Incidence, clinical characteristics and prognosis of tumor lysis syndrome following B-cell maturation antigen-targeted chimeric antigen receptor-T cell therapy in relapsed/refractory multiple myeloma.

Background aims: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). However, CAR-T-related tumor lysis syndrome (TLS) has been observed. We aimed to elucidate the incidence, clinical and laboratory characteristics, and prognosis of CAR-T cell-related TLS. Methods: Patients (n=105) with r/r MM treated with BCMA-targeted CAR-T cell therapy were included. Patient characteristics, laboratory parameters, and clinical outcomes were assessed. Results: Eighteen (17.1%) patients developed TLS after BCMA-targeted CAR-T cell therapy. The median time till TLS onset was 8 days. Patients with TLS had steep rise in uric acid (UA), creatinine, and lactate dehydrogenase (LDH) within 6 days following CAR-T cell infusion and presented earlier and persistent escalation of cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-γ [IFN-γ], and ferritin levels). All 18 patients had cytokine release syndrome (CRS), of which 13 (72.2%) developed grade 3-4 CRS. Three of 18 patients (16.7%) developed immune effector cell-associated neurotoxicity syndrome (ICANS): two patients with grade 1 ICANS and one with grade 2 ICANS. TLS development had a negative effect on the objective response rate (77.8% in the TLS group vs. 95.4% in the non-TLS group, p<0.01). During the median follow-up of 15.1 months, the median PFS was poorer of patients with TLS (median: 3.4 months in the TLS group vs. 14.7 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.5 [95% confidence interval [CI] 1.5-8.5]). Also, TLS development exhibited significant effects on OS (median: 5.0 months in the TLS group vs. 39.8 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.7 [95% CI 1.3-10.3]). TLS was associated with a higher tumor burden, elevated baseline creatinine and UA levels, severe CRS, pronounced CAR-T cell expansion, and corticosteroid use. Conclusion: TLS is a frequently observed CAR-T therapy complication and negatively influences clinical response and prognosis. Close monitoring for TLS should be implemented during CAR-T cell therapy, especially for those at high TLS risk.

Long-term follow-up of donor-derived CD7 CAR T-cell therapy in patients with T-cell acute lymphoblastic leukemia.

BACKGROUND: Donor-derived CD7-directed chimeric antigen receptor (CAR) T cells showed feasibility and early efficacy in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (r/r T-ALL), in a previous phase I trial report, at a median follow-up of 6.3 months. Here we report long-term safety and activity of the therapy after a 2-year follow-up. METHODS: Participants received CD7-directed CAR T cells derived from prior stem cell transplantation (SCT) donors or from HLA-matched new donors after lymphodepletion. The target dose was 1 × 106 (± 30%) CAR T cells per kg of patient weight. The primary endpoint was safety with efficacy secondary. This report focuses on the long-term follow-up and discusses them in the context of previously reported early outcomes. RESULTS: Twenty participants were enrolled and received infusion with CD7 CAR T cells. After a median follow-up time of 27.0 (range, 24.0-29.3) months, the overall response rate and complete response rate were 95% (19/20 patients) and 85% (17/20 patients), respectively, and 35% (7/20) of patients proceeded to SCT. Six patients experienced disease relapse with a median time-to-relapse of 6 (range, 4.0-10.9) months, and 4 of these 6 patients were found to have lost CD7 expression on tumor cells. Progression-free survival (PFS) and overall survival (OS) rates 24 months after treatment were respectively 36.8% (95% CI, 13.8-59.8%) and 42.3% (95% CI, 18.8-65.8%), with median PFS and OS of respectively 11.0 (95% CI, 6.7-12.5) months and 18.3 (95% CI, 12.5-20.8) months. Previously reported short-term adverse events (< 30 days after treatment) included grade 3-4 cytokine release syndrome (CRS; 10%) and grade 1-2 graft-versus-host disease (GVHD; 60%). Serious adverse events reported > 30 days after treatment included five infections and one grade 4 intestinal GVHD. Despite good CD7 CAR T-cell persistence, non-CAR T and natural killer cells were predominantly CD7-negative and eventually returned to normal levels in about half of the participants. CONCLUSIONS: In this 2-year follow-up analysis, donor-derived CD7 CAR T-cell treatment demonstrated durable efficacy in a subset of patients with r/r T-ALL. Disease relapse was the main cause of treatment failure, and severe infection was a noteworthy late-onset adverse event. TRIAL REGISTRATION: ChiCTR2000034762.

