrovascular risk factors, management and outcomes from 2005 to 2015. METHODS: We used a two-stage random sampling survey to create a nationally representative sample of patients admitted for ischaemic stroke in 2005, 2010 and 2015. We sampled participating hospitals with an economic-geographical region-stratified random-sampling approach first and then obtained patients with a systematic sampling approach. We weighed our survey data to estimate the national-level results and assess changes from 2005 to 2015. RESULTS: We analysed 28 277 ischaemic stroke admissions from 189 participating hospitals. From 2005 to 2015, the estimated national hospital admission rate for ischaemic stroke per 100 000 people increased (from 75.9 to 402.7, Ptrend<0.001), and the prevalence of risk factors, including hypertension, diabetes, dyslipidaemia and current smoking, increased. The composite score of diagnostic tests for stroke aetiology assessment (from 0.22 to 0.36, Ptrend<0.001) and secondary prevention treatments (from 0.46 to 0.70, Ptrend<0.001) were improved. A temporal decrease was found in discharge against medical advice (DAMA) (from 15.2% (95% CI 13.7% to 16.7%) to 8.6% (8.1% to 9.0%); adjusted Ptrend=0.046), and decreases in in-hospital mortality (0.7% in 2015 vs 1.8% in 2005; adjusted OR (aOR) 0.52; 95% CI 0.32 to 0.85) and the composite outcome of in-hospital mortality or DAMA (8.4% in 2015 vs 13.9% in 2005; aOR 0.65; 95% CI 0.47 to 0.89) were observed. Disparities between rural and urban hospitals narrowed; however, disparities persisted in in-hospital management (brain MRI: rural-urban difference from -14.4% to -11.2%; cerebrovascular assessment: from -20.3% to -16.7%; clopidogrel: from -2.1% to -10.3%; anticoagulant for atrial fibrillation: from -10.9% to -8.2%) and in-hospital outcomes (DAMA: from 2.7% to 5.0%; composite outcome of in-hospital mortality or DAMA: from 2.4% to 4.6%). CONCLUSIONS: From 2005 to 2015, improvements in hospital admission and in-hospital management for ischaemic stroke in China were found. A temporal improvement in DAMA and improvements in in-hospital mortality and the composite outcome of in-hospital mortality or DAMA were observed. Disparities between rural and urban hospitals generally narrowed but persisted.

Allogeneic TCRαß deficient CAR T-cells targeting CD123 in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a disease with high incidence of relapse that is originated and maintained from leukemia stem cells (LSCs). Hematopoietic stem cells can be distinguished from LSCs by an array of cell surface antigens such as CD123, thus a candidate to eliminate LSCs using a variety of approaches, including CAR T cells. Here, we evaluate the potential of allogeneic gene-edited CAR T cells targeting CD123 to eliminate LSCs (UCART123). UCART123 cells are TCRαßneg T cells generated from healthy donors using TALEN® gene-editing technology, decreasing the likelihood of graft vs host disease. As safety feature, cells express RQR8 to allow elimination with Rituximab. UCART123 effectively eliminates AML cells in vitro and in vivo with significant benefits in overall survival of AML-patient derived xenograft mice. Furthermore, UCART123 preferentially target AML over normal cells with modest toxicity to normal hematopoietic stem/progenitor cells. Together these results suggest that UCART123 represents an off-the shelf therapeutic approach for AML.

Impact of global budget combined with pay-for-performance on the quality of care in county hospitals: a difference-in-differences study design with a propaensity-score-matched control group using data from Guizhou province, China.

BACKGROUND: Provider payment system has a profound impact on health system performance. In 2016, a number of counties in rural Guizhou, China, implemented global budget (GB) for county hospitals with quality control measures. The aim of this study is to measure the impact of GB combined with pay-for-performance on the quality of care of inpatients in county-level hospitals in China. METHODS: Inpatient cases of four diseases, including pneumonia, chronic asthma, acute myocardial infarction and stroke, from 16 county-level hospitals in Guizhou province that implemented GB in 2016 were selected as the intervention group, and similar inpatient cases from 10 county-level hospitals that still implemented fee-for-services were used as the control group. Propensity matching score (PSM) was used for data matching to control for age factors, and difference-in-differences (DID) models were constructed using the matched samples to perform regression analysis on quality of care for the four diseases. RESULTS: After the implementation of GB, rate of sputum culture in patients with pneumonia, rate of aspirin at discharge, rate of discharge with ß-blocker and rate of smoking cessation advice in patients with acute myocardial infarction increased. Rate of oxygenation index assessment in patient with chronic asthma decreased 20.3%. There are no significant changes in other indicators of process quality. CONCLUSIONS: The inclusion of pay-for-performance in the global budget payment system will help to reduce the quality risks associated with the reform of the payment system and improve the quality of care. Future reform should also consider the inclusion of the pay-for-performance mechanism.

