BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models / 医学前沿

OX40 is a costimulatory receptor that is expressed primarily on activated CD4+, CD8+, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

Modelling the impact of rapid tests, tracing and distancing in lower-income countries suggest optimal policies varies with rural-urban settings

Low- and middle-income countries (LMICs) remain of high potential for hotspots for COVID-19 deaths and emerging variants given the inequality of vaccine distribution and their vulnerable healthcare systems. We aim to evaluate containment strategies that are sustainable and effective for LMICs. We constructed synthetic populations with varying contact and household structures to capture LMIC demographic characteristics that vary across communities. Using an agent- based model, we explored the optimal containment strategies for rural and urban communities by designing and simulating setting-specific strategies that deploy rapid diagnostic tests, symptom screening, contact tracing and physical distancing. In low-density rural communities, we found implementing either high quality (sensitivity > 50%) antigen rapid diagnostic tests or moderate physical distancing could contain the transmission. In urban communities, we demonstrated that both physical distancing and case finding are essential for containing COVID-19 (average infection rate < 10%). In high density communities that resemble slums and squatter settlements, physical distancing is less effective compared to rural and urban communities. Lastly, we demonstrated contact tracing is essential for effective containment. Our findings suggested that rapid diagnostic tests could be prioritised for control and monitor COVID-19 transmission and highlighted that contact survey data could guide strategy design to save resources for LMICs. An accompanying open source R package is available for simulating COVID-19 transmission based on contact network models.

Liver regeneration after hemihepatectomy in patients with HBV-related hepatocellular carcinoma / 中华普通外科杂志

Objective:To investigate the clinical impact factors of liver regeneration after hemihepatectomy in patients with hepatocellular carcinoma (HCC).Methods:Patients who underwent hemihepatectomy due to HCC from Sep 2013 to Sep 2018 were included in the study. Liver volumes were calculated by perioperative simulations to analyze the influencing factors of postoperative liver regeneration, and to compare the albumin bilirubin (ABLI) score and the end-stage liver disease (MELD) score at weeks 1, 5, 9, and 13 after operation.Results:A total of 163 patients were included, of which 13 developed postoperative liver failure. The median liver regeneration rates at 1, 5, 9 and 13 weeks after operation were 22.0%, 32.2%, 33.7% and 35.4%, respectively. Multivariate analysis showed that remnant liver volume (RLV) <611.1 cm 3, %RLV and liver cirrhosis were the influencing factors of liver regeneration. ALBI score and MELD score were lower in the low regeneration group compared to the high regeneration group in the first 5 weeks after operation. Conclusion:RLV and cirrhosis are influential factors in postoperative liver regeneration. Liver regeneration proceeded rapidly within 1 week and slowed down until week 5.

Insights into the practical effectiveness of RT-PCR testing for SARS-CoV-2 from serologic data, a cohort study

BackgroundVirologic detection of SARS-CoV-2 through Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) has limitations for surveillance. Serologic tests can be an important complementary approach. ObjectiveAssess the practical performance of RT-PCR based surveillance protocols, and the extent of undetected SARS-CoV-2 transmission in Shenzhen, China. DesignCohort study nested in a public health response. SettingShenzhen, China; January-May 2020. Participants880 PCR-negative close-contacts of confirmed COVID-19 cases and 400 residents without known exposure (main analysis). Fifty-seven PCR-positive case contacts (timing analysis). MeasurementsVirological testing by RT-PCR. Measurement of anti-SARS-CoV-2 antibodies in PCR-negative contacts 2-15 weeks after initial testing using total Ab ELISA. Rates of undetected infection, performance of RT-PCR over the course of infection, and characteristics of seropositive but PCR-negative individuals were assessed. ResultsThe adjusted seropositivity rate for total Ab among 880 PCR-negative close-contacts was 4.1% (95%CI, 2.9% to 5.7%), significantly higher than among residents without known exposure to cases (0.0%, 95%CI, 0.0% to 1.0%). PCR-positive cases were 8.0 times (RR; 95% CI, 5.3 to 12.7) more likely to report symptoms than the PCR-negative individuals who were seropositive, but otherwise similar. RT-PCR missed 36% (95%CI, 28% to 44%) of infected close-contacts, and false negative rates appear to be highly dependent on stage of infection. LimitationsNo serological data were available on PCR-positive cases. Sample size was limited, and only 20% of PCR-negative contacts met inclusion criteria. ConclusionEven rigorous RT-PCR testing protocols may miss a significant proportion of infections, perhaps in part due to difficulties timing testing of asymptomatics for optimal sensitivity. Surveillance and control protocols relying on RT-PCR were, nevertheless, able to contain community spread in Shenzhen. Funding sourceBill & Melinda Gates Foundation, Special Foundation of Science and Technology Innovation Strategy of Guangdong Province of China, and Key Project of Shenzhen Science and Technology Innovation Commission, Shenzhen, China