Allogenic and autologous anti-CD7 CAR-T cell therapies in relapsed or refractory T-cell malignancies.

Chimeric antigen receptor-T (CAR-T) therapy remains to be investigated in T-cell malignancies. CD7 is an ideal target for T-cell malignancies but is also expressed on normal T cells, which may cause CAR-T cell fratricide. Donor-derived anti-CD7 CAR-T cells using endoplasmic reticulum retention have shown efficacy in patients with T-cell acute lymphoblastic leukemia (ALL). Here we launched a phase I trial to explore differences between autologous and allogeneic anti-CD7 CAR-T therapies in T-cell ALL and lymphoma. Ten patients were treated and 5 received autologous CAR-T therapies. No dose-limiting toxicity or neurotoxicity was observed. Grade 1-2 cytokine release syndrome occurred in 7 patients, and grade 3 in 1 patient. Grade 1-2 graft-versus-host diseases were observed in 2 patients. Seven patients had bone marrow infiltration, and 100% of them achieved complete remission with negative minimal residual disease within one month. Two-fifths of patients achieved extramedullary or extranodular remission. The median follow-up was 6 (range, 2.7-14) months and bridging transplantation was not administrated. Patients treated with allogeneic CAR-T cells had higher remission rate, less recurrence and more durable CAR-T survival than those receiving autologous products. Allogeneic CAR-T cells appeared to be a better option for patients with T-cell malignancies.

Anti-G Protein-Coupled Receptor, Class C Group 5 Member D Chimeric Antigen Receptor T Cells in Patients With Relapsed or Refractory Multiple Myeloma: A Single-Arm, Phase â ¡ Trial.

PURPOSE: G protein-coupled receptor, class C group 5 member D (GPRC5D) is considered to be a promising surface target for multiple myeloma (MM) immunotherapy. Here, we report the efficacy and safety of anti-GPRC5D chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory (R/R) MM. METHODS: This phase Ⅱ, single-arm study enrolled patients (18-70 years) with R/R MM. Lymphodepletion was performed before patients received 2 × 106/kg anti-GPRC5D CAR T cells. The primary end point was the proportion of patients who achieved an overall response. Safety was also evaluated in eligible patients. RESULTS: From September 1, 2021, to March 23, 2022, 33 patients were infused with anti-GPRC5D CAR T cells. At a median follow-up of 5.2 months (range, 3.2-8.9), the overall response rate was 91% (95% CI, 76 to 98; 30 of 33 patients), including 11 (33%) stringent complete responses, 10 (30%) complete responses, four (12%) very good partial responses, and five (15%) partial responses. Partial responses or better were observed in nine (100%) of nine patients with previous anti-B-cell maturation antigen (BCMA) CAR T-cell therapy, including two patients who had received repeated anti-BCMA CAR T-cell infusions with no responses at the last time. Grade 3 or higher hematologic toxicities were neutropenia (33 [100%]), anemia (17 [52%]), and thrombocytopenia (15 [45%]). Cytokine release syndrome occurred in 25 (76%) of 33 patients (all were grade 1 or 2), and neurotoxicities in three patients (one grade 2 and one grade 3 ICANSs and one grade 3 headache). CONCLUSION: Anti-GPRC5D CAR T-cell therapy showed an encouraging clinical efficacy and manageable safety profile in patients with R/R MM. For patients with MM that progressed after anti-BCMA CAR T-cell therapy or that is refractory to anti-BCMA CAR T cell, anti-GPRC5D CAR T-cell therapy might be a potential alternative option.

HBV reactivation in patients with chronic or resolved HBV infection following BCMA-targeted CAR-T cell therapy.

