Lipiodol combined with drug-eluting beads versus drug-eluting beads alone for transarterial chemoembolization of hepatocellular carcinoma: a multicenter study.

RATIONALE AND OBJECTIVES: This study aimed to propose a novel approach of lipiodol combined with drug-eluting beads transarterial chemoembolization (Lipiodol-DEB TACE) and to compare the safety and efficacy with DEB-TACE alone for patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From the database of four centers, the records of patients with HCC who received DEB-TACE or Lipiodol-DEB TACE as initial treatment were retrospectively evaluated. The tumor response was measured based on the Modified Response Evaluation Criteria in Solid Tumors. Overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were compared between two groups. RESULTS: A total of 244 patients were included with 160 patients receiving DEB-TACE and 84 patients receiving Lipiodol-DEB TACE. Lipiodol-DEB TACE group had higher objective response rate (86.9 % vs. 76.3 %), higher disease control rate (97.6 % vs. 88.8 %), longer median OS (42.6 vs. 25.8 months) and longer median PFS (34.0 vs. 17.0 months) than DEB-TACE group (P < 0.05). There was no significant difference observed in the incidence of AEs between two groups. Cox analysis identified total bilirubin level, maximum tumor diameter, TACE method and portal vein invasion as independent prognostic factors. CONCLUSION: Lipiodol-DEB TACE was a safe option and associated with improved tumor response and survival outcome compared to DEB-TACE alone for selected patients with HCC.

A Novel JAK1 Inhibitor SHR0302 Combined With Prednisone for First-Line Treatment of Chronic Graft-Versus-Host Disease: A Phase I Clinical Trial.

Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation. Standard steroid first-line treatment could not satisfy therapeutic needs due to limited efficacy. As a highly selective Janus kinase (JAK) 1 inhibitor, SHR0302 exhibits a reduced inhibition effect on JAK2 and might have less effect on hematopoiesis. This phase I clinical trial investigated the tolerability and safety of SHR0302 in combination with prednisone, and its early efficacy evidence as a potential first-line treatment to moderate/severe cGVHD. The standard 3 + 3 dose escalation was implemented to find the optimal dose of SHR0302. And prednisone was concurrently administrated with a dose of 1 mg/kg/d and then gradually tapered after 2 weeks. Eighteen patients were enrolled into the study. Grade ≥ 3 treatment-related adverse events were observed in 38.9% of patients. Only one patient developed DLT (grade ≥ 3 hypercholesterolemia) in the highest dose-level group who had pre-existing hypercholesterolemia. The maximum tolerated dose was not reached. No patient discontinued treatment due to AEs. Sixteen out of 18 patients were evaluable for responses, the ORR at week 4 and week 24 were 94.4 and 87.5%, respectively. Overall, the treatment of SHR0302 combined with prednisone was safe and well-tolerated, preliminary clinical results presented a high response for previously untreated cGVHD and a significant reduction in prednisone use in this study. A phase II trial will be conducted to further investigate its therapeutic effects clinically.

Low-dose anti-thymocyte globulin plus low-dose post-transplant cyclophosphamide-based regimen for prevention of graft-versus-host disease after haploidentical peripheral blood stem cell transplants: a large sample, long-term follow-up retrospective study.

