Objective This study investigated the regulatory effect of high mobility group protein B1 (HMGB1) in the peripheral blood of patients with primary immune thrombocytopenia (ITP) on myeloid dendritic cells (mDC) and Th17/regulatory T cells (Treg) balance. Methods The study enrolled 30 newly diagnosed ITP patients and 30 healthy controls.Flow cytometry was used to measure the proportion of mDC, Th17, and Treg cells in the peripheral blood of ITP patients and healthy controls. ELISA was conducted to quantify the serum levels of HMGB1, interleukin 6 (IL-6), IL-23, IL-17, and transforming growth factor β(TGF-β). The mRNA levels of retinoic acid-related orphan receptor γt(RORγt) and forehead box P3(FOXP3) were detected by real-time PCR. The correlation between the abovementioned cells, cytokines, and platelet count was assessed using Pearson linear correlation analysis. Results The proportion of Th17 cells and the expression levels of HMGB1, IL-6, IL-23, IL-17 and the level of RORγt mRNA in the peripheral blood of ITP patients were higher than those in healthy controls. However, the Treg cell proportion and TGF-β level were lower in ITP patients than those in healthy controls. In patients with ITP, the proportion of mDC and the level of FOXP3 mRNA did not show significant changes. The proportion of mDC cells was significantly correlated with the expression of IL-6 and IL-23. Moreover, the expression of HMGB1 showed a significant correlation with the expression of mDC, IL-6, IL-23, RORγt mRNA, and IL-17. Notably, both the proportion of mDC cells and the expression of HMGB1 were negatively correlated with platelet count. Conclusion The high expression of HMGB1 in peripheral blood of ITP patients may induce Th17/Treg imbalance by promoting the maturation of mDC and affecting the secretion of cytokines, thereby potentially playing a role in the immunological mechanism of ITP.

Introduction Sovleplenib, a novel spleen tyrosine kinase (SYK) inhibitor, demonstrated promising safety and efficacy in primary immune thrombocytopenia (ITP) patients (pts) in phase 1b/2 trials, with these favorable outcomes subsequently confirmed in double-blinded phase 3 ESLIM-01 study (NCT05029635). This final analysis of ESLIM-01 sought to report the long-term efficacy and safety of sovleplenib in adult pts with ITP. Methods In ESLIM-01, adult pts with chronic primary ITP were randomized 2:1 to receive oral sovleplenib 300 mg once daily or placebo for 24 weeks. Pts who completed 24 weeks double-blinded treatment or demonstrating non-response within initial 12 weeks in ESLIM-01 were enrolled in an open-label extension sub-study (sovleplenib 300 mg once daily). Long-term efficacy and safety evaluations encompassed all participants who received ≥1 dose of sovleplenib (all Sov group), including placebo-crossover subjects (P-Sov group). Main efficacy endpoints included durable response in long-term follow up (PLT ≥ 50×10/L at ≥ 2 of 3 any 12-week consecutive protocol-defined visits after receiving sovleplenib for 12 weeks, not impacted by rescue treatment) and complete response rate (the proportion of pts with at least one PLT ≥100×10⁹/L under sovleplenib treatment, not impacted by rescue treatment). Results As of the March 31, 2025 data cutoff, 179 pts (all Sov) received at least one dose of sovleplenib treatment. Of these, 126 pts received sovleplenib initially during double-blinded period, while 53 pts (P-Sov) switched from placebo. The two groups were comparable in terms of baseline characteristics. At baseline, the median age in all Sov group was 43.0 years (range, 18.0-72.0) and 41.0 years (range, 18.0-69.0) in P-Sov group. The median platelet counts at baseline were 12.0×10⁹/L in both the all Sov and P-Sov groups. The proportion of pts who received concomitant anti-ITP medication at baseline was 30.7% in all Sov group and 26.4% in P-Sov group. 