B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). Concern of the safety and efficacy of CAR-T cell therapy in patients with chronic or resolved HBV infection is raised. In this study, we retrospectively reviewed 99 patients with r/r MM treated with BCMA-targeted CAR-T cell therapy, of which 7 (7.1%) patients had chronic HBV infection, 43 (43.4%) with resolved HBV infection, and the remaining 49 (49.49%) HBV-uninfected. Patients' characteristics before CAR-T cell administration were comparable in different status of HBV infection. Patients' liver function, cytokine levels, CAR-T cell expansion and cytokine release syndrome (CRS) grade after CAR-T cell therapy did not differ in different HBV serologic status. Furthermore, chronic HBV infection or resolved HBV infection did not affect clinical response, progress-free survival (PFS), or overall survival (OS). Four (4.04%) patients experienced HBV reactivation, 3 (6.98%) with resolved HBV infection, and 1 (14.29%) chronic HBV infection. Of 4 patients with HBV reactivation, 2 cases (50%) of severe hepatitis were noted and reported. Drops of serum IgG and elevation of alanine aminotransferase (ALT), alanine aminotransferase (AST), total bilirubin (TB) were observed in all four patients around the date of HBV reactivation.

Safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell therapy for patients with relapsed/refractory B-ALL.

BACKGROUND: Murine chimeric antigen receptor T (CAR-T) cell therapy has demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, the potential immunogenicity of the murine single-chain variable fragment domain may limit the persistence of CAR-T cell, leading to relapse. METHODS: We performed a clinical trial to determine the safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell (hCART19) for R/R B-ALL. Fifty-eight patients (aged 13-74 years) were enrolled and treated between February 2020 and March 2022. The endpoints were complete remission (CR) rate, overall survival (OS), event-free survival (EFS), and safety. RESULTS: Overall, 93.1% (54/58) of patients achieved CR or CR with incomplete count recovery (CRi) by day 28, with 53 patients having minimal residual disease negativity. With a median follow-up of 13.5 months, the estimated 1-year OS and EFS were 73.6% (95% CI 62.1% to 87.4%) and 46.0% (95% CI 33.7% to 62.8%), with a median OS and EFS of 21.5 months and 9.5 months, respectively. No significant increase in human antimouse antibodies was observed following infusion (p=0.78). Duration of B-cell aplasia in the blood was observed for as long as 616 days, which was longer than that in our prior mCART19 trial. All toxicities were reversible, including severe cytokine release syndrome, which developed in 36% (21/58) of patients and severe neurotoxicity, which developed in 5% (3/58) of patients. Compared with our prior mCART19 trial, patients treated with hCART19 had longer EFS without increased toxicity. Additionally, our data also suggest that patients treated with consolidation therapy, including allogeneic hematopoietic stem cell transplantation or CD22-targeted CAR-T cell, following hCART19 therapy had a longer EFS than those without consolidation therapy. CONCLUSION: hCART19 has good short-term efficacy and manageable toxicity in R/R B-ALL patients. TRIAL REGISTRATION NUMBER: NCT04532268.

Maslinic Acid Inhibits the Growth of Malignant Gliomas by Inducing Apoptosis via MAPK Signaling.

Background: Gliomas are primary malignant brain tumors. Despite recent advances in surgery and clinical neuro-oncology, the prognosis of patients with glioma is still poor. Therefore, there is an urgent need to find new therapeutic drugs. Methods: Here, we have studied the anticancer effect of maslinic acid in glioma and explored its potential molecular mechanism. CCK-8, Ki67 immunofluorescence, and colony formation tests are used to detect the proliferation of glioma cells. Transwell and migration experiments are used to detect the function of cell invasion and migration, and RNA-seq was performed to identify differentially expressed genes. Western blot analysis helps us identify important signaling pathways. Finally, the anticancer effect of maslinic acid was confirmed in vivo through tumor xenografting experiments. Results: Our experiments obtained high-throughput data on the treatment of maslinic acid in glioma. We found that maslinic acid significantly inhibits the proliferation, invasion, and migration of glioma cells and promotes the apoptosis of glioma cells via suppressing MAPK signaling. Conclusions: This is the first time to analyze the mechanism of maslinic acid against glioma based on transcription. Our experiments show that maslinic acid may be a useful natural product for the treatment of glioma.

Peripheral leukemia burden at time of apheresis negatively affects the clinical efficacy of CART19 in refractory or relapsed B-ALL.