Introduction: The novel low-dose anti-thymocyte (ATG, 5 mg/kg) plus low-dose post-transplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy)-based regimen had promising activity for prevention of graft-versus-host disease (GVHD) in haploidentical-peripheral blood stem cell transplantation (haplo-PBSCT), but its impacts on long-term outcomes remain to be defined. Methods: We performed a large sample, long-term follow-up retrospective study to evaluate its efficacy for GVHD prophylaxis. Results: The study enrolled 260 patients, including 162 with myeloid malignancies and 98 with lymphoid malignancies. The median follow-up time was 27.0 months. For the entire cohort, the cumulative incidences (CIs) of grade II-IV and III-IV acute GVHD (aGVHD) by 180 days were 13.46% (95% CI, 9.64%-17.92%) and 5.77% (95% CI, 3.37%-9.07%); while total and moderate/severe chronic GVHD (cGVHD) by 2 years were 30.97% (95% CI, 25.43%-36.66%) and 18.08% (95% CI, 13.68%-22.98%), respectively. The 2-year overall survival (OS), relapse-free survival (RFS), GVHD-free, relapse-free survival (GRFS), non-relapse mortality (NRM), and CIs of relapse were 60.7% (95% CI, 54.8%-67.10%), 58.1% (95% CI, 52.2%-64.5%), 50.6% (95% CI, 44.8-57.1%), 23.04% (95% CI, 18.06%-28.40%), and 18.09% (95% CI, 14.33%-23.97%, respectively. The 1-year CIs of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation were 43.46% (95% CI, 37.39%-49.37%) and 18.08% (95% CI, 13.68%-22.98%), respectively. In multivariate analysis, the disease status at transplantation was associated with inferior survivor outcomes for all patients and myeloid and lymphoid malignancies, while cGVHD had superior outcomes for all patients and myeloid malignancies, but not for lymphoid malignancies. Discussion: The results demonstrated that the novel regimen could effectively prevent the occurrence of aGVHD in haplo-PBSCT.

Metagenomic Next-Generation Sequencing for Pathogens in Bronchoalveolar Lavage Fluid Improves the Survival of Patients with Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation.

INTRODUCTION: Unbiased metagenomic next-generation sequencing (mNGS) has been used for infection diagnosis. In this study, we explored the clinical diagnosis value of mNGS for pulmonary complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: From August 2019 to June 2021, a prospective study was performed to comparatively analyze the pathogenic results of mNGS and conventional tests for bronchoalveolar lavage fluid (BALF) from 134 cases involving 101 patients with pulmonary complications after allo-HSCT. RESULTS: More pathogens were identified by mNGS than with conventional tests (226 vs 120). For bacteria, the diagnostic sensitivity (P = 0.144) and specificity (P = 0.687) were similar between the two methods. For fungus except Pneumocystis jirovecii (PJ), conventional tests had a significantly higher sensitivity (P = 0.013) with a similarly high specificity (P = 0.109). The sensitivities for bacteria and fungi could be increased with the combination of the two methods. As for PJ, both the sensitivity (100%) and specificity (99.12%) of mNGS were very high. For viruses, the sensitivity of mNGS was significantly higher (P = 0.021) and the negative predictive value (NPV) was 95.74% (84.27-99.26%). Pulmonary infection complications accounted for 90.30% and bacterium was the most common pathogen whether in single infection (63.43%) or mixed infection (81.08%). The 6-month overall survival (OS) of 88.89% in the early group (mNGS ≤ 7 days) was significantly higher than that of 65.52% (HR 0.287, 95% CI 0.101-0.819, P = 0.006) in the late group (mNGS > 7 days). CONCLUSIONS: mNGS for BALF could facilitate accurate and fast diagnosis for pulmonary complications. Early mNGS could improve the prognosis of patients with pulmonary complications after allo-HSCT. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04051372.

Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness.

Tonic signaling of chimeric antigen receptor (CAR), i.e., the spontaneous CAR activation in the absence of tumor antigen stimulation, is considered to be a pivotal event controlling CAR-T efficacy. However, the molecular mechanism underlying the spontaneous CAR signals remains elusive. Here, we unveil that positively charged patches (PCPs) on the surface of the CAR antigen-binding domain mediate CAR clustering and result in CAR tonic signaling. For CARs with high tonic signaling (e.g., GD2.CAR and CSPG4.CAR), reducing PCPs on CARs or boosting ionic strength in the culture medium during ex vivo CAR-T cell expansion minimizes spontaneous CAR activation and alleviates CAR-T cell exhaustion. In contrast, introducing PCPs into the CAR with weak tonic signaling, such as CD19.CAR, results in improved in vivo persistence and superior antitumor function. These results demonstrate that CAR tonic signaling is induced and maintained by PCP-mediated CAR clustering. Notably, the mutations we generated to alter the PCPs maintain the antigen-binding affinity and specificity of the CAR. Therefore, our findings suggest that the rational tuning of PCPs to optimize tonic signaling and in vivo fitness of CAR-T cells is a promising design strategy for the next-generation CAR.