A Modelling Study for Designing a Multi-layered Surveillance Approach to Detect the Potential Resurgence of SARS-CoV-2

BackgroundCountries achieving control of COVID-19 after an initial outbreak will continue to face the risk of SARS-CoV-2 resurgence. This study explores surveillance strategies for COVID-19 containment based on polymerase chain reaction tests. MethodsUsing a dynamic SEIR-type model to simulate the initial dynamics of a COVID-19 introduction, we investigate COVID-19 surveillance strategies among healthcare workers, hospital patients, and community members. We estimate surveillance sensitivity as the probability of COVID-19 detection using a hypergeometric sampling process. We identify test allocation strategies that maximise the probability of COVID-19 detection across different testing capacities. We use Beijing, China as a case study. FindingsSurveillance subgroups are more sensitive in detecting COVID-19 transmission when they are defined by more COVID-19 specific symptoms. In this study, fever clinics have the highest surveillance sensitivity, followed by respiratory departments. With a daily testing rate of 0.07/1000 residents, via exclusively testing at fever clinic and respiratory departments, there would have been 598 [95% eCI: 35, 2154] and 1373 [95% eCI: 47, 5230] cases in the population by the time of first case detection, respectively. Outbreak detection can occur earlier by including non-syndromic subgroups, such as younger adults in the community, as more testing capacity becomes available. InterpretationA multi-layer approach that considers both the surveillance sensitivity and administrative constraints can help identify the optimal allocation of testing resources and thus inform COVID-19 surveillance strategies. FundingBill & Melinda Gates Foundation, National Institute of Health Research (UK), National Institute of Health (US), the Royal Society, and Wellcome Trust.

What is required to prevent a second major outbreak of the novel coronavirus SARS-CoV-2 upon lifting the metropolitan-wide quarantine of Wuhan city, China

BackgroundThe Chinese government implemented a metropolitan-wide quarantine of Wuhan city on 23rd January 2020 to curb the epidemic of the coronavirus COVID-19. Lifting of this quarantine is imminent. We modelled the effects of two key health interventions on the epidemic when the quarantine is lifted. MethodWe constructed a compartmental dynamic model to forecast the trend of the COVID-19 epidemic at different quarantine lifting dates and investigated the impact of different rates of public contact and facial mask usage on the epidemic. ResultsWe estimated that at the end of the epidemic, a total of 65,572 (46,156-95,264) individuals would be infected by the virus, among which 16,144 (14,422-23,447, 24.6%) would be infected through public contacts, 45,795 (32,390-66,395, 69.7%) through household contact, 3,633 (2,344-5,865, 5.5%) through hospital contacts (including 783 (553-1,134) non-COVID-19 patients and 2,850 (1,801-4,981) medical staff members). A total of 3,262 (1,592-6,470) would die of COVID-19 related pneumonia in Wuhan. For an early lifting date (21st March), facial mask needed to be sustained at a relatively high rate ([≥]85%) if public contacts were to recover to 100% of the pre-quarantine level. In contrast, lifting the quarantine on 18th April allowed public person-to-person contact adjusted back to the pre-quarantine level with a substantially lower level of facial mask usage (75%). However, a low facial mask usage (<50%) combined with an increased public contact (>100%) would always lead a significant second outbreak in most quarantine lifting scenarios. Lifting the quarantine on 25th April would ensure a smooth decline of the epidemics regardless of the combinations of public contact rates and facial mask usage. ConclusionThe prevention of a second epidemic is viable after the metropolitan-wide quarantine is lifted but requires a sustaining high facial mask usage and a low public contact rate.

