Tislelizumab in previously treated,locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors

Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8%)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8%).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7%;95%confidence interval(95%CI),35.1−58.6;one-sided P<0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1%(95%CI,25.1–54.6);gastric/gastroesophageal junction(n=9):55.6%(95%CI,21.2−86.3);others(n=20):60.0%(95%CI,36.1−80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10%;five(6.7%)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade≥3 occurred in 53.8%of patients;7.5%of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

A proposal:a comprehensive platform to characterize tumors in Chinese and improve success in cancer drug discovery and development

Cancer is a collection of complex diseases in which cell proliferation and apoptosis are dysregulated due to the acquisition of genetic changes in cancer cells.These genetic changes,combined with the interrelated physiologic adaptations of neo-angiogenesis,recruitment of stromal support tissues,and suppression of immune recognition,are measurable characteristics in tumor gene expression profiles and biochemical pathways.These measures can lead to identification of disease drivers and,ultimately,can be used to assign therapy.With advances in RNA sequencing technologies,the ability to simultaneously measure all genetic and gene expression changes with a single technology is now possible.The ability to create a comprehensive catalog of genotypic and phenotypic changes in a collection of histologically similar but otherwise distinct tumors should allow for a more precise positioning of existing targeted therapies and identification of new targets for intervention.

A New Prognostic Model Covering All Stages of Intrahepatic Cholangiocarcinoma

Background and Aims:Intrahepatic cholangiocarcinoma(ICC)is the second most common primary hepatic malignancy that causes a poor survival.We aimed to identify its prognostic factors and to develop a nomogram that will predict survival of ICC patients among all stages.Methods:A total of 442 patients with pathology-proven ICC registered at the Fifth Medical Center of PLA General Hospital between July 2007 and December 2019 were enrolled.Subjects were followed for survival status until June 30,2020.A prognostic model visualized as a nomogram was constructed in the training cohort using multivariate cox model,and was then validated in the validation cohort.Results:The median age was 55 years.With a median follow-up of 50.4 months,337 patients died.The median survival was 11.6 months,with 1-,3-and 5-year survival rates of 48.3%,22.7%and 16.2%,respectively.Factors associated with overall survival were multiple tumors,lymph node involvement,vascular invasion,distant metastasis,decreased albumin,elevated lactate dehydrogenase(LDH),decreased iron,elevated fi-brinogen,elevated CA125 and elevated CA19-9.A nomo-gram predicting survival of ICC patients at the time of di-agnosis achieved a Harrel’s c-statistic of 0.758,significantly higher than the 0.582 of the TNM stage alone.Predicted median survivals of those within the low,mid and high-risk subgroups were 35.6,12.1 and 6.2 months,respectively.Conclusions:A nomogram based on imaging data and serum biomarkers at diagnosis showed good ability to predict survival in patients with all stages of ICC.Further studies are needed to validate the prognostic capability of our new model.

Experimental and numerical study on the shrinkage-deformation of carrot slices during hot air drying

In order to further understand the mechanism of material volume change in the drying process,numerical simulations(considering or neglecting shrinkage)of heat and mass transfer during convective drying of carrot slices under constant and controlled temperature and relative humidity were carried out.Simulated results were validated with experimental data.The results of the simulation show that the Quadratic model fitted well to the moisture ratio and the material temperature data trend with average relative errors of 5.9%and 8.1%,respectively.Additionally,the results of the simulation considering shrinkage show that the moisture and temperature distributions during drying are closer to the experimental data than the results of the simulation disregarding shrinkage.The material moisture content was significantly related to the shrinkage of dried tissue.Temperature and relative humidity significantly affected the volume shrinkage of carrot slices.The volume shrinkage increased with the rising of the constant temperature and the decline of relative humidity.This model can be used to provide more information on the dynamics of heat and mass transfer during drying and can also be adapted to other products and dryers devices.

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

t 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.

Effects of pulsation ratio on center temperature and drying characteristics of pineapple slices with pulsed vacuum drying

This research explored the application of pulsed vacuum technology on the drying(PVD)of pineapple slices.Influences of drying temperature and pulsed vacuum ratio(PVR)on drying characteristics and pineapple quality(color,rehydration characteristics,microstructure,and texture)were analyzed.As expected,increasing the drying temperature resulted in a higher drying rate and effective moisture diffusivity.The optimal PVR of 5:5 was beneficial in accelerating the drying rate of pineapple slices and the corresponding effective moisture diffusion coefficient(8.9601×10^(-10))was higher than other PVR conditions based on material center temperature.The material temperature increased during the normal pressure period and decreased rapidly when the pressure dropped to the vacuum condition,which indirectly reflected the moisture transfer that occurred during the vacuum holding period,while moisture diffusion happened during the atmospheric pressure holding period.The optimal pulsed vacuum drying process(PVR of 5:5)could expand air and water vapor and create a looser structure so as to obtain better rehydration performance(rehydration ratio(RR)was 5.43).High drying temperature led to the decrease of L^(*)value,the increase ofΔE value,and even the formation of surface scorch at 80℃.At the same drying temperature,the color quality depended on the drying time,and the color difference increased with the extension of the drying time.The chewiness and hardness of pineapple slices dried by PVD were significantly higher than those of fresh samples,which was conducive to the chewing taste.