Impact of Lymphocyte Subsets of Grafts on the Outcome of Haploidentical Peripheral Blood Stem Cell Transplantation.

The contribution of lymphocyte subset composition of the graft on the outcomes following haploidentical peripheral blood stem cell transplantation (haploPBSCT) is not fully elucidated. We retrospectively analyzed 314 patients with hematological malignancies who underwent haploPBSCT from 2016 to 2020 in our center. We obtained a cutoff value of CD3+ T cell dose (2.96 × 108/kg) that separated the risk of II-IV acute graft-versus-host disease (aGvHD) and divided patients into the low CD3+ T cell dose group (CD3+ low) and the high CD3+ T cell dose (CD3+ high) group. Significantly higher incidences of I-IV aGvHD, II-IV aGvHD, and III-IV aGvHD were identified in the CD3+ high group (50.8%, 19.8%, and 8.1% in the high group, 23.1%, 6.0%, and 0.9% in the low group, P < 0.0001, P = 0.002, and P = 0.02, respectively). We found that CD4+ T cell and its naïve and memory subpopulations of grafts had a significant impact on aGvHD (P = 0.005, P = 0.018, and P = 0.044). Besides, we found an inferior reconstitution of natural killer (NK) cells in the CD3+ high group than in the low group within the first-year posttransplant (239 cells/µL vs 338 cells/µL, P = 0.0003). No differences in engraftment, chronic GvHD (cGvHD), relapse rate, transplant-related mortality (TRM), and overall survival (OS) were identified between the two groups. In conclusion, our study found that a high CD3+ T cell dose led to a high risk of aGvHD and inferior reconstitution of NK cells in the haploPBSCT setting. In the future, carefully manipulating the composition of lymphocyte subsets of grafts might reduce the risk of aGvHD and improve the transplant outcome.

Immune reconstitution and survival of patients after allogeneic hematopoietic stem cell transplantation from older donors.

BACKGROUND: The impact of donor age on the immune reconstitution of patients with hematological malignancies who underwent hematopoietic cell transplantation (HCT) is unclear. METHOD: We retrospectively compared the outcomes of 381 patients who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from 308 donors under 50 years of age and 73 donors over 50 years of age. IVIG was regularly supplemented for patients in the first 3 months post-HCT. RESULTS: The counts of CD8+CD45RA+ naïve T cells were significantly lower in patients of the older donor group than in the younger donor group in the first year after PBSCT (190.6 cells/µl vs. 239.6 cells/µl, p = .018). Patients in the older donor group had significantly fewer CD19+ B cells on day +270 (123.4 cells/µl vs. 183.5 cells/µl, p = .021) and day +365 (169 cells/µl vs. 271.1 cells/µl, p = .01) after PBSCT. Serum IgA (.76 g/L vs. .97 g/L, p < .001) and IgM levels (.75 g/L vs. 1.04 g/L, p < .001) were significantly lower in patients in the older donor group from day +60 to +365 after PBSCT. The EBV reactivation rate within the first 3 months after PBSCT was significantly higher in patients in the older donor group (48.6% vs. 38.3%, p = .034). However, the incidences of CMV reactivation, II-IV acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), 3-year relapse rate, 3-year transplant-related mortality (TRM) and 3-year overall survival (OS) were not significantly different between the two groups. CONCLUSION: In conclusion, donors ≥50 years old were associated with inferior immune reconstitution and higher EBV reactivation in patients after PBSCT, but no change in OS.

