Impact of immunosenescence and inflammaging on the effects of immune checkpoint inhibitors

Immune checkpoint inhibitors(ICIs)are employed in immunotherapeutic applications for patients with weakened immune systems and can improve the ability of T cells to kill cancer cells.Although ICIs can potentially treat different types of cancers in various groups of patients,their effectiveness may differ among older individuals.The reason ICIs are less effective in older adults is not yet clearly understood,but age-related changes in the immune system,such as immunosenescence and inflammation,may play a role.Therefore,this review focuses on recent advances in understanding the effects of immunosenescence and inflammation on the efficacy of ICIs.

Two cases on primary bone marrow lymphoma

Managing Editor:Peng Lyu Primary bone marrow lymphoma(PBML)is a rare lymphoma accounting for 1.23%of non-Hodgkin lymphoma(NHL)cases.It is characterized by tumor cells invading only the bone marrow without systemic lymphadenopathy or extranodal organ involvement.Owing to the lack of standardized treatment regimens,most patients are treated using rituximab with cyclophosphamide,doxorubicin,vincristine,and prednisone(R-CHOP)regimens;however,their efficacy needs to be further investigated.

Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients:a randomized,double-blind,placebo-controlled phase 2 trial

Treatment of severe Coronavirus Disease 2019(COVID-19)is challenging.We performed a phase 2 trial to assess the efficacy andsafety of human umbilical cord-mesenchymal stem cells(UC-MScs)to treat severe coViD-19 patients with lung damage,based onour phase 1 data.In this randomized,double-blind,and placebo-controlled trial,we recruited 101 severe coVID-19 patients withlung damage.They were randomly assigned at a 2:1 ratio to receive either UC-MSCs(4×10^(7)cells per infusion)or placebo on day 0,3,and 6.The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28.Other imagingoutcomes,6-minute walk test(6-MWT),maximum vital capacity,diffusing capacity,and adverse events were recorded and analyzed.In all,100 COVID-19 patients were finally received either UC-MSCs in=65)or placebo(n=35).UC-MSCs administrationexerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo(the mediandifference was-13.31%,95%Cl-29.14%,2.13%,P=0.08).UC-MSCs significanty reduced the proportions of solid componentlesion volume compared with the placebo(median difference:-15.45%;95%CI-30.82%,-0.39%;P=0.043).The 6-MWT showedan increased distance in patients treated with UC-MSCs(difference:27.00 m;95%CI 0.00,57.00;P=0.057).The incidence of adverseevents was similar in the two groups.These results suggest that UC-MSCs treatment is a safe and potentially effective therapeuticapproach for COVID-19 patients with lung damage.A phase 3 trial is required to evaluate effects on reducing mortality andpreventing long-term pulmonary disability.

Effect of Methylprednisolone on Mortality and Clinical Courses in Patients with Severe CoVID-19: A Propensity Score Matching Analysis

