The incidence of cytokine release syndrome and neurotoxicity of CD19 chimeric antigen receptor-T cell therapy in the patient with acute lymphoblastic leukemia and lymphoma.

Our objective was to summarize the side effect of chimeric antigen receptor (CAR)-T cell therapy in patients with acute lymphocytic leukemia (ALL) and lymphoma. Two independent reviewers extracted relevant data. A total of 35 hematologic malignancy studies with CD19 CAR-T cell were included (1412 participants). Severe cytokine release syndrome (sCRS) proportion was experienced by 18.5% (95% confidence interval [CI], 0.128-0.259; P = 0.000) of 982 patients with the National Cancer Institute/Lee/common terminology criteria for adverse events grading system. The pooled neurotoxicity proportion was 21.7% (95% CI, 0.167-0.287; P = 0.000) of 747 patients with the same grading system. For all of the 25 clinical trials with the same grading system, subgroup analysis was performed. Based on the different disease type, a pooled prevalence of 35.7% was observed with event rate (ER) of 0.358 (95% CI, 0.289-0.434; P = 0.000) for ALL in 12 clinical trials. For lymphoma, a pooled prevalence of 13% was observed with ER of 0.073 (95% CI, 0.028-0.179; P = 0.000) in eight clinical trials. It was demonstrated that the patients who were older than 18 years of age have the lower sCRS incidence of 16.1% (95% CI, 0.110-0.250; P = 0.000) compared with 28.6% of the remaining population who were younger than 18 years of age (95% CI, 0.117-0.462: P = 0.023) in our analysis. Based on the different co-stimulatory domain, the sCRS of 16.5% was observed with ER of 0.175 (95% CI, 0.090-0.312; P = 0.000) for 4-1BB. The sCRS of 22.2% was observed with ER of 0.193 (95% CI, 0.107-0.322; P = 0.000) for CD28. For both the CD28 and 4-1BB, the sCRS of 17.3% was observed with ER of 0.170 (95% CI, 0.067-0.369; P = 0.003). Sub-analysis sCRS of the impact with cell dose and specific disease indication were also demonstrated. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. These results are helpful for physicians, patients and the other stakeholders to understand the adverse events and to further promote the improvement of CAR-T cell therapy in the future.

Assessment of the efficacy of passive cellular immunotherapy for glioma patients.

To evaluate the therapeutic efficacy of passive cellular immunotherapy for glioma, a total of 979 patients were assigned to the meta-analysis. PubMed and the Cochrane Central Register of Controlled Trials were searched initially from February 2018 and updated in April 2019. The overall survival (OS) rates and Karnofsky performance status (KPS) values of patients who underwent passive cellular immunotherapy were compared to those of patients who did not undergo immunotherapy. The proportion of survival rates was also evaluated in one group of clinical trials. Pooled analysis was performed with random- or fixed-effects models. Clinical trials of lymphokine-activated killer cells, cytotoxic T lymphocytes, autologous tumor-specific T lymphocytes, chimeric antigen receptor T cells, cytokine-induced killer cells, cytomegalovirus-specific T cells, and natural killer cell therapies were selected. Results showed that treatment of glioma with passive cellular immunotherapy was associated with a significantly improved 0.5-year OS (p = 0.003) as well as improved 1-, 1.5-, and 3-year OS (p ≤ 0.05). A meta-analysis of 206 patients in one group of clinical trials with 12-month follow-up showed that the overall pooled survival rate was 37.9% (p = 0.003). Analysis of KPS values demonstrated favorable results for the immunotherapy arm (p < 0.001). Thus, the present meta-analysis showed that passive cellular immunotherapy prolongs survival and improves quality of life for glioma patients, suggesting that it has some clinical benefits.

The efficacy of anti-CD19 chimeric antigen receptor T cells for B-cell malignancies.

Immunotherapy with chimeric antigen receptor T (CAR-T) cells has proved remarkably effective in recently published clinical trials. In this meta-analysis, we performed a systematic review in terms of the clinical response treated with CAR-T cells in acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and lymphomas patients. Thirty-eight published clinical studies including 665 patients were eligible for response rate (RR) evaluation. The overall pooled RR of CD19-CAR-T cells was 72% (95% confidence interval: 62-77%). The various clinical parameters were analyzed. RR was 81% in ALL, 68% in lymphoma and 70% in CLL. RR in patients who received interleukin (IL)-2 was 70%, whereas in those who did not receive IL-2, it was 74%. RR was 75% with lymphodepletion and 56% without lymphodepletion. RR with autologous cells was 76% and 57% with allogeneic cells. In conclusion, this meta-analysis showed a high clinical RR of CD19-CAR-T cell-based immunotherapy in patients with refractory B-cell malignancies.