Our previous clinical study achieved complete remission (CR) rates of >90% following chimeric antigen receptor T cells targeting CD19 (CART19) treatment of refractory/relapsed B cell acute lymphoblastic leukemia (r/r B-ALL); however, the influence of the leukemia burden in peripheral blood (PB) blasts remains unclear. Here, we retrospectively analyzed 143 patients treated with CART19 (including 36 patients with PB blasts) to evaluate the effect of peripheral leukemia burden at the time of apheresis. One hundred seventeen patients with high disease burdens achieved 91.5% CR or incomplete count recovery CR and 86.3% minimal residual disease-negative CR, and 26 patients with low disease burdens obtained 96.2% MRD- CR. Collectively, 9 of 36 (25%) patients with PB blasts and 2 of 107 (1.87%) patients without PB blasts did not respond to CART19 therapy. The leukemia burden in PB negatively influenced ex vivo cell characteristics, including the transduction efficiency of CD3+ T cells and their fold expansion, and in vivo cell dynamics, including peak CART19 proportion and absolute count, fold expansion, and persistence duration. Further studies showed that these patients had higher programmed death-1 expression in CART19 products. Our data imply that PB blasts negatively affected CART19 production and the clinical efficacy of CART19 therapy in patients with r/r B-ALL.

Efficacy and Safety of Chimeric Antigen Receptor T Cells in Acute Lymphoblastic Leukemia With Post-Transplant Relapse.

Twenty patients with relapsed B-ALL after HSCT were treated with CAR T cell therapy and were evaluated for efficacy and safety. Twelve patients previously received haploidentical transplantation, while 8 patients received HLA-matched transplantation. The median relapse time was 12 months (range, 4 to 72). Thirteen patients received autologous CAR T cells, and 7 patients received allogeneic CAR T cells, which were derived from transplant donors. The median infusion dose was 2.9×106/kg (range, 0.33 to 12×106/kg). Nineteen patients were evaluated for efficacy, among which 17 patients (89.5%) achieved MRD negative. The CR rates in the HLA-matched transplantation group and haploidentical transplantation group were 100% (7/7) and 83.3% (10/12), respectively. The median follow-up time was 9.80 months (range, 2.40 to 64.97). Ten patients (50%) died of relapse, 3 patients (15%) died of infection, and 1 patient (5%) died of aGVHD. Fifteen patients (75%) developed CRS, including 3 (20%) grade 1 CRS, 6 (40%) grade 2 CRS, and 6 (40%) grade 3 CRS. Ten patients (50%) developed aGVHD, including 1 (10%) grade I aGVHD, 6 (60%) grade II aGVHD, and 3 (30%) grade III aGVHD. The log rank test showed that CAR T cell origin was correlated with aGVHD occurrence in the haploidentical transplantation group (P = 0.005). The authors' study indicated that the initial efficacy and safety of CAR T cell therapy for patients with post-transplant relapse were satisfactory. However, aGVHD was a concern in patients with a history of haploidentical transplantation occupied with allogeneic CAR T cells, which warrants clinical attention.

Risk Factors Associated with Durable Progression-Free Survival in Patients with Relapsed or Refractory Multiple Myeloma Treated with Anti-BCMA CAR T-cell Therapy.

