Efficacy and safety of chimeric antigen receptor T-cells treatment in central nervous system lymphoma: a PRISMA-compliant single-arm meta-analysis.

BACKGROUND: Chimeric antigen receptor (CAR) T cells are used to treat refractory and recurrent B-cell lymphoma. When administered intravenously, CAR T cells can be detected in cerebrospinal fluid, and thus represent a promising method for the treatment of central nervous system lymphoma (CNSL). This meta-analysis aimed to clarify the effectiveness and safety of CAR T-cell therapy in the treatment of CNSL. METHODS: Studies involving patients with CNSL who received CAR T-cell therapy that reported overall response (OR), complete response (CR), and partial response (PR) were included. A random-effects or fixed-effects model with double arcsine transformation was used for the pooled analysis and 95% confidence intervals (CI) were determined for all outcomes. RESULTS: Eight studies, comprising 63 patients, were identified and were included in the meta-analysis. The pooled OR and CR rates after treatment with CAR T cells were 69% (95% CI, 56-81%) and 51% (95% CI, 37-64%), respectively. The pooled rate of progressive disease after remission was 38% (95% CI, 21-55%). The pooled rate for neurotoxicity grade 3 or above was 12% (95% CI, 3-24%, I2 = 0.00%, p = 0.53). No treatment-related deaths were reported. CONCLUSIONS: CAR T-cell therapy is a promising option for the treatment of CNSL owing to a high short-term remission rate and controllable side effects. However, the high recurrence rate after remission must be addressed. Long-term follow-up data with large sample sizes are also needed to better assess the effectiveness and safety of CAR T-cell therapy. REGISTRATION: This meta-analysis was registered in the international prospective register of systematic reviews (PROSPERO) (CRD42022301332).

Bovine Serum Albumin Coated Upconversion Nanoparticles for Near Infrared Fluorescence Imaging in Mouse Model.

The unique properties of upconversion nanoparticles (UCNPs) facilitate them to be good candidates for cell and animal imaging. In our work, we developed a facile approach to synthesize nano-composites which is composed of UCNPs and bovine serum albumin (BSA). The nano-composites (UCNPs@BSA) exhibited dual fluorescence in the visible range and NIR range simultaneously. The low cytotoxicity of UCNPs and UCNPs@BSA was demonstrated in L02 and HepG-2 cell lines respectively. The cell imaging investigations verified the biological imaging capability of UCNPs@BSA. Furthermore, UCNPs@BSA displayed favorable in vivo imaging capability in tumor-bearing mice. Consequently, the dual fluorescence emission probe was demonstrated to be a promising candidate for cell and tumor imaging.

Challenges in the management of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma. Stereotactic biopsy remains the gold standard for the pathological diagnosis of PCNSL. However, certain new auxiliary diagnostic methods are considered to have good application prospects; these include cytokine and tumor circulating DNA, among others. Although new drugs such as immunomodulators, immune checkpoint inhibitors, chimeric antigen receptor T-cells, and Bruton tyrosine kinase inhibitors have brought hope owing to their improved efficacy, the high recurrence rate and subsequent high mortality remain barriers to long-term survival. Increasing emphasis is therefore being placed on consolidation treatments. Consolidation treatment strategies include whole brain radiotherapy, autologous hematopoietic stem cell transplantation, and non-myeloablative chemotherapy. As studies directly comparing the effectiveness and safety of different consolidation treatment schemes are lacking, the optimal consolidation strategy remains uncertain. This article will review the diagnosis and treatment of PCNSL, focusing on the progress in research pertaining to consolidation therapy.

Efficacy and Safety of Hypomethylating Agents in Chronic Myelomonocytic Leukemia: A Single-Arm Meta-analysis.