BCL6 maintains survival and self-renewal of primary human acute myeloid leukemia cells.

B-cell lymphoma 6 (BCL6) is a transcription repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). BCL6 was expressed at variable and often high levels in AML cell lines and primary AML samples. AMLs with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors, with the exception of those with monocytic differentiation. Gene expression profiling of AML cells treated with a BCL6 inhibitor revealed induction of BCL6-repressed target genes and transcriptional programs linked to DNA damage checkpoints and downregulation of stem cell genes. Ex vivo treatment of primary AML cells with BCL6 inhibitors induced apoptosis and decreased colony-forming capacity, which correlated with the levels of BCL6 expression. Importantly, inhibition or knockdown of BCL6 in primary AML cells resulted in a significant reduction of leukemia-initiating capacity in mice, suggesting ablation of leukemia repopulating cell functionality. In contrast, BCL6 knockout or inhibition did not suppress the function of normal hematopoietic stem cells. Treatment with cytarabine further induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to cytarabine. Treatment of AML patient-derived xenografts with BCL6 inhibitor plus cytarabine suggested enhanced antileukemia activity with this combination. Hence, pharmacologic inhibition of BCL6 might provide a novel therapeutic strategy for ablation of leukemia-repopulating cells and increased responsiveness to chemotherapy.

Socioeconomic differences in health-care use and outcomes for stroke and ischaemic heart disease in China during 2009-16: a prospective cohort study of 0·5 million adults.

BACKGROUND: China initiated major health-care reforms in 2009 aiming to provide universal health care for all by 2020. However, little is known about trends in health-care use and health outcomes across different socioeconomic groups in the past decade. METHODS: We used data from the China Kadoorie Biobank (CKB), a nationwide prospective cohort study of adults aged 30-79 years in 2004-08, in ten regions (five urban, five rural) in China. Individuals who were alive in 2009 were included in the present study. Data for all admissions were obtained by linkage to electronic hospital records from the health insurance system, and to region-specific disease and death registers. Generalised linear models were used to estimate trends in annual hospital admission rates, 28-day case fatality rates, and mean length of stay for stroke, ischaemic heart disease, and any cause in all relevant individuals. FINDINGS: 512 715 participants were recruited to the CKB between June 25, 2004, and July 15, 2008, 505 995 of whom were still alive on Jan 1, 2009, and contributed to the present study. Among them, we recorded 794 824 hospital admissions (74 313 for stroke, 69 446 for ischaemic heart disease) between 2009 and 2016. After adjustment for demographic, socioeconomic, lifestyle, and morbidity factors, hospitalisation rates increased annually by 3·6% for stroke, 5·4% for ischaemic heart disease, and 4·2% for any cause, between 2009 and 2016. Higher socioeconomic groups had higher hospitalisation rates, but the annual proportional increases were higher in those with lower education or income levels, those enrolled in the urban or rural resident health insurance scheme, and for those in rural areas. Lower socioeconomic groups had higher case fatality rates for stroke and ischaemic heart disease, but greater reductions in case fatality rates than higher socioeconomic groups. By contrast, mean length of stay decreased by around 2% annually for stroke, ischaemic heart disease, and any cause, but decreased to a greater extent in higher than lower socioeconomic groups for stroke and ischaemic heart disease. INTERPRETATION: Between 2009 and 2016, lower socioeconomic groups in China had greater increases in hospital admission rates and greater reductions in case fatality rates for stroke and ischaemic heart disease. Additional strategies are needed to further reduce socioeconomic differences in health-care use and disease outcomes. FUNDING: Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, China Ministry of Science and Technology, and Chinese National Natural Science Foundation.

Quality of care in large Chinese hospitals: an observational study.