110 pts (61.5%) in all Sov group and 34 pts (64.2%) in P-Sov group achieved durable response in long-term follow up, respectively. The complete response rate was 67.6% in all Sov group and 68.0% in P-Sov group. The maximum continuous duration of PLT ≥ 50×10⁹/L (or≥ 30×10⁹/L) was 25.9 weeks (or 37.0 weeks) in all Sov group, and 20.4 weeks (or 35.6 weeks) in P-Sov group. Cumulative duration of PLT ≥ 50×10⁹/L (or≥ 30×10⁹/L) in all Sov group was 66.7 weeks (or 77.0 weeks) and 50.4 weeks (or 68.1 weeks) in P-Sov group. 16 pts (8.9%) reduced/discontinued concomitant anti-ITP medication in all Sov group and 5 pts (9.4%) in P-Sov group. The median duration (min, max) of exposure was 604.0 days (14.0, 1093.0) in all Sov group and 617.0 days (14.0, 1093.0) in P-Sov group. Treatment-related adverse events (TRAEs) were reported in 87.2% (156/179) of patients in all Sov group and 88.7% (47/53) in P-Sov group. The majority of AEs were Grade 1-2. The long-term safety profiles were consistent with those in sovleplenib group in ESLIM-01. The most common (>2.0%) TRAEs of grade ≥3 in all Sov group were alanine aminotransferase increased (4 [2.2%]), neutrophil count decreased (5 [2.8%]); for P-Sov group, it was aspartate aminotransferase increased (2 [3.8%]). Major bleeding events (ISTH criteria) occurred in 2.2% of all Sov group and 3.8% of P-Sov group. The study had no mortality events. Conclusions Long-term treatment with sovleplenib demonstrated clinically meaningful and sustained platelet responses in adult pts with ITP in China, while maintaining a tolerable safety profile. These findings support sovleplenib as a promising therapeutic option for adult pts with chronic primary ITP.Keywords: SYK, Immune thrombocytopenia (ITP), Sovleplenib, ESLIM-01

Introduction Sovleplenib, a novel spleen tyrosine kinase (SYK) inhibitor, showed a clinically meaningful sustained platelet response with a tolerable safety profile in adults with immune thrombocytopenia (ITP) in a randomized, double-blind, placebo-controlled phase 3 study (ESLIM-01) in China1. Here we reported the long-term safety and efficacy data of ESLIM-01 extension stage in a follow-on, open-label sub-study (NCT05029635). Methods ESLIM-01 enrolled adults with chronic primary ITP who failed to ≥1 prior ITP treatment, and the mean platelet counts (PLT) < 30×10⁹/L at 3 screening visits. Eligible patients (pts) were randomized (2:1) to receive sovleplenib 300 mg orally once daily (QD), or placebo for 24 weeks (wks). Pts who completed 24 wks of treatment, or did not respond during the first 12 wks of treatment in ESLIM-01 could be enrolled in an open-label sub-study to receive sovleplenib 300mg QD treatment. The long-term safety and efficacy were assessed in all treated pts with at least one dose of sovleplenib (all Sov group), including the cross-over pts from placebo (P-Sov group). The main efficacy endpoint of durable response was defined as: PLT ≥50 × 10⁹/L at ≥4 of 6 scheduled visits during wks 14 to 24 in ESLIM-01 or, PLT ≥50×10⁹/L at ≥ 2 of 3 protocol-defined visits during the second 12 wks of 24 wks in the open-label sub-study. Long-term durable response was defined as after receiving sovleplenib for 12 wks, PLT ≥ 50×109/L at ≥ 2 of 3 any 12-week consecutive protocol-defined visits. Overall response was defined as at least one PLT ≥50 × 10⁹/L under sovleplenib treatment. Any PLT impacted by rescue therapy was not considered for efficacy endpoint derivation. Results At data cutoff date (Jan 31, 2024), a total of 179 pts (all Sov) were treated with at least one dose of sovleplenib. Among them, 126 pts initially received sovleplenib and 53 pts (P-Sov) initially received placebo in ESLIM-01. 99 (55.3%) of 179 pts in all Sov group, and 28 (52.8%) of 53 pts in P-Sov group were still on the treatment in the sub-study. The median duration (min, max) of exposure was 56.6 wks (2.0, 105.3) in all sov group and 52.3 wks (2.0, 102.9) in P-Sov group. Baseline characteristics were generally similar between the two groups. The median age was 43.0 years in all Sov group and 41.0 years in P-Sov group, median duration from the first PLT reduction to the first sovleplenib dose was 7.7 years in all Sov group and 8.0 years in P-Sov group, and pts in both groups had a median of 4.0 lines of prior medications for ITP, including 72.6% and 67.9% of patients who received prior TPO/TPO-RA treatment in all Sov group and P-Sov group, respectively. An overall response was achieved by 145 of 179 pts (81.0%) in all Sov group, and 44 of 53 pts (83.0%) in P-Sov group. 