Tumor microenvironment and CAR-T cell immunotherapy in B-cell lymphoma.

Chimeric receptor antigen T cell (CAR-T cell) therapy has demonstrated effectiveness and therapeutic potential in the immunotherapy of hematological malignancies, representing a promising breakthrough in cancer treatment. Despite the efficacy of CAR-T cell therapy in B-cell lymphoma, response variability, resistance, and side effects remain persistent challenges. The tumor microenvironment (TME) plays an intricate role in CAR-T cell therapy of B-cell lymphoma. The TME is a complex and dynamic environment that includes various cell types, cytokines, and extracellular matrix components, all of which can influence CAR-T cell function and behavior. This review discusses the design principles of CAR-T cells, TME in B-cell lymphoma, and the mechanisms by which TME influences CAR-T cell function. We discuss emerging strategies aimed at modulating the TME, targeting immunosuppressive cells, overcoming inhibitory signaling, and improving CAR-T cell infiltration and persistence. Therefore, these processes enhance the efficacy of CAR-T cell therapy and improve patient outcomes in B-cell lymphoma. Further research will be needed to investigate the molecular and cellular events that occur post-infusion, including changes in TME composition, immune cell interactions, cytokine signaling, and potential resistance mechanisms. Understanding these processes will contribute to the development of more effective CAR-T cell therapies and strategies to mitigate treatment-related toxicities.

Immune microenvironment associated with the severity of Langerhans cell histiocytosis in children.

The aim of this study is to investigate the clinical potential of immune microenvironment in peripheral blood for the severity and therapeutic efficacy of Langerhans cell histiocytosis (LCH). A total of 200 newly diagnosed children with LCH during 10 years was enrolled for analysis in this study. Peripheral blood samples were acquired from patients before treatment in our hospital and immune indicators were detected by a four-color flow cytometer. The levels of CD3 + CD8 + T cell, CD3 + CD4 + HLA-DR + T cell, CD3 + CD8 + HLA-DR + T cell, IL-4, IL-6, IL-10 and IFN-γ in peripheral blood were markedly elevated in LCH patients vs. healthy controls. Patients with multiple system with risk organ involvement (MS-RO + ) exhibited higher levels in IL-6, IL-10 and IFN-γ, CD3 + CD4 + HLA-DR + T cell and CD3 + CD8 + HLA-DR + T cell, compared to those in patients without risk organ involvement (RO-). Patients who responded effectively to initial chemotherapy showed significantly lower levels of IL-4, IL-10, IFN-γ, CD3 + CD4 + HLA-DR + T cell and CD3 + CD8 + HLA-DR + T cell in peripheral blood, compared to those in patients who did not respond to initial chemotherapy. Furthermore, univariate analyses were performed that the higher levels of CD3 + CD4 + HLA-DR + T cells, CD3 + CD8 + HLA-DR + T cells and IL-10 in peripheral blood were related to non-response in LCH after initial chemotherapy. Immune microenvironment in peripheral blood may be associated with the severity and treatment response of LCH. The levels of CD3 + CD4 + HLA-DR + T cells, CD3 + CD8 + HLA-DR + T cells and IL-10 may be biomarkers to predict treatment response of LCH patients.

Flow cytometry assessment of reactive T-cells distinguishes classic Hodgkin lymphoma from benign lymphadenopathy in children.

BACKGROUND: Detection of classic Hodgkin lymphoma (cHL) neoplastic cells using flow cytometric immunophenotyping (FCI) remains limited. We hypothesized that characterization of the reactive infiltrates could assist in diagnosing cHL in children. METHODS: FCI using four-color staining approaches was performed on 156 lymph node specimens with the following histopathologic diagnoses: cHL (25 cases), reactive lymphoid hyperplasia (RLH, 44 cases), and non-Hodgkin lymphoma (87 cases). RESULTS: The overall concordance of FCI data with the histopathologic results of these cases was 81.4%. A reactive expansion of T-cells with increased expression of CD45RO was present in the reactive infiltrate of cHL (CD45RO/CD3, 67.5%) and Epstein-Barr virus (EBV) infected RLH (62.7%) but not in EBV-negative RLH (28.0%). The mean fluorescence intensity (MFI) of CD7 was higher for cHL and differed significantly from EBV-positive RLH (138.5 vs. 63.8). A proposed diagnostic algorithm markedly elevated the overall concordance rate from 81.4% to 97.4%. CONCLUSIONS: Immunophenotyping the reactive infiltrate of lymphoid tissue using flow cytometry is a reliable supplement to histopathology for the rapid diagnosis of pediatric cHL.