Background Whether methylprednisolone therapy can reduce the mortality rate of patients with severe coronavirus disease 2019(COVID-19)remains controversial,and its effects on the length of hospital stay and virus shedding time are also unknown.This retrospective study investigates the previous issues to provide more evidence for methylprednisolone treatment in severe COVID-19.Methods This retrospective study included 563 of 4827 patients with confirmed COVID-19 admitted to Wuhan Huoshenshan Hospital or Wuhan Guanggu Hospital between February 3,2020 and March 30,2020 who met the screening criteria.The participants’epidemiological and demographic data,comorbidities,laboratory test results,treatments,outcomes,and vital clinical time points were extracted from electronic medical records.The primary outcome was in-hospital death,and the secondary outcomes were 2 clinical courses:length from admission to viral clearance and discharge.Univariate and multivariate logistic or linear regression analyses were used to assess the role of methylprednisolone in different outcomes.Propensity score matching was performed to control for confounding factors.Results Of the 563 patients who met the screening criteria and were included in the subsequent analysis,138 were included in the methylprednisolone group and 425 in the nonmethylprednisolone group.The in-hospital death rate between the methylprednisolone and nonmethylprednisolone groups showed a significant difference(23.91%vs.1.65%,P<0.001),which was maintained after propensity score matching(13.98%vs.5.38%,P=0.048).However,univariate logistic analysis in the matched groups showed that methylprednisolone treatment(odds ratio[OR],5.242;95%confidence interval[CI],0.802 to 34.246;P=0.084)was not a risk factor for in-hospital death in severe patients.Further multivariate logistic regression analysis found comorbidities(OR,3.327;95%CI,1.702 to 6.501;P<0.001),lower lymphocyte count(OR,0.076;95%CI,0.012 to 0.461;P=0.005),higher lactate dehydrogenase(LDH)levels(OR,1.008;95%CI,1.003 to 1.013;P=0.002),and anticoagulation therapy(OR,11.187;95%CI,2.459 to 50.900;P=0.002)were associated with in-hospital mortality.Multivariate linear regression analysis in the matched groups showed that methylprednisolone treatment was not a risk factor for a prolonged duration from admission to viral clearance(βValue 0.081;95%CI,−1.012 to 3.657;P=0.265)or discharge(βValue 0.114;95%CI,−0.723 to 6.408;P=0.117).d-dimer(βValue,0.144;95%CI,0.012 to 0.817;P=0.044),LDH(βValue 0.260;95%CI,0.010 to 0.034;P<0.001),and antiviral therapy(βValue 0.220;95%CI,1.373 to 6.263;P=0.002)were associated with a longer length from admission to viral clearance.The lymphocyte count(βValue−0.206;95%CI,−6.248 to−1.197;P=0.004),LDH(βValue 0.231;95%CI,0.012 to 0.048;P=0.001),antiviral therapy(βValue 0.143;95%CI,0.058 to 7.497;P=0.047),and antibacterial therapy(βValue 0.152;95%CI,0.133 to 8.154;P=0.043)were associated with a longer hospitalization duration from admission to discharge.Further stratified analysis revealed that the low daily dose group(≤60 mg/d)and the low total dose group(≤200 mg)had shorter duration from admission to viral clearance(Z=−2.362,P=0.018;Z=−2.010,P=0.044)and a shorter hospital stay(Z=−2.735,P=0.006;Z=−3.858,P<0.001).Conclusions In patients with severe COVID-19,methylprednisolone is safe and does not prolong the duration from admission to viral clearance or discharge.Low-dose,short-term methylprednisolone treatment may be more beneficial in shortening the disease course.

A case of diffuse large B-cell lymphoma with interstitial pneumonia

This report involves a 54-year-old female patient diagnosed with diffuse large B-cell lymphoma who developed interstitial pneumonia(IP)during treatment.The patient presented to the ward with enlarged lymph nodes in the neck and was treated with the standard regimen,which included rituximab,cyclophosphamide,doxorubicin liposomes,vincristine,and prednisone(R-CDOP regimen).After 3 cycles,the treatment was assessed as effective.However,following the 4th cycle,the patient experience shortness of breath after physical activity.A repeat lung computer tomography indicated IP,which completely recovered after receiving“full coverage”treatment.Subsequently,the patient underwent 2 cycles of cyclophosphamide,doxorubicin liposomes,vincristine,and prednisone(CDOP),followed by local radiotherapy.Currently,the patient is now being followed up with regular reviews.

Combination of two target agonists of the thrombopoietin and thrombopoietin receptor in the treatment of elderly patients with refractory immune thrombocytopenia

Immune thrombocytopenia(ITP)is common in the elderly.Because of the coexistence of multiple diseases,there are many reservations regarding corticosteroid use in the elderly.Thrombopoietin(TPO)and its analogs can promote platelet production,but it is often difficult to correct TP in a short period.Recombinant human TPO(rh-TPO)acting on the cell membrane and the small-molecule TPO-receptor(MPL)agonist acting on the transmembrane receptor may have synergistic effects and accelerate platelet production because of different sites of action in the signaling pathway.In this study,two elderly patients with refractory ITP were successfully treated with two TPO-MPL signaling pathway agonists:recombinant human thrombopoietin(rh-TPO)and eltrombopag.This combination is safe with rapid and lasting effects.However,in elderly patients with refractory,recurrent,and glucocorticoid contraindications,the combination of different TPO agonists'clinical efficacy and adverse reactions needs to be further evaluated.