[The positive inotropic effect after washout of acetylcholine in isolated rabbit hearts].

AIM: To study the regular pattern and mechanism of positive inotropic effect after washout of ACh (rebound of myocardial contractile force) in isolated rabbit hearts. METHODS: The changes of myocardial contractile force after perfusion and washout of ACh were observed in isolated Langendorff perfused rabbit hearts. RESULTS: Maximum rebound rate induced by ACh of 10(-8)-10(-3) mol/L were 2.20% +/- 1.70%, 6.71% +/- 3.40%, 9.18% +/- 3.54%, 14.16% +/- 3.27%, 4.37% +/- 5.86% and 1.03% +/- 6.86%, respectively. Compared with the ACh of 10(-5) mol/L in control group, adrenaline enhanced rebound of myocardial contractile force, maximum rebound rate in adrenaline group was 29.25% +/- 5.83% (P < 0.05), propranolol reduced rebound, and maximum rebound rate in propranolol group was 5.15% +/- 4.45% (P < 0.05), we had not detected rebound of myocardial contractile force in 800 s after addition ACh in verapamil group. CONCLUSION: In isolated rabbit heart, positive inotropic effect after washout of ACh has relevance to the activities of calcium current channel and beta-adrenergic receptor. Perhaps there are some different aspects in the mechanism of positive inotropic effect between perfusion of high concentration and after washout of ACh.

[Effects of chloride channel blockers on excitatory junction potentials in smooth muscle cells of cochlear spiral modiolar artery in guinea pigs].

Chloride channels have been identified in vascular smooth muscle cells (SMCs). It has been shown that these channels are involved in myogenic tone regulation and neuromuscular transmission in various vascular beds. However, whether the chloride channels are responsible for the formation of excitatory junction potentials (EJPs) of SMCs in the spiral modiolar artery (SMA) remains unelucidated. In the present study, the effects of chloride channel blockers (niflumic acid, NFA; indanyloxyacetic acid 94, IAA-94; disodium 4, 4'-diisothiocyanatostilbene-2, 2'-disulfonate, DIDS) on EJP were explored in guinea pigs, using intracellular recording techniques on acutely isolated SMA. It was found that EJP was evoked in the majority of the SMCs (75%, n=49) with an adequate electronic stimulation. The amplitude of the EJP was partially blocked (30% approximately 80%) by combined application of alpha(1) receptor antagonist (prazosin) and alpha(2) receptor antagonist (idazoxan) at concentration of up to 1 micromol/L, and P(2x) receptor antagonist (PPADS, 10 approximately 100 micromol/L). NFA (100 micromol/L) could further inhibit the residual EJP in the presence of alpha(1), alpha(2)-adrenergic and P(2x) receptor antagonists. IAA-94 or DIDS not only inhibited the amplitude but also shortened the duration of EJP. Decrease of extracellular chloride concentration from 135.6 mmol/L to 60 mmol/L would enhance EJP. Moreover, IAA-94 (100 micromol/L) and DIDS (200 mumol/L) could reverse the enhancement of EJP by low extracellular Cl(-). NFA (100 micromol/L) could also block the residual depolarizations evoked by norepinephrine (NE, 1 approximately 50 micromol/L). Based on these results, it is inferred that NE could activate a novel adrenoceptor to open the chloride channel on the membrane of the SMCs, leading to a transmembrane Cl(-) current. This current is involved, at least partially, in the formation of EJP.

[Study on the characteristics and compositions of fine particles left in the solution after decomposition of plant samples].

After decomposition of plant standard reference materials bush twigs and leaves (GBW07602, GBW07603), poplar leaves (GBW07604) and tea (GBW07605) with either dry ashing method or wet digestion method, all kinds of fine particles left in the solution were collected and examined carefully by a scanning electron microscope (SEM), and their chemical composition were investigated by a SEM-affiliated energy-dispersive X-ray spectrometer at the same time. Moreover, the concentrations of some metal elements distributed among four different tea SRM-originated particle fractions extracted following the BCR sequential extraction procedure were determined by AAS and ICP-AES. It was found that decomposition methods have a great influence on the structure of fine particles. When dry ashing method is used, grey-colored, fluffy and porous partices can be produced, whereas fewer white-colored, compact particles can be produced when another method is used. As for chemical composition, all kinds of fine particles are almost the same, with silicon and aluminium as their main constituents, and calcium, iron, potassium, titanium and so on as their minor ones. The elementaI distribution percentages in four different particle fractions in two kinds of plant-originated particles differ from element to element, which can result in severe negative errors when plant samples are decomposed and determined for elemental concentrations.