Serum suPAR levels help differentiate steroid resistance from steroid-sensitive nephrotic syndrome in children.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) has been regarded as a permeability factor in proteinuria, though its role in primary nephrotic syndrome remains to be elucidated further. METHODS: Plasma samples and clinical information from 176 children with primary nephrotic syndrome were collected and concentrations of suPAR were measured. We evaluated the correlation between suPAR concentrations and clinical features, and the value of the plasma suPAR level in predicting steroid-resistant nephrotic syndrome (SRNS). RESULTS: There is a significant difference in plasma suPAR concentration between SRNS and steroid-sensitive nephrotic syndrome (SSNS) groups (3,744.1 ± 2,226.0 vs. 2,153.5 ± 1,167.0, p < 0.05). The area under the curve (AUC) was 0.80, with p < 0.001 for the receiver operating characteristic (ROC) curve analysis using suPAR to predict SRNS. The suspicious range for predicting SRNS was estimated to be 1,907.0 pg/ml to 3,043.5 pg/ml (χ(2) = 14.775, p = 0.001). CONCLUSIONS: From ROC curve analysis, we demonstrated the significance of the suPAR level in predicting SRNS with a high specificity but low sensitivity. However, the clinical value of suPAR to predict steroid resistance and guide therapy remains to be investigated further.

Seroprevalence of Epstein-Barr virus infection in children during the COVID-19 pandemic in Zhejiang, China.

Aim: We aimed to investigate the seroprevalence of Epstein-Barr virus (EBV) infection in children before and during the COVID-19 pandemic. Methods: All children admitted to the Children's Hospital Affiliated to Zhejiang University from January 2019 to December 2021 with suspected EBV-associated disease and EBV antibodies were detected by a two-step indirect method of chemiluminescence technology. A total of 44,943 children were enrolled in this study. The seroprevalence of EBV infections was compared from January 2019 to December 2021. Results: The total seropositive rate of EBV infections was 61.02% between January 2019 and December 2021, and the seropositive trend decreased year by year. The total number of seropositive EBV infections in 2020 was reduced by 30% compared to that in 2019. In particular, nearly 30% and 50% reductions in the number of acute EBV infections and EBV reactivations or late primary infections from 2019 to 2020 were found, respectively. The number of acute EBV infections in children aged 1-3 years and EBV reactivation or late primary infection in children aged 6-9 years in 2020 sharply dropped by approximately 40% and 64% compared to that in 2019. Conclusions: Our study further demonstrated that the prevention and control measures for COVID-19 in China had a certain effect on containing acute EBV infections and EBV reactivations or late primary infections.

The relationship between the level of serum creatinine, modified diet and renal disease formula, Cockcroft-Gault formula, and renal tubulointerstitial lesion.

OBJECTIVE: This study investigated the relationship between the levels of serum creatinine (SCr), the estimated glomerular filtration rate (eGFR), and the degree of tubulointerstitial injury. METHODS: A total of 511 patients of Zhongshan hospital in China were hospitalized due to physical abnormalities and diagnosed with kidney disease by renal biopsy. The clinical and pathological data were retrospectively analyzed. The level of SCr was determined in all patients, and the eGFR was calculated with modification of diet in renal disease and Cockcroft-Gault formulae, whereas the renal histopathology was quantified according to the Katafuchi semi-quantitative standards. RESULTS: With the aggravation of tubulointerstitial injury, SCr level increased and eGFR decreased gradually. The degree of tubulointerstitial lesion showed a positive correlation with SCr level and negative correlation with Cockcroft-Gault formula and modification of diet in renal disease (r = 0.627, -0.649, -0.626; p < 0.001). When the SCr was in the normal range, above 90% of the patients had various degrees of tubulointerstitial damage and 12.2% of the patients had moderate-to-severe tubulointerstitial lesions. The correlation between SCr level and tubulointerstitial damage became weak. CONCLUSIONS: The morphologic changes of tubulointerstitium are closely linked with renal function, but incompletely parallel. SCr in the abnormal range could be used to diagnose tubulointerstitial injury well. However, when the level of SCr was in the so-called normal range, eGFR by the modification of diet in renal disease or Cockcroft-Gault formula may be preferred to assess renal tubulointerstitial injury.