Low-Dose Anti-Thymocyte Globulin Plus Low-Dose Posttransplant Cyclophosphamide as an Effective Regimen for Prophylaxis of Graft Versus Host Disease After Haploidentical Peripheral Blood Stem Cell Transplantation With Maternal/Collateral Related Donors.

Maternal and collateral donors were associated with a higher incidence of graft-versus-host disease (GvHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). A more effective regimen for GvHD prophylaxis after haplo-HSCT with maternal/collateral donors needed to be explored. A retrospective study was performed on 62 patients after haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with maternal/collateral donors, which included 35 patients with low-dose antithymocyte globulin (ATG) plus low-dose posttransplant cyclophosphamide-based (low-dose ATG/PTCy-based) and 27 with ATG-based regimens for GvHD prophylaxis. The 180-day cumulative incidences (CIs) of grades II-IV and III-IV acute GvHD (aGvHD) were 17.7% and 6.8% in low-dose ATG/PTCy-based group, which were significantly lower than that in ATG-based group (55.4% and 31.9%) (P = 0.003 for grade II-IV and P = 0.007 for III-IV aGvHD). In low-dose ATG/PTCy-based group, the 1-year overall survival (OS) and relapse-free survival (RFS) were 80.0%and 80.4%, which were higher than that in ATG-based group with OS of 59.4% and RFS of 62.0%. In multivariate analysis, the low-dose ATG/PTCy-based regimen significantly reduced the risk of grade II-IV (HR = 0.357; P = 0.049) and grade III-IV aGvHD (HR = 0.190; P = 0.046) as an independent risk factor. The results suggested that the low-dose ATG/PTCy-based regimen could effectively prevent the occurrence of aGvHD after haplo-PBSCT with maternal/collateral donors compared with the ATG-based regimen.

Total Body Irradiation-Based Conditioning Regimen Improved the Survival of Adult Patients With T-Cell Lymphoblastic Lymphoma After Allogeneic Peripheral Blood Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the consolidation modalities for adult patients with T-cell lymphoblastic lymphoma (T-LBL). However, the optimal conditioning regimen needs to be explored. In the present study, 40 patients with T-LBL undergoing allo-HSCT were retrospectively analyzed, including 23/40 (57.5%) with total body irradiation (TBI)-based conditioning regimen and 17/40 (42.5%) with busulfan (BU)-based regimen. TBI-based regimen significantly increased the cumulative incidence (CI) of grade II to IV acute graft-versus-host disease (aGvHD) as compared with BU-based regimen (13.0% vs 0%, P = 0.000). The relapse risk was significantly lowered in TBI-based group with a 2-year CI of relapse (CIR) of 9.1% as compared with that of 49.6% in BU-based group (P = 0.008). The 1-year and 2-year non-relapse mortalities (NRMs) for all patients were 5.0% and 10.3%, respectively. The 1-year and 2-year NRMs were 8.9% and 16.0% in TBI-based group, and 0.00% and 0.00% in BU-based group (P = 0.140). The 2-year probabilities of overall survival (OS) and relapse-free survival (RFS) were 83.0% [95% confidence interval, 63.4%-100%] and 74.0% (95% confidence interval, 54.4%-93.6%) in TBI-based group, which were higher than that of 35.0% (95% confidence interval, 0.0%-72.2%) and 50.0% (95% confidence interval, 24.5%-75.4%) in BU-based group, respectively (P = 0.020 for OS and P = 0.081 for RFS). In multivariate analysis, TBI-based regimen significantly reduced the risk of relapse [subdistribution hazard ratio (SHR) = 0.030, 95% CI, 0.002-0.040, P = 0.000] and improved the OS [hazard ratio (HR) 0.121, 95% CI, 0.021-0.683, P = 0.017] as an independent prognostic factor. These results suggested that TBI-based regimen might be an optimal choice for adult patients with T-LBL undergoing allo-HSCT.