PURPOSE: B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy results in high remission rates in patients with relapsed/refractory (R/R) multiple myeloma. However, the factors associated with prognosis following CAR T-cell therapy are unknown. PATIENTS AND METHODS: Between July 1, 2018 and July 31, 2020, 61 patients with R/R multiple myeloma received anti-BCMA CAR T-cell therapy (Chictr.org number, ChiCTR1800017404). Step-wise multivariate Cox regression and competing risk analyses were conducted to identify poor prognosis-associated risk factors. RESULTS: Sixty patients (98.4%) experienced cytokine release syndrome (CRS), including 33, 23, and 4 cases of CRS grades 1 to 2, 3, and 4, respectively. The objective response rate (ORR) was 98.3%, and the complete remission (CR) rate was 70.3%. With a median follow-up period of 21.1 months, the 1-year overall survival (OS) and progression-free survival (PFS) rates were 78.0% and 50.2%, respectively. The median PFS was 12.7 months. Cox modeling revealed that poor PFS was associated with extramedullary disease [HR = 2.59, 95% confidence interval (95% CI) = 1.29-5.21, P = 0.008], light chain multiple myeloma (HR = 2.53, 95% CI = 1.03-5.97, P = 0.035), high-risk cytogenetics (HR = 2.80, 95% CI = 1.27-6.14, P = 0.01), and prior treatment with more than 3 therapeutic lines (HR = 3.14, 95% CI = 1.34-7.34, P = 0.008). Among the 41 CR cases, competing risk analyses demonstrated higher relapse predispositions in those with extramedullary disease (HR = 4.51, 95% CI = 1.86-10.9, P = 0.001), light chain multiple myeloma (HR = 4.89, 95% CI = 1.52 - 15.7, P = 0.008), or high-risk cytogenetics (HR = 5.09, 95% CI = 1.63-15.9, P = 0.005). CONCLUSIONS: Anti-BCMA CAR T-cell therapy is safe and effective for R/R multiple myeloma. For patients with high-risk factors, improvements to extend remission and more specific individualized therapies are needed.

Purification and antioxidant properties of triterpenic acids from blackened jujube (Ziziphus jujuba Mill.) by macroporous resins.

In order to investigate the purification process and antioxidant activity of triterpenic acids from blackened jujube, the macroporous resin was applied to purify the crude extract from blackened jujube. The adsorption and desorption characterizations of five different macroporous adsorption resins (AB-8, D-101, X-5, HPD-100, S-8) for triterpenic acids of blackened jujube were compared, the optimum purification resins were screened, and the purification parameters were optimized. The antioxidant activity of crude extracts and purified products from blackened jujube was analyzed. The results showed that D-101 resin possessed the best effect on the purification of blackened jujube triterpenic acids. The optimum purification parameters were as follows: sample concentration 25.5 µg/ml, 130 ml of the sample volume was with a flow rate of 2.0 ml/min, eluted with 95% ethanol, and speed flow was 1.0 ml/min. The purity of triterpenic acids was increased by 2.49 times after purification with a recovery rate of (78.58 ± 0.67)%. Furthermore, the IC50 values of hydroxyl radical scavenging capacity from triterpenic acids crude extract and purified substances were 0.900 and 0.850 mg/ml, respectively, and the IC50 values of superoxide anion radical were 0.745 and 0.594 mg/ml, respectively, indicating that the antioxidative capacity of the purified product was stronger than the crude extract. The purified triterpenic acids (PTA) groups at different doses had excellent protective effects on H2O2-induced damage HUVEC cells. Results have revealed that triterpenic acids of blackened jujube have good antioxidant function and utilization and development prospects.

CD19/CD22 Dual-Targeted CAR T-cell Therapy for Relapsed/Refractory Aggressive B-cell Lymphoma: A Safety and Efficacy Study.

Chimeric antigen receptor (CAR) T-cell therapies that target either CD19 or CD22 alone have potent antilymphoma effects. However, antigen escape-mediated relapse often occurs. CAR T cells targeting both CD19 and CD22 may overcome this limitation. In this study, we developed bispecific CAR T cells simultaneously recognizing CD19- and CD22-expressing targets and assessed their safety and efficacy profiles in patients with relapsed/refractory aggressive B-cell lymphoma. Twenty-four patients were screened, and 16 were found eligible for the study. CAR T-cell-associated toxicities were recorded. Responses, overall survival (OS), and progression-free survival (PFS) were assessed. Of the 16 eligible patients, 14 (87.5%) achieved objective response and 10 (62.5%) achieved complete response (CR). The 2-year OS and PFS rates were 77.3% and 40.2%, respectively. Achieving CR (P = 0.046) and the number of prior chemotherapy lines (n = 2; P = 0.047) were independent prognostic factors associated with favorable PFS. The 2-year OS and PFS among patients who achieved CR were higher than among those who did not (P = 0.015 and P < 0.001, respectively). The 2-year PFS among patients who received two prior lines of chemotherapy was higher than that among patients who received more than two lines of chemotherapy (P = 0.049); OS did not differ between the groups. Severe grade 4 cytokine-release syndrome (CRS) was observed in 1 patient; 4 and 11 patients had grades 1 and 2 CRS, respectively. No patients developed neurotoxicity. CD19/CD22 dual-targeted CAR T cells may be a safe, potent antilymphoma cell-based targeted immunotherapy.