92 pts (51.4%) in all Sov group, and 23 pts (43.4%) in P-Sov group achieved durable response, respectively. The durable response rates were highly consistent with that in sovleplenib group (48%) in ESLIM-011. Long-term durable response rate was 59.8% in all Sov group and 64.2% in P-Sov group. The median cumulative duration of PLT ≥50 × 10⁹/L (or ≥30 × 10⁹/L) was 38.9 wks (or 48.2 wks) in all Sov group, and 35.1 wks (or 43.4 wks) in P-Sov group. 22.9% of pts in all Sov group and 18.9% of pts in P-Sov group received rescue therapy. Compared to the data in ESLIM-01 (22% of sovleplenib vs. 35% of placebo)1, long-term treatment did not increase the patient proportion for rescue therapy. The incidence of major bleeding events per ISTH criteria in all Sov group was 2.2%, consistent with that of sovleplenib group in ESLIM-01. The most frequent (>1.0%) TRAEs of grade 3 or higher in all Sov group were alanine aminotransferase increased (4 [2.2%]), neutrophil count decreased (3 [1.7%]), gamma-glutamyltransferase increased (3 [1.7%]), aspartate aminotransferase increased (2 [1.1%]), and hypertension (2 [1.1%]); for P-Sov group, they were 1 (1.9%), 0, 1 (1.9%), 2 (3.8%), and 0, respectively. There were no deaths in ESLIM-01 extension stage. Conclusions Long-term treatment with sovleplenib was effective in increasing and maintaining platelet count with well tolerated safety in adults with chronic primary ITP in China. No new safety signals were identified. Key words: sovleplenib, immune thrombocytopenia, ITP, SYK inhibitor, SYK References: Yu Hu, et al. Lancet Haematol. 2024 Jun 13: S2352-3026(24)00139-X.

RATIONALE:Primary plasma cell leukemia is a rare and highly aggressive malignancy of the blood system, with rapid disease progression and a high early mortality rate. Currently, there is no recognized therapeutic regimen, leading to the adoption of strategies typically utilized for multiple myeloma, which, however, exhibit limited efficacy. Selinexor is considered effective in treating relapsed/refractory multiple myeloma, but there are currently no reports on its application in primary plasma cell leukemia. Here, we reported a case of primary plasma cell leukemia with multiple high-risk genetic factors (including 1q21+, 17p-, and 13q-) who received a chemotherapy regimen including selinexor, pomalidomide, and dexamethasone. PATIENT CONCERNS:This case was a 58-year-old male presenting with lower back pain, abdominal pain, and various systemic symptoms. DIAGNOSES:The initial diagnosis of intestinal obstruction at a local hospital was followed by a referral to our emergency department due to abnormal blood test results indicative of a hematologic disorder. Further investigations confirmed a rare diagnosis of primary plasma cell leukemia of the IgA-k light chain subtype. INTERVENTIONS:The patient was promptly treated with a chemotherapy regimen comprising selinexor, pomalidomide, and dexamethasone in addition to supportive care. OUTCOMES:Subsequent assessments showed a significant response to treatment, with improvement in symptoms, normalization of blood parameters, and achievement of very good partial response. However, due to financial constraints, the patient declined hematopoietic stem cell transplantation and eventually opted to discontinue treatment, leading to disease progression. LESSONS:The combination of selinexor with pomalidomide and dexamethasone has shown good efficacy in primary plasma cell leukemia with high-risk genetic abnormalities. Our case may provide evidence for developing an effective selinexor-based regimen for treating primary plasma cell leukemia with high-risk genetic abnormalities.