Immune reconstitution and survival of patients with parvovirus B19 related pure red cell aplasia after haplo-PBSCT.

Parvovirus B19 (PvB19) infection and PvB19 related pure red cell aplasia (PRCA) in recipients with allogeneic hematopoietic stem cell transplantation have been reported sporadically. However, clinical studies with large sample sizes are lacking, especially in patients undergoing HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). In addition, clinical features, immune reconstitution, and outcomes of these patients are not clear. We conducted a retrospective analysis of 164 patients who received haplo-PBSCT with low-dose anti-thymocyte globulin (ATG) plus low-dose posttransplant cyclophosphamide (PTCy)-based regimen as graft-versus-host disease (GVHD) prophylaxis. We analyzed the incidence of PvB19 related PRCA and compared the clinical characteristics, immune reconstitution, incidence of GVHD, relapse rate, and survival between patients with and without PvB19 related PRCA. A total of 14 (8.5%) recipients developed PvB19 related PRCA after a median of 5.3 months after haplo-PBSCT. These patients with PvB19 related PRCA had slower immune reconstitution, but similar incidences of GVHD, relapse rate, and overall survival compared with recipients without PvB19 related PRCA. PvB19 related PRCA indicated relative delayed and poor immune reconstitution of the recipients early after haplo-PBSCT. PvB19 related PRCA had no effects on GVHD, relapse, and survival.

Lower Absolute Lymphocyte Count Before Conditioning Predicts High Relapse Risk in Patients After Haploidentical Peripheral Blood Stem Cell Transplantation With Low Dose Anti-Thymocyte Globulin/Post-Transplant Cyclophosphamide for GvHD Prophylaxis.

Standard anti-thymocyte globulin (ATG) weight-based dosing often resulted in highly variable ATG exposure, which had profound effects on relapse and survival, especially in recipients with relatively low absolute lymphocyte count (ALC) before conditioning. Data regarding rabbit ATG pharmacokinetics and pharmacodynamics in the setting of HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) is lacking. We conducted a retrospective study on 90 consecutive patients who underwent haplo-PBSCT with low dose rabbit ATG (5 mg/kg) plus low dose post-transplant cyclophosphamide (50 mg/kg) based regimen for graft-versus-host disease (GvHD) prophylaxis. We compared serum concentration of ATG and post-transplant results between patients with ALC<500/µl and ALC≥500/µl before conditioning. Patients with ALC<500/µl had higher ATG concentrations, delayed immune reconstitution, lower incidence of grade II-IV acute GvHD (0 vs. 19.42%, P = 0.043), higher risk of Epstein-Barr virus infection within 100 days post-transplant (47.78% vs. 22.22%, P = 0.020) and 1-year relapse rate (33.33% vs.11.59%, P = 0.041), and lower 1-year overall survival (OS) (52.38% vs.79.71%, P = 0.004), 1-year relapse free survival (RFS) (47.62% vs. 75.36% for RFS, P = 0.014), and 1-year GvHD free relapse-free survival (GRFS) (42.89% vs. 65.22%, P = 0.043). ALC<500/µl before conditioning was a significant poor risk factor for relapse, OS, RFS, and GRFS.

Analysis of flavors and fragrances by HPLC with Fe3O4@GO magnetic nanocomposite as the adsorbent.

In this article, a method for the analysis of flavors and fragrances including ethyl vanillin, trans-cinnamic acid, methyl cinnamate, ethyl cinnamate, and benzyl cinnamate in foods by HPLC with Fe3O4@GO nanocomposite as the adsorbent of magnetic solid-phase extraction was developed. The magnetic Fe3O4@GO nanocomposite was prepared and characterized by transmission electron microscope, infrared spectroscopy, X-ray diffraction and vibrating sample magnetometer. The as-prepared Fe3O4@GO nanocomposite was used as adsorbent for extraction and preconcentration of flavors and fragrances in foods. The extraction and desorption conditions including amount of materials, extraction time and desorption solvents were investigated. The analytes were separated within 10min and detected with LODs ranged from 0.02 to 0.04µg/mL. The recovery obtained from the analysis of spiked juice sample was between 71.5% and 112.4% with RSDs lower than 4.14%. The developed method was successfully applied to the analysis of real samples including orange juice, chocolate and fruit sugar.