Donor-Derived CD7 Chimeric Antigen Receptor T Cells for T-Cell Acute Lymphoblastic Leukemia: First-in-Human, Phase I Trial.

PURPOSE: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have few options and poor prognosis. The aim was to assess donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell safety and efficacy in patients with r/r T-ALL. METHODS: In this single-center, phase I trial, we administered anti-CD7 CAR T cells, manufactured from either previous stem-cell transplantation donors or new donors, to patients with r/r T-ALL, in single infusions at doses of 5 × 105 or 1 × 106 (±30%) cells per kilogram of body weight. The primary end point was safety with efficacy secondary. RESULTS: Twenty participants received infusions. Adverse events including cytokine release syndrome grade 1-2 occurred in 90% (n = 18) and grade 3-4 in 10% (n = 2), cytopenia grade 3-4 in 100% (n = 20), neurotoxicity grade 1-2 in 15% (n = 3), graft-versus-host disease grade 1-2 in 60% (n = 12), and viral activation grade 1-2 in 20% (n = 4). All adverse events were reversible, except in one patient who died through pulmonary hemorrhage related to fungal pneumonia, which occurred at 5.5 months, postinfusion. Ninety percent (n = 18) achieved complete remission with seven patients proceeding to stem-cell transplantation. At a median follow-up of 6.3 months (range, 4.0-9.2), 15 remained in remission. CAR T cells were still detectable in five of five patients assessed in month 6, postinfusion. Although patients' CD7-positive normal T cells were depleted, CD7-negative T cells expanded and likely alleviated treatment-related T-cell immunodeficiency. CONCLUSION: Among 20 patients with r/r T-ALL enrolled in this trial, donor-derived CD7 CAR T cells exhibited efficient expansion and achieved a high complete remission rate with manageable safety profile. A multicenter, phase II trial of donor-derived CD7 CAR T cells is in progress (NCT04689659).

Characterizations of Ischemic Stroke Complications in Cardiac Myxoma Patients at a Single Institution in Eastern China.

BACKGROUND: Cardiac myxoma is the most common primary cardiac tumor. Even though it rarely causes a stroke, it is an important risk factor. Here, we compared our clinical experience in managing myxoma patients who developed stroke complications with those who did not present with this condition at the First Affiliated Hospital of Wenzhou Medical University. PATIENTS AND METHODS: The medical records were reviewed of 160 cardiac myxoma patients who were treated in our facility from January 2006 to December 2019. They were separated into either a stroke group or non-stroke group. RESULTS: Cardiac obstructive symptoms, embolic events and constitutional symptoms were observed in 92 (57.7%), 25 (15.6%) and 18 (11.2%) patients, respectively. Among 23 cardiac myxoma ischemic stroke patients, hypoesthesia (60.9%), hemiparesis (56.5%) and facial paresis (47.8%) were the three most common neurological symptoms. The middle cerebral artery (82.6%) was the most commonly affected vessel, whereas 73.9% of the ischemic patients had multiple stroke lesions. Binary logistic regression analysis showed that coronary heart disease and tumor sizes were independently associated in the stroke group (p <0.05). The 10 years cumulative survival rate was 87.9% for all patients after surgical intervention. There was no significant difference in the 10 years cumulative survival rate between the two groups (80.0% vs 88.9%, p =0.274 > 0.05). CONCLUSION: The three most common neurological symptoms (hypoesthesia, hemiparesis and facial paresis), the middle cerebral artery and multiple lesions involvements were the definitive markers of patients afflicted with cardiac myxoma stroke. Small tumor sizes were independently associated with these patients. Surgical resection is a relatively safe procedure for treating both the stroke and non-stroke patients.

Fine-Mapping of the PLCL2 Gene Identifies Candidate Variants Associated With Ischaemic Stroke Risk in Metabolic Syndrome Patients.