Epidemiological Study on Mycoplasma pneumoniae and Chlamydia pneumoniae Infection of Hospitalized Children in a Single Center During the COVID-19 Pandemic.

Background: Since the outbreak of COVID-19, a series of preventive and control measures in China have been used to effectively curb the spread of COVID-19. This study aimed to analyze the epidemiological characteristics of Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP) in hospitalized children with acute respiratory tract infection during the COVID-19 pandemic. Methods: MP IgM antibody and CP IgM antibody were detected in all hospitalized children due to acute respiratory tract infection in the Children's Hospital Affiliated to Zhejiang University from January 2019 to December 2020. These data were compared between 2019 and 2020 based on age and month. Results: The overall detection rate of MP and CP in 2020 was significantly lower than that in 2019 (MP: 21.5% vs 32.9%, P<0.001; CP: 0.3% vs 0.9%, P<0.001). This study found a 4-fold reduction in the number of children positive for MP and a 7.5-fold reduction in the number of children positive for CP from 2019 to 2020. The positive cases were concentrated in children aged >1 year old. In 2019, the positive rate of MP was detected more commonly in children 3 years of age or older than in younger children. In 2020, the higher positive rate of MP reached a peak in the 3- to 6-year age group (35.3%). CP was detected predominantly in children aged 6 years older in 2019 and 2020, with positive rates of 4.8% and 2.6%, respectively. Meanwhile, the positive rates of MP in 2019 were detected more commonly in July, August and September, with 47.2%, 46.7% and 46.3%, respectively. Nevertheless, the positive rates of MP from February to December 2020 apparently decreased compared to those in 2019. The positive rates of CP were evenly distributed throughout the year, with 0.5%-1.6% in 2019 and 0.0%-2.1% in 2020. Conclusions: A series of preventive and control measures for SARS-CoV-2 during the COVID-19 pandemic can not only contain the spread of SARS-CoV-2 but also sharply improve the infection of other atypical pathogens, including MP and CP.

High percentages of peripheral blood T-cell activation in childhood Hodgkin's lymphoma are associated with inferior outcome.

The aims of this study were to investigate the activation of T lymphocytes in peripheral blood from children with Hodgkin's lymphoma (HL) and explore their roles for prognosis in HL. A cohort of 52 newly diagnosed children with HL during the past 10 years was enrolled for analysis in this study. Peripheral blood samples of the patients were acquired before treatment in our hospital, and T-cell subsets were detected by a four-color flow cytometer. CD4+ T cells and CD4+/CD8+ T-cell ratio decreased significantly in patients with HL vs. healthy controls. CD8+ T cells, CD3+CD4+HLA-DR+ T cells, and CD3+CD8+HLA-DR+ T cells increased markedly in patients with HL vs. healthy controls. Receiver-operating characteristic (ROC) curve analysis showed that CD3+CD4+HLA-DR+ T cells and CD3+CD8+HLA-DR+ T cells each distinguished the high-risk group from the low- and intermediate-risk group. The area under the ROC curve for predicting high-risk patients was 0.795 for CD3+CD4+HLA-DR+ T cell and 0.784 for CD3+CD8+HLA-DR+ T cell. A comparison of peripheral blood T-cell subsets that responded differently to therapy showed significantly higher percentages of CD3+CD4+HLA-DR+ T cells and CD3+CD8+HLA-DR+ T cells in patients who achieved complete remission compared to those who did not achieve complete remission. In addition, high percentages of both CD3+CD4+HLA-DR+ T cells and CD3+CD8+HLA-DR+ T cells were associated with inferior event-free survival. Peripheral immune status may be related to disease severity in HL. CD3+CD4+HLA-DR+ T cells and CD3+CD8+HLA-DR+ T cells may be a novel indicator for risk stratification of HL and may be an independent risk factor for inferior outcome in childhood HL.

IgG4-associated tubulointerstitial nephritis: two case reports and a literature review.

IgG4-related systemic disease (IgG4-RSD) is an autoimmune disease that includes a wide variety of lesions. IgG4-RSD is characterized by high levels of serum IgG4, abundant levels of IgG4-positive plasma cells and T-lymphocyte infiltration in various organs. Tubulointerstitial nephritis (TIN) is a major finding when the kidneys are involved and is effectively treated with corticosteroid therapy. We herein describe two cases of IgG4-related TIN. Such cases have rarely been reported in China.