Graphene oxide-SiO2 nanocomposite as the adsorbent for extraction and preconcentration of plant hormones for HPLC analysis.

In this research, a modified Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) method based on graphene oxide@SiO2(SiO2@GO) nanocomposite as adsorbent of dispersive solid-phase extraction (dSPE) combined with high performance liquid chromatography (HPLC) for the analysis of four plant hormones in different plants was established. The as-prepared SiO2@GO was characterized by scanning electron microscopy, transmission electron microscopy and infrared spectroscopy. The experimental conditions for dSPE, including the ratio of material to liquid, pH of sample, adsorption and desorption time, desorption temperature as well as desorption solution, were investigated. The detection limits for the analysis of indole-3-acetic acid, indole-3-butyric acid, 1-naphthylacetic acid and abscisic acid were achieved below 0.05µgmL-1. The established method was applied to the analysis of the plant hormones in fruits, vegetables and other food samples. The obtained results indicated that the method was sensitive, accurate, convenient and quick, which provided an alternative analytical approach for plant hormones in complex matrices.

Highly Efficient, Rapid, and Simultaneous Removal of Cationic Dyes from Aqueous Solution Using Monodispersed Mesoporous Silica Nanoparticles as the Adsorbent.

In this work, a highly efficient and rapid method for simultaneously removing cationic dyes from aqueous solutions was developed by using monodispersed mesoporous silica nanoparticles (MSNs) as the adsorbents. The MSNs were prepared by a facile one-pot method and characterized by scanning electron microscopy, transmission electron microscopy, Fourier-transform infrared spectroscopy, and Brunauer-Emmett-Teller. Experimental results demonstrated that the as-prepared MSNs possessed a large specific surface area (about 585 m²/g), uniform particle size (about 30 nm), large pore volume (1.175 cm³/g), and narrow pore size distribution (1.68 nm). The materials showed highly efficient and rapid adsorption properties for cationic dyes including rhodamine B, methylene blue, methyl violet, malachite green, and basic fuchsin. Under the optimized conditions, the maximum adsorption capacities for the above mentioned cationic dyes were in the range of 14.70 mg/g to 34.23 mg/g, which could be achieved within 2 to 6 min. The probable adsorption mechanism of MSNs for adsorption of cationic dyes is proposed. It could be considered that the adsorption is mainly controlled by electrostatic interactions and hydrogen bonding between the cationic dyes and MSNs. As a low-cost, biocompatible, and environmentally friendly material, MSNs have a potential application in wastewater treatment for removing some environmental cationic contaminants.

Novel electrochemical sensing platform for quantitative monitoring of Hg(II) on DNA-assembled graphene oxide with target recycling.

This work designs a new electrochemical sensing platform for the quantitative monitoring of mercury ion (Hg(2+)) on poly-T(15) oligonucleotide-functionalized graphene oxide by coupling with DNase I-assisted target recycling amplification. The assay was carried out on the basis of T-Hg(2+)-T coordination chemistry by using target-induced dissociation of indicator-labeled poly-T(15) oligonucleotide from graphene oxide nanosheets. The electronic signal was amplified through DNase I-triggered target recycling. Experimental results indicated that the amperometric response of DNA-based sensing platform deceased with the increasing Hg(2+) concentration in the sample, and has a detection limit of 0.12nM with a dynamic working range of up to 50nM. Our strategy afforded exquisite selectivity for Hg(2+) against other environmentally related metal ions. More significantly, this methodology displayed high reproducibility and acceptable accuracy, thus representing an optional sensing scheme for the screening of Hg(2+) in environmental water samples.