The human immune system has the regulatory functions of eradicating pathogens and limiting excessive inflammation, which protect the surrounding tissue from being damaged. The immune bal-ance of self-limiting is mainly controlled by complex interactions between antigen-presenting cells ( APCs ) and T cells. However, the immune balance is destroyed in cancer, which results in immune evasion and tumor metastasis or promotes the development of drug resistance. Immune checkpoints play critical roles in the immune system. Therefore, blocking tumor immune evasion by targeting the immune checkpoints has be-come a research focus in the treatment of relapsed or refractory malignant tumors. Currently, in the studies of malignant lymphomas, some phaseⅠ/Ⅱclinical studies of immune checkpoint inhibitors have achieved sur-prising results. This review will discuss the regulation and immunotherapy of immune checkpoints in malig-nant lymphomas.

Objective:This study aimed to investigate the inhibitory effect of zoledronic acid (ZOL) alone or the combined treat-ment of ZOL and paclitaxel (PTX) on the cell growth of lung cancer cell line in vitro. Methods:The effects of different concentrations of ZOL alone, 2 nM PTX, and combined treatment of ZOL and PTX on the growth of A-549 cell line were determined using methyl thi-azolyl tetrazolium (MTT) method. The mechanism of the curative effect was analyzed by flow cytometry on the basis of apoptotic rate. AKT, phospho-AKT, ERK, phospho-ERK, and Bcl-2 expressions were determined by western blot analysis. AKT and ERK gene ex-pressions were determined by RT-PCR. Results:MTT results showed that ZOL alone could inhibit the growth of lung cancer cell line A-549 in a dose-dependent manner. The combined therapy of ZOL and PTX could inhibit cell growth. This combined treatment is more effective than the single treatment with either ZOL or PTX alone. The synergistic inhibition rate is dependent on drug sequencing. Fur-thermore, maximum inhibition was induced by sequence order, i.e., initial treatment with PTX and then with ZOL. RT-PCR results dem-onstrated that the mRNA of ERK and AKT of the group treated with PTX and then ZOL were lower than that in other treatment groups. Western blot analysis results demonstrated that the ERK and AKT levels of the treated groups were parallel in the cell line. However, the lowest phospho-ERK, phospho-AKT, and Bcl-2 levels were observed in the PTX then ZOL group. The cell lines treated with PTX alone and ZOL alone ranked second and third among the lowest results, respectively. The highest level was observed in the control group. Conclusion: The combined ZOL and PTX treatment induced the downregulation of phospho-ERK, phospho-AKT, and Bcl-2 protein expressions in RAF/MEK/ERK and PI3K/AKT signaling pathway. This pathway could be one of the synergistic antitumor mechanisms of the two drugs.

Objective:This study was conducted to evaluate and discuss the curative effect and toxicity of gemcitabine, navel-bine, and therarubicin (GNT) regimen for patients with refractory or relapsed T-cell lymphoma (TCL). Methods:A total of 69 patients with refractory or relapsed TCL treated with GNT were enrolled. The treatment protocol was set as follows:800 mg/m2 gemcitabine ad-ministered at 1 and 8 d;25 mg/m2 navelbine administered at 1 d;and 20 mg/m2 therarubicin administered at 1 d. This protocol was re-peated every three weeks. The median cycle was 4 (range:2 to 6). Results:The overall response rate was 65.2%and the achieved com-plete remission was 29.0%. Hematology toxicities were the main adverse reactions observed in all of the patients. The incidence rates of grades 1 and 2 toxicity in leukopenia or neutropenia, anemia, and thrombocytopenia were 50.7%, 33.3%, and 26.1%, respectively. Grades 3 and 4 treatment-associated toxicities were detected in 23.1%of the responding patients. One-, three-, and five-year estimated overall survival (OS) of the whole cohort were 71.7%, 47.3%, and 32.4%, respectively. The median OS was 36 months. Conclusion:GNT was effective and suitable for patients with refractory or relapsed TCL.

Objective To explore the clinical significance of plasma D-dimer level before and after chemotherapy in patients with malignant lymphoma.Methods 402 patients admitted to Tianjin Medical University Cancer Institute and Hospital and pathologically diagnosed with malignant lymphoma were retrospectively analyzed to investigate the relationship between patients' plasma D-dimer level and their clinic pathology.Meanwhile,the association between patients' plasma D-dimer level change after chemotherapy and therapeutic effect was also evaluated.Results The median plasma D-dimer levels in malignant lymphoma patients (734.51ng/ml) was distinctly higher than that in normal population (＜500 ng/ml).The plasma D-dimer level had obvious correlation with age,pathological type,level of LDH,clinical stage,B symptom and IPI score.The level of plasma D-dimer in positive response group significantly decreased from 949.40 ng/ml to 499.88 ng/ml after chemotherapy (P ＜ 0.05),whereas that in the negtive response group significantly increased from 611.09 ng/ml to 899.76 ng/ml (P ＜ 0.05).Conclusion The level of plasma D-dimer may provide the basis for evaluating the chemotherapeutic effect in patients with malignant lymphoma.