OBJECTIVE: To empirically assess the quality of hospital care in China and trends over a 5-year period during which the government significantly increased its investment in healthcare. DESIGN: Retrospective, observational study comparing hospital quality between two periods: October 2012-March 2013 and October 2017-March 2018. SETTING: 1-2 of the most reputable large tertiary hospitals in each of the 25 provinces in Mainland China (total of 33). PARTICIPANTS: Adults 18 years or older admitted with acute myocardial infarction (AMI) (n = 7031), cerebral ischaemic stroke (n = 12 008), chronic obstructive pulmonary disease (COPD) (n = 11 836) and bacterial pneumonia (n = 4263). MAIN OUTCOME MEASURES: Process-based quality measures, including seven AMI measures, three stroke measures, four COPD measures and six pneumonia measures. RESULTS: In 2012/2013, Chinese hospitals had variable performance on AMI measures, including prescribing aspirin on arrival (80.7%), and discharging patients on aspirin (79.2%), ß-blockers (60.8%) or statins (75.8%). This was similar for stroke cases and pneumonia cases. Smoking cessation advice was given at high rates across conditions though rates of influenza/pneumococcal vaccines were performed <1%. In 2017/2018, Chinese hospitals experienced no differences across most quality measures. Performance declined for two measures: aspirin on arrival for AMI cases and blood cultures before antibiotics for pneumonia cases. Performance increased for two measures: percutaneous coronary intervention within 90 min in ST segment elevation myocardial infarction cases (66.6% vs 80.1%, p<0.001) and statins at discharge for stroke cases (64.7% vs 78.7%, p<0.001). Compared with US hospitals, Chinese hospitals underperformed across most measures. CONCLUSIONS: Chinese hospitals had low and variable performances across most quality measures for common medical conditions. Quality of care generally does not appear to be improving post national health reform. The Chinese government should include quality of care improvement in its health reform priorities to ensure patients receive appropriate and effective care.

Managing health expenditure inflation under a single-payer system: Taiwan's National Health Insurance.

As nations strive to achieve and sustain universal health coverage (UHC), they seek answers as to what health system structures are more effective in managing health expenditure inflation. A fundamental macro-level choice a nation has to make is whether to adopt a single- or a multiple-payer health system. Using Taiwan's National Health Insurance (NHI) as a case, this paper examines how a single-payer system manages its health expenditure growth and draws lessons for other countries whose socioeconomic development is similar to Taiwan's. Our analyses show that as a single payer, Taiwan's NHI is able to exercise its monopsony power to manage its health expenditure growth. This is achieved primarily through the adoption of a system-wide global budget. The global budget sets a hard aggregate budget cap to limit NHI's total spending to its expected revenue, with the annual budget growth rate established by a process of negotiation among key stakeholders. The global budget system is complemented by comprehensive and continuous monitoring and review of encounter records of all providers and patients, enabled by the NHI's advanced information technology. However, by paying its providers using a point-based fee schedule, Taiwan's NHI suffers from inefficient service provision. In particular, providers have incentives to increase use of services and drugs with positive profit margins. Furthermore, Taiwan demonstrates that its control of NHI expenditure growth might be leading it to inadequately meet the changing needs of the population, resulting in the rapid growth of private insurance to cover services excluded or not fully covered by the NHI. If this trend persists and results in a two-tier system, Taiwan's NHI may risk compromising the equity it has achieved in the past two decades.

What can be achieved with a single-payer NHI system: The case of Taiwan.

The United Nations has incorporated the noble goal of Universal Health Coverage (UHC) in its 2030 Agenda for Sustainable Development. Most nations have already embraced UHC as their goal. However, an intense policy debate has risen about which health system structure can best achieve UHC. Is a single-payer system more efficient, equitable and effective than a multiple-payer system for middle income countries? We argue that empirical evidence and in-depth analysis of single-payer and multiple-payer systems should inform this debate. First, we need a clear definition of single- and multiple-payer health systems that enables us to compare their differences and clarify the issues to be debated. Second, at least four key issues confront any nation that wishes to achieve UHC: (1) how to design an affordable comprehensive health benefit package for UHC and to finance it (2) how the health expenditure inflation rate can be managed to sustain UHC (3) how modern information technology can be used to enhance efficiency and quality of healthcare and (4) how to assure an adequate supply of high-quality services will be distributed equitably throughout a nation. This paper offers a definition of single- and multiple-payer and compares them. We then use Taiwan's National Health Insurance system to address the four key issues, and illuminate how its policies and operations led to Taiwan's successful UHC.

Throwing the dart blind-folded: comparison of computed tomography versus magnetic resonance imaging-guided brachytherapy for cervical cancer with regard to dose received by the 'actual' targets and organs at risk.