Background Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm with features of the myelodysplastic syndromes (MDSs) and myeloproliferative neoplasm presenting with peripheral blood monocytosis and an inherent risk for transformation to acute myeloid leukemia, while the abnormal DNA methylation plays a critical role in the pathogenesis of MDS, which is a disease of disordered differentiation. Recently, with the rapid development of molecular biology, hypomethylating agents (HMAs) for the treatment of MDS has gradually become a research focus. The objective of this study was to evaluate the benefits and risks of HMAs for patients with CMML. Materials and Methods PubMed, Embase, the Cochrane Library, and three Chinese databases were searched for studies published before November 2020 that used HMAs in CMML. Results The pooled objective response rate (ORR), complete response (CR), and partial response (PR) were 50.0, 21.0, and 2.0%, respectively. The proportion of patients with minor response (MR) was significantly higher for decitabine (DAC) than for azacitidine (AZA). There was no significant difference in hematologic improvement, ORR, CR, and PR rates between the DAC and AZA groups. Hematological toxicity included neutropenia grade 3/4 (14.0%), anemia grade 3/4 (17.0%), and thrombocytopenia grade 3/4 (22.0%). Conclusion This study showed that HMAs were effective and safe in the treatment of CMML, but large multicenter study would be needed to confirm the efficacy of HMAs for the treatment of CMML with different risk level and genetic abnormality, to support individualization treatment theoretically.

Clinical Application of Liquid Biopsy in Non-Hodgkin Lymphoma.

Non-Hodgkin lymphoma (NHL) is a common type of hematological malignant tumor, composed of multiple subtypes that originate from B lymphocytes, T lymphocytes, and natural killer cells. A diagnosis of NHL depends on the results of a pathology examination, which requires an invasive tissue biopsy. However, due to their invasive nature, tissue biopsies have many limitations in clinical applications, especially in terms of evaluating the therapeutic response and monitoring tumor progression. To overcome these limitations of traditional tissue biopsies, a technique known as "liquid biopsies" (LBs) was proposed. LBs refer to noninvasive examinations that can provide biological tumor data for analysis. Many studies have shown that LBs can be broadly applied to the diagnosis, treatment, prognosis, and monitoring of NHL. This article will briefly review various LB methods that aim to improve NHL management, including the evaluation of cell-free DNA/circulating tumor DNA, microRNA, and tumor-derived exosomes extracted from peripheral blood in NHL.

Efficacy and Safety of Ibrutinib in Central Nervous System Lymphoma: A PRISMA-Compliant Single-Arm Meta-Analysis.

BACKGROUND: Central nervous system lymphoma (CNSL) is an aggressive lymphoma. Studies investigating primary CNSL determined that the Bruton tyrosine kinase (BTK) played an important role in pathogenesis. Ibrutinib, an oral BTK inhibitor, is a new treatment strategy for CNSL. The purpose of this meta-analysis was to clarify the effectiveness and safety of ibrutinib in the treatment of CNSL. METHODS: A systematic search of PubMed, Embase, Cochrane library, Wanfang Data Knowledge Service Platform, and China National Knowledge Infrastructure databases was conducted through to 31 October 2019. Studies involving patients with CNSL who received ibrutinib that reported the overall response (OR), complete remission (CR), and partial response (PR) were included. The random-effects or fixed-effects model with double arcsine transformation was used for the pooled rates and 95% confidence intervals (CI) were determined for all outcomes. RESULTS: Eight studies including 162 patients were identified and included in the meta-analysis. The pooled OR rate after treatment with ibrutinib was 69% (95% CI, 61-79%, I2 = 47.57%, p = 0.06), while the pooled CR and PR was 52% (95% CI, 35-68%, I2 = 74.95%, p = 0.00) and 17% (95% CI, 7-30%, I2 = 67.85%, p = 0.00), respectively. Among PCNSL patients, including new diagnoses PCNSL and R/R PCNSL, the pooled OR rate was 72% (95% CI, 63-80%, I2 = 49.20%, p = 0.06) while the pooled CR and PR rates were 53% (95% CI, 33-73%, I2 = 75.04%, p = 0.00) and 22% (95% CI, 14-30%, I2 = 46.30%, p = 0.07), respectively. Common adverse events above grade 3 included cytopenia and infections. CONCLUSIONS: The ibrutinib-containing therapy was well tolerated and offered incremental benefit to patients with CNSL. However, randomized-controlled studies that directly compare efficacy and adverse events of ibrutinib are still needed. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42020218974.