A clinical study of standard remnant liver volume in predicting post-hepatectomy liver failure in patients with hepatocellular carcinoma after hemihepatectomy of cirrhotic liver / 中国肿瘤临床

Objective: To explore the correlation between standard remnant liver volume(SRLV) and post-hepatectomy liver failure (PHLF)in patients with hepatocellular carcinoma(HCC)and cirrhotic livers.Methods:In total,181 patients who underwent hemihepa-tectomy in Affiliated Tumor Hospital of Guangxi Medical University from September 2013 to August 2016 were enrolled in the study. Total liver,tumor,remnant liver,and resected liver volumes were measured using the Myrian liver surgical planning system before sur-gery. Intraoperative resected liver volume (including resected normal liver and tumor volumes) were collected using the drainage method.The patients were divided into the PHLF(22 cases)and non-PHLF groups(159 cases)according to whether PHLF occurred based on the"50/50"criteria.The risk factors of PHLF were then explored.The cut-off of SRLV and efficiency of predicting PHLF were analyzed in the subgroup of patients with cirrhotic livers.The grade of liver cirrhosis was retrospectively analyzed using helical comput-ed tomography(CT).Results:Twenty-two of the 181 patients developed PHLF and one died of it.Preoperative total bilirubin levels and SRLV were identified as independent factors for predicting PHLF using a Logistic regression model.In total,102 patients with cirrhotic livers were selected in subgroup analysis based on postoperative cirrhotic pathology.Eighteen patients developed PHLF and one died of PHLF in the subgroup.Using receiver-operating characteristic(ROC)curve analysis,340 mL/m2was the cut-off of SRLV for patients with HCC and cirrhotic livers(area under the curve:0.861,P<0.01;sensitivity and specialty rates were 94.4% and 74.7%,respectively). Eighty-four cases were of grade Ⅰ or Ⅱ cirrhosis,18 cases were of grade Ⅲ cirrhosis,and there were no cases of grade Ⅳ cirrhosis based on retrospective analysis using helical CT.Conclusions:Patients with cirrhotic livers with an anticipated SRLV of≤340 Ml/m2after he-patic resection are at increased risk for PHLF after emihepatectomy.

Influence of preoperative antiviral therapy on HBV reactivation and liver function after liver resection in HBV-DNA-negative hepatocellular carcinoma patients / 中国肿瘤临床

Objective:To evaluate the effect of antiviral therapy on HBV reactivation and liver function after liver resection in patients with hepatocellular carcinoma (HCC). Methods:A total of 174 HBV-DNA(?) HCC patients were recruited into two groups:antiviral ther-apy group (66 cases) and control group (108 cases). In the antiviral group, patients were given entecavir dispersible tablet, whereas no antiviral therapies were given in the control group. The HBV reactivation and liver function index rates were statistically analyzed. Re-sults:Rates of HBV reactivation after hepatectomy were 3.0%and 27.8%in the antiviral therapy group and control group, respectively. Multivariate analysis revealed that minor hepatectomy (HR, 4.695;95%CI, 1.257-17.537, P=0.021) and no antiviral therapy (HR, 8.164;95%CI, 1.831-36.397, P=0.006) were independent risk factors for HBV reactivation. The levels of ALT, TBil, ALB, and PT within 7 days af-ter liver resection were similar between the antiviral therapy group and the control group and between the reactivation group and no-reactivation group. However, the ALT and ALB levels were significantly better in the antiviral group compared with that in the control group after 30 days. Conclusion:HBV reactivation can occur after liver resection for HBV-DNA(?) HCC patients. Preoperative antiviral therapy can reduce the risk of HBV reactivation, thus protecting liver function in patients undergoing liver resection.