A genome-wide association study (GWAS) reported PLCL2 on chromosome 3p24. 3 (rs4618210:A>G) as a novel susceptibility locus for myocardial infarction in the Japanese population. As the most common pathological process, atherosclerosis leads to metabolic syndrome (MetS)-related ischaemic stroke (IS) and myocardial infarction. Hypothesizing that polymorphisms of the PLCL2 gene might be associated with the onset and prognosis of IS in MetS patients, we performed the following study in a Chinese Han population. A total of 709 cases (patients with MetS plus IS) and 711 controls (patients with MetS) were enrolled. A fine-mapping strategy was adopted to identify tagged single nucleotide polymorphisms (SNPs) of the PLCL2 gene, and improved multiplex ligation detection reaction (iMLDR) technology was used to genotype the selected SNPs. Logistic regression was used to analyse the values of the selected SNPs for the risk of IS between the cases and controls, adjusting for sex, age, hypertension, dyslipidaemia, hyperglycaemia, smoking and drinking. To compare the mean age of IS onset among different risk score groups, a genetic risk score was constructed for each case. The cumulative risk of IS events in the case group was presented using a cumulative incidence curve. All cases were followed up for 3 months, and functional outcomes were recorded prospectively. Two SNPs (rs4685423 and rs4618210) were significantly related to the risk of IS in MetS patients. For rs4685423, patients who were AA homozygotes were less likely to suffer from IS than C-allele carriers (OR 0.718; 95% CI 0.567-0.909; multivariate-adjusted, P = 0.006). For rs4618210, A-allele carriers were less likely to develop IS than patients who were GG homozygotes (OR 0.679; 95% CI 0.548-0.841; multivariate-adjusted, P < 0.001). As the genetic risk score increased, the mean age at IS onset decreased (log-rank P = 0.010). There was no statistically significant difference in the distribution of the 90-day modified Rankin Scale (mRS) outcomes across the rs4685423 (P = 0.319) or rs4618210 polymorphisms (P = 0.148). Our findings suggested that genetic polymorphisms of PLCL2 might be associated with the onset of MetS-related IS. Further studies are warranted to validate our findings in other ethnic populations.

Single-Cell Transcriptomic Analysis Reveals BCMA CAR-T Cell Dynamics in a Patient with Refractory Primary Plasma Cell Leukemia.

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the clinical treatment of hematological malignancies due to the prominent anti-tumor effects. B cell maturation antigen (BCMA) CAR-T cells have demonstrated promising effects in patients with relapsed/refractory multiple myeloma. However, the dynamics of CAR-T cell proliferation and cytotoxicity in clinical patients remains unexplored. Here, we longitudinally profiled the transcriptomes of 55,488 T cells including CAR-T products, CAR-T cells, and endogenous T cells at the peak and remission phases in a plasma cell leukemia (PCL) patient treated with BCMA CAR-T cells by single-cell transcriptomic analysis. Our results showed distinct CAR-T and endogenous T cell subsets indicating stage-specific expression in proliferation, cytotoxicity, and intercellular signaling pathways. Furthermore, we found that CAR-T cells at peak phase gradually convert to a highly cytotoxic state from a highly proliferative state along a development trajectory. Moreover, re-analysis of a single cell study from CD8+ CD19 CAR-T confirmed our findings. These commonalities suggest conserved mechanisms for CAR-T treatment across hematological malignancies. Taken together, our current study provides insight into CAR-T cell dynamics during CAR-T therapy and proves that both BCMA CAR-T and CD19 CAR-T have similar transcriptional characteristics, especially at the CAR-T peak phase.

Baohuoside I via mTOR Apoptotic Signaling to Inhibit Glioma Cell Growth.