PURPOSE: Computed tomography (CT) is inferior to magnetic resonance imaging (MRI) in cervical tumor delineation, but similar in identification of organs at risk (OAR). The trend to over-estimate high-risk and low-risk clinical target volume (HRCTV, IRCTV) on CT can lead to under-estimation of dose received by 90% (D90) of the 'actual' CTV. This study aims to evaluate whether CT-guided planning delivers adequate dose to the 'actual' targets while spares the OAR similarly. MATERIAL AND METHODS: MRI-guided high-dose-rate image-guided brachytherapy (IGBT) was performed in 11 patients. The pre-brachytherapy CTs were retrospectively contoured to generate CT-guided plans. MRI-based contours (HRCTVmri, IRCTVmri, bladdermri, rectummri, and sigmoidmri) were fused to CT plans for dosimetric comparison with MRI-guided plans. Paired 2-tailed t-test and Wilcoxon signed-rank test were used to analyze data. RESULTS: 63.6% of CT plans achieved the HRCTVmriD90 constraint (≥ 7.2 Gy in one fraction), compared with 90.9% for MRI plans. > 90% of both modalities achieved the OAR's constraints (EMBRACE). The percentage of CT and MRI plans that achieved the aims (EMBRACE II) for bladder, rectum, and sigmoid were 36.4% vs. 81.8%, 63.6% vs. 63.6%, and 72.7% vs. 72.7%, respectively. There were no statistically significant differences in HRCTVmriD90, IRCTVmriD90, or dose received by the most exposed 2 cm3 (D2cc) of OARmri between the modalities. Excluding the CT plans not achieving HRCTVmriD90 constraint, there were significant increase in bladdermriD2cc, rectummriD2cc, and sigmoidmriD2cc, compared with MRI plans (0.9 Gy/Fr, 95% CI 0.2-1.5, p = 0.018; 0.9 Gy/Fr, 95% CI 0.3-1.4, p = 0.009; 0.5 Gy/Fr, 95% CI 0.2-0.9, p = 0.027, respectively). CONCLUSIONS: MRI-based IGBT remains the gold standard. CT planning may compromise HRCTVmriD90 or increase OARmriD2cc, which could decrease local control or increase treatment toxicity.

Realigning demand and supply side incentives to improve primary health care seeking in rural China.

China's recent and ambitious health care reform involves a shift from the reliance on markets to the reaffirmation of the central role of the state in the financing and provision of services. In collaboration with the Government of the Ningxia province, we examined the impact of two key features of the reform on health care utilisation using panel household data. The first policy change was a redesign of the rural insurance benefit package, with an emphasis on reorientating incentives away from inpatient towards outpatient care. The second policy change involved a shift from a fee-for-service payment method to a capitation budget with pay-for-performance amongst primary care providers. We find that the insurance intervention, in isolation, led to a 47% increase in the use of outpatient care at village clinics and greater intensity of treatment (e.g. injections). By contrast, the two interventions in combination showed no effect on health care use over and above that generated by the redesign of the insurance benefit package.

An experiment in payment reform for doctors in rural China reduced some unnecessary care but did not lower total costs.

Inefficiency and low quality of health services are common in many developing countries. To mitigate these problems, we conducted an experiment in rural China in which we changed the existing fee-for-service method of paying village doctors to a mixed payment method that included a salary plus a bonus based on performance. The new payment method also removed a feature that previously allowed doctors to purchase medications to prescribe to patients and earn a markup on each prescription. Changing these payment incentives reduced spending at the village level, curbed unnecessary care for healthier patients, and also decreased the prescribing of unnecessary drugs. However, other features of the arrangement encouraged doctors to refer sicker patients to township and county facilities, where costs were higher. As a result, total health care spending was not significantly reduced. The findings underscore that policy makers should design payment methods carefully to both contain costs and improve quality.

China's health system and its reform: a review of recent studies.

This paper provides a survey of the recent empirical research on China's 'old' health system (i.e. prior to the spate of reforms beginning in 2003). It argues that this research has enhanced our understanding of the system prior to 2003, in some cases reinforcing conclusions (e.g. the demand-inducement associated with perverse incentives) while in other cases suggesting a slightly less clear storyline (e.g. the link between insurance and out-of-pocket spending). It also concludes that the research to date points to the importance of careful evaluation of the current reforms, and its potential to modify policies as the rollout proceeds. Finally, it argues that the research on the pre-2003 system suggests that while the recently announced further reforms are a step in the right direction, the hoped-for improvements in China's health system will far more likely occur if the reforms become less timid in certain key areas, namely provider payments and intergovernmental fiscal relations.