Dual fluorescence nanoconjugates for ratiometric detection of reactive oxygen species in inflammatory cells.

Reactive oxygen species (ROS) are largely produced under pathological situations. To understand the etiology of disease, it is urgent to develop efficacious probes for detecting ROS. Herein, a novel nanoconjugate detection system constructed from gold clusters (AuNCs) and quantum dots (QDs) for fluorescence ratiometric-sensing ROS was reported. Upon interacting with ROS, the red emission fluorescence (645 nm from QDs) in the detection system gradually decreased, while the green fluorescence (480 nm from AuNCs) changed little. The fluorescence ratio at the 2 wavelengths (I480 nm /I645 nm ) was linearly correlated with the ROS, which could be used for the real-time ratiometric detection of ROS. The developed nanoconjugates could be applied to monitor the ROS in inflammatory cells for its ability of generating abundant ROS and uptaking ability to nanoparticles. The stimulated ROS in inflammatory cells were monitored by AuNC-QD and the results were consistent with the traditional 2', 7'-dichlorofluorescin diacetate method, confirming the reliability of the developed method. Featured with the merits of higher photostability, low background, high accuracy of ratiometric detection, the AuNC-QD conjugate demonstrated its potential to be the probe for real-time ROS detection in inflammatory cells.

Cypate-mediated thermosensitive nanoliposome for tumor imaging and photothermal triggered drug release.

It is an emerging focus to explore controlled release drug delivery systems for simultaneous cancer imaging and therapy. Herein, we synthesized a photothermal sensitive multifunctional nano-liposome drug delivery system, with doxorubicin wrapped in the hydropholic layer as the therapeutical agent and cypate doped in the hydrophobic layer as the diagnostic agent. A series of in vitro and in vivo characterization demonstrated the stability of synthesized liposome, as the DL% was 9 ± 1.5 and the EE% was 82.7 ± 2.1. And the liposome achieved the functions of target-delivery, enhanced photochemical internalized drug release, and simultaneous chemotherapy and thermal therapy, indicating that this multifunctional nano-liposome is a promising drug delivery system for tumor diagnosis and targeting therapy.

Photodynamic Therapy Induced Enhancement of Tumor Vasculature Permeability Using an Upconversion Nanoconstruct for Improved Intratumoral Nanoparticle Delivery in Deep Tissues.

Photodynamic therapy (PDT) has recently emerged as an approach to enhance intratumoral accumulation of nanoparticles. However, conventional PDT is greatly limited by the inability of the excitation light to sufficiently penetrate tissue, rendering PDT ineffective in the relatively deep tumors. To address this limitation, we developed a novel PDT platform and reported for the first time the effect of deep-tissue PDT on nanoparticle uptake in tumors. This platform employed c(RGDyK)-conjugated upconversion nanoparticles (UCNPs), which facilitate active targeting of the nanoconstruct to tumor vasculature and achieve the deep-tissue photosensitizer activation by NIR light irradiation. Results indicated that our PDT system efficiently enhanced intratumoral uptake of different nanoparticles in a deep-seated tumor model. The optimal light dose for deep-tissue PDT (34 mW/cm(2)) was determined and the most robust permeability enhancement was achieved by administering the nanoparticles within 15 minutes following PDT treatment. Further, a two-step treatment strategy was developed and validated featuring the capability of improving the therapeutic efficacy of Doxil while simultaneously reducing its cardiotoxicity. This two-step treatment resulted in a tumor inhibition rate of 79% compared with 56% after Doxil treatment alone. These findings provide evidence in support of the clinical application of deep-tissue PDT for enhanced nano-drug delivery.