Anaplastic lymphoma kinase (ALK)-positive diffuse large B-cell lymphoma (DLBCL) is a rare and distinct variant of DLBCL. It is classified as a unique subtype of DLBCL in the 2008 WHO classification of lymphomas. No standard and effective therapeutic regi-men is available for ALK+DLBCL because it shows a more aggressive clinical course and frequent relapse. Therefore, a standardized and individualized treatment is needed to benefit more patients diagnosed with ALK+DLBCL through a multiple disciplinary team. This arti-cle presents a case of an ALK+DLBCL patient who relapsed after transplantation and was successfully treated with the ALK kinase inhibi-tor Crizotinib.

Objective:To detect Bruton tyrosin kinase (BTK) expression in patients with mantle cell lymphoma (MCL) and analyze its correlation with clinical features and prognosis. Methods:A total of 32 cases of MCL tissues and 10 cases of benign lymph nodes were sampled and stained with immunohistochemical (IHC) staining. Clinical data of these patients were analyzed using SPSS 17.0. Results:BTK was positively expressed in MCL and normal lymphoid tissues and was more strongly expressed in MCL tissue than in normal lym-phoid tissue. Moreover, BTK expression level was correlated with Ki-67 and MIPI scores. Prognosis analysis showed that patients with high BTK expression exhibited shorter progression-free survival (PFS) than patients with low expression levels (P=0.030);however, no significant difference in overall survival (OS) was observed (P=0.073). Single-factor analysis of PFS showed that age≥65 years, ECOG score≥2, bone marrow involvement, strongly positive BTK expression, Ki-67>30%, and MIPI score≥6 are poor prognostic factors for patients with MCL. Only MIPI score≥6 is considered an independent poor prognostic factor in the multivariate analysis. Conclusion:BTK is strongly and positively expressed in patients with MCL, and its expression level is correlated with Ki-67 and MIPI scores. Patients with high-level BTK expression usually exhibit shorter PFS than those with low-level BTK expression;however, owing to short follow-up time and limited sample size, high-level BTK expression cannot be considered an independent poor prognostic factor for PFS.

Lymphoma refers to a group of heterogeneous malignancies originating from the reticuloendothelial and lymphatic systems. The clinical manifestations, treatment strategies, and disease outcomes of different types of lymphoma considerably vary. Recent developments in high-throughput sequencing technologies have enhanced understanding of the pathogenesis and molecular stratification of lymphoma. In the era of new drugs, precise stratification and targeted drug selection can not only improve the prognosis of patients with lymphoma but also reduce the toxic side effects of traditional chemotherapy, ultimately achieving the accurate diagnosis and individualized treatment of tumors. This article reviews the research progress of molecular diagnosis and individualized treatment of different lymphoma subtypes and lymphoma-related research in important meetings such as ASCO, EHA, and ICML in 2023.

The immune checkpoint inhibitors (ICI) represented by programmed death 1/programmed death ligand 1 (PD-1/PD-L1) antibody opened a new era of immunotherapy. However, PD-1/PD-L1 inhibitors have not been approved for indications in the field of malignant lymphoma except for classic Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma. Researchers have actively explored different lymphoma subtypes with single drugs or combined therapy, and achieved certain effect initially. The latest advances of ICI in cHL, B-cell non-Hodgkin lymphoma and T-cell lymphoma and the management of immune-related adverse events are briefly introduced in this paper.

Chimeric antigen receptor T-cell (CAR-T) is one of the effective methods for treatment of lymphoma. The way to improve the efficacy and control the reverse reactions still needs to be explored further. Several clinical trials have indicated CAR-T could have favorable effects on the B-cell lymphoma patients with controllable reverse reactions. However, antigen loss is a major factor for the acquired resistance to CD19 CAR-T therapy. Other clinical researches, including CD22 for treatment of B-cell lymphoma and CD30 for Hodgkin lymphoma, have increased the efficacy of CAR-T. Moreover, lots of trials have suggested that the patients who received cyclophosphamide or bendamustine plus fludarabine lymphodepletion can get a high effective rate.

Cancer immunotherapy uses the host′s immune system to mobilize immune cells to rec-ognize and eventually eliminate cancer cells .At present, studies in terms of cancer immunotherapy mainly focus on programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) antibody, cytotoxic T-lymphocyte-associated protein 4 ( CTLA-4 ) antibody, chimeric antigen receptor T-cell immunotherapy (CAR-T), T cell receptor Immunotherapy (TCR-T), etc.Despite the fact that cancer immunotherapies elicit unprecedented durable responses in clinical therapy , they appear to be ineffective to some patients .In addition, some responders relapse and show resistance to immunotherapies even if their symptoms are re -lieved for a time .Resistance to cancer immunotherapy can be categorized into primary , adaptive and ac-quired, which can occur in every stage during the process of anti-tumor response.In this review, we discuss the known mechanisms of resistance and provide a rationale for the use of combination therapy to overcome resistance.