INTRODUCTION: Baohuoside I, a novel oncotherapeutic agent, has been reported to have anti-cancer effects on a variety of cancers, but its role in glioma and its molecular mechanism are still unclear. METHODS: The proliferation of U251 cells was detected by real-time cellular analysis (RTCA), CCK-8, Ki67 immunofluorescence and colony formation assay. The effect of Baohuoside I on the invasion and migration of U251 cells was measured by transwell and scratch tests. The apoptosis of U251 cells was detected by flow cytometry. The expression level of related protein was detected by western blotting. RESULTS: Baohuoside I could inhibit the proliferation of human glioma cells and induce apoptosis. Further study showed that the migration and invasion ability of glioma was significantly decreased by Baohuoside I. Western blot revealed the expression of p-AMPKα1 protein was up-regulated, and the expression of p-mTOR and p-S6K was down-regulated after Baohuoside I treatment. Tumorigenesis in nude mice showed that Baohuoside I had an anti-glioma effect in vivo. CONCLUSION: We propose a natural product, which can inhibit the proliferation, invasion and migration of glioma and may be a valuable anti-tumor candidate. The inhibitory effect of Baohuoside I on the glioma is achieved by inducing the apoptosis of the tumor cells, rather than autophagy. In addition, the pathway to induce cell apoptosis of Baohuoside I is to target the mTOR signal.

Resources utilisation and economic burden of percutaneous vertebroplasty or percutaneous kyphoplasty for treatment of osteoporotic vertebral compression fractures in China: a retrospective claim database study.

BACKGROUND: Osteoporotic vertebral compression fractures (OVCF) is a common and often debilitating complication of osteoporosis, leading to significant morbidity and increased mortality. Percutaneous vertebroplasty (PVP) and Percutaneous kyphoplasty (PKP) are recommendable surgical treatments for OVCF. OBJECTIVE: To evaluate PVP/PKP utilisation and their related direct medical costs for OVCF treatment in China from the payer perspective. METHODS: A population-based medical claims database of a metropolitan city in China was analysed from the payer perspective, which included all inpatient claims from 01/01/2015 to 31/12/2017. All vertebral fractures patients that met the eligibility criteria (aged ≥50 years old, having vertebral fracture diagnosis, without unrelated diseases diagnoses such as tumour and scoliosis, received PVP/PKP) were deemed as OVCF patients. Baseline characteristics, surgery rate, length of stay in hospital, time to re-surgery, and costs (including costs per hospitalisation and annual costs) were described. Survival analysis function was used to estimate the re-surgery rate. RESULTS: Of the 50,686 patients with OVCF identified, 14,527 (28.66%) received a total number of 15,599 records of PVP/PKP surgeries from 2015 to 2017. Mean age was 75 at the first surgery captured in the database analysis period; females accounted for 79.54% of all cases. The median length of surgery stay was 9 days. Cumulative re-surgery rates were 1.22% in 30 days, 2.58% in 90 days, 3.61% in 183 days, 5.42% in 1 year, and 7.95% in 2 years. There was no significant difference in re-surgery rate between PVP and PKP (p = 0.3897). The median time to the re-surgery was 139 days. Mean costs per PVP/PKP-related hospitalisation were 35,906 CNY/5122 USD (34,195 CNY/4878USD for PVP, 44,414 CNY/6336 USD for PKP, p < 0.01). The overall costs of hospitalisation averaged 186.61 million CNY (26.62 million USD) per year in this metropolitan city. CONCLUSION: From 2015 to 2017, nearly one-third of OVCF inpatients received PVP/PKP and the re-surgery rate was 7.95%. PVP/PKP procedures for OVCF place a high economic burden for both the healthcare system and patients. Early detection and treatment of patients with osteoporosis are critical in China.

CD19/CD22 chimeric antigen receptor T-cell therapy for refractory acute B-cell lymphoblastic leukemia with FLT3-ITD mutations.

Treatment of acute lymphoblastic leukemia (ALL) is still a challenge despite years of researching, especially for those of poor prognosis. Zhang and his team recently proved that FLT3 gene mutation was identified in ~5% of ALL and the mutation spectrum is different from AML. Recently, chimeric antigen receptor T cells (CART) therapy presents great efficacy in treating refractory leukemia. We report a case of a refractory ALL patient with FLT3-ITD mutations and unfavorable karyotypes, who failed to respond to chemotherapy and small molecule tyrosine kinase inhibitors, successfully treated by CART therapy. FLT3-ITD mutations were downregulated dramatically into 14.1% positive 3 days after the infusion and remained negative until now. MRD has stayed to be negative from the 10th day. This case suggests that CART-cell therapy might be effective in treating FLT3-ITD positive refractory ALL, implying the possibility to overcome the traditional prognosis scoring system for leukemia and providing a new chance for other leukemia patients with inferior prognosis factors.