Pathogenesis of premature coronary artery disease:Focus on risk factors and genetic variants

The development of premature coronary artery disease(PCAD)is dependent on both genetic predisposition and traditional risk factors.Strategies for unraveling the genetic basis of PCAD have evolved with the advent of modern technologies.Genome-wide association studies(GWASs)have identified a considerable number of common genetic variants that are associated with PCAD.Most of these genetic variants are attributable to lipid and blood pressure-related single-nucleotide polymorphisms(SNPs).The genetic variants that predispose individuals to developing PCAD may depend on race and ethnicity.Some characteristic genetic variants have been identified in Chinese populations.Although translating this genetic knowledge into clinical applications is still challenging,these genetic variants can be used for CAD phenotype identification,genetic prediction and therapy.In this article we will provide a comprehensive review of genetic variants detected by GWASs that are predicted to contribute to the development of PCAD.We will highlight recent findings regarding CAD-related genetic variants in Chinese populations and discuss the potential clinical utility of genetic variants for preventing and managing PCAD.

Effect of methylprednisolone therapy on hospital stay and viral clearance in patients with moderate COVID-19

Background:The benefits and harms of methylprednisolone treatment in patients with moderate coronavirus disease 2019(COVID-19)remain controversial.In this study,we investigated the effect of methylprednisolone on mortality rate,viral clearance,and hospitalization stay in patients with moderate COVID-19.Methods:This retrospective study included 4827 patients admitted to Wuhan Huoshenshan and Wuhan Guanggu hospitals from February to March 2020 diagnosed with COVID-19 pneumonia.The participants’epidemiological and demographic data,comorbidities,laboratory test results,treatments,outcomes,and vital clinical time points were extracted from electronic medical records.The primary outcome was in-hospital death;secondary outcomes were time from admission to viral clearance and hospital stay.Univariate and multivariate logistic or linear regression analysis were used to assess the roles of methylprednisolone in different outcomes.The propensity score matching(PSM)method was used to control for confounding factors.Results:A total of 1320 patients were included in this study,of whom 100 received methylprednisolone.Overall,in-hospital mortality was 0.91%(12/1320);the 12 patients who died were all in the methylprednisolone group,though multivariate logistic regression analysis showed methylprednisolone treatment was not a risk factor for in-hospital death in moderate patients before or after adjustment for confounders by PSM.Methylprednisolone treatment was correlated with longer length from admission to viral clearance time and hospital stay before and after adjustment for confounders.Conclusions:Methylprednisolone therapy was not associated with increased in-hospital mortality but with delayed viral clearance and extended hospital stay in moderate COVID-19 patients.

Bioinformatics analysis of SARS-CoV-2 infectionassociated immune injury and therapeutic prediction for COVID-19

Background:Severe acute respiratory syndrome coronavirus 2 is a highly contagious viral infection,without any available targeted therapies.The high mortality rate of COVID-19 is speculated to be related to immune damage.Methods:In this study,clinical bioinformatics analysis was conducted on transcriptome data of coronavirus infection.Results:Bioinformatics analysis revealed that the complex immune injury induced by coronavirus infection provoked dysfunction of numerous immune-related molecules and signaling pathways,including immune cells and toll-like receptor cascades.Production of numerous cytokines through the Th17 signaling pathway led to elevation in plasma levels of cytokines(including IL6,NF-kB,and TNF-a)followed by concurrent inflammatory storm,which mediates the autoimmune response.Several novel medications seemed to display therapeutic effects on immune damage associated with coronavirus infection.Conclusions:This study provided insights for further large-scale studies on the target therapy on reconciliation of immunological damage associated with COVID-19.