Background Sovleplenib, a novel spleen tyrosine kinase (SYK) inhibitor, showed promising safety and activity in patients with primary immune thrombocytopenia in a phase 1b/2 trial. We aimed to evaluate the efficacy and safety of sovleplenib in patients with chronic primary immune thrombocytopenia. Methods This randomised, double-blind, placebo-controlled, phase 3 trial (ESLIM-01) was done in 34 clinical centres in China. Eligible patients, aged 18-75 years, had chronic primary immune thrombocytopenia, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and received one or more previous treatments. Patients were randomly assigned (2:1) to receive oral sovleplenib or placebo, 300 mg once daily, for 24 weeks. Randomisation was stratified by baseline platelet counts, previous splenectomy, and concomitant treatment for anti-immune thrombocytopenia at baseline. The primary endpoint was durable response rate (proportion of patients with a platelet count of >= 50 x 10(9)/L on at least four of six scheduled visits between weeks 14 and 24, not affected by rescue treatment) assessed by intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT05029635, and the extension, open- label phase is ongoing. Findings Between Sept 29, 2021, and Dec 31, 2022, 188 patients were randomly assigned to receive sovleplenib (n=126) or placebo (n=62). 124 (66%) were female, 64 (34%) were male, and all were of Asian ethnicity. Median previous lines of immune thrombocytopenia therapy were 40, and 134 (71%) of 188 patients had received previous thrombopoietin or thrombopoietin receptor agonist. The primary endpoint was met; durable response rate was 48% (61/126) with sovleplenib compared with zero with placebo (difference 48% [95% CI 40-57]; p<00001). The median time to response was 8 days with sovleplenib compared with 30 days with placebo. 125 (99%) of 126 patients in the sovleplenib group and 53 (85%) of 62 in the placebo group reported treatment-emergent adverse events (TEAEs), and most events were mild or moderate. Frequent TEAEs of grade 3 or higher for sovleplenib versus placebo were platelet count decreased (7% [9/126] vs 10% [6/62]), neutrophil count decreased (3% [4/126] vs 0% [0/62]), and hypertension (3% [4/126] vs 0% [0/62]). Incidences of serious TEAEs were 21% (26/126) in the sovleplenib group and 18% (11/62) in the placebo group. There were no deaths in the study. Interpretation Sovleplenib showed a clinically meaningful sustained platelet response in patients with chronic primary immune thrombocytopenia, with a tolerable safety profile and improvement in quality of life. Sovleplenib could be a potential treatment option for patients with immune thrombocytopenia who received one or more previous therapy.

Objective:QL0911, a recombinant human thrombopoietin mimetic peptide-Fc fusion protein, is a romiplostim (Nplate®) biosimilar used to treat primary immune thrombocytopenia (ITP). This phase III study aimed to assess the efficacy and safety of QL0911 in adult patients with chronic primary ITP over a 24-week treatment period. Methods:We conducted a double-blind, placebo-controlled, phase III study in patients diagnosed with primary ITP for at least 12 months who had received at least one first-line ITP treatment with no response or recurrence after treatment, or who relapsed after splenectomy at 44 sites in China. Patients were randomly allocated (2:1 ratio) to QL0911 or placebo injection subcutaneously once weekly at an initial dose of 1 μg/kg for 24 weeks. The doses were adjusted to maintain the target platelet counts from 50 × 109/L to 200 × 109/L. Patients and investigators were blinded to the assignment. The primary endpoints were the proportion of patients who achieved a durable platelet response at week 24 (platelet count, ≥ 50 × 109/L during 6 of the last 8 weeks of treatment) and safety. The study was registered at ClinicalTrials.gov (NCT05621330). Results:Between October 2019 and December 2021, 216 patients were randomly assigned (QL0911,144; placebo,72). A durable platelet response was achieved by significantly more patients in the QL0911 group (61.8%, 95% CI: 53.3-69.8; P < 0.0001) than in the placebo group (0%). The mean duration of platelet responses was 15.9 (SE: 0.43) weeks with QL0911, and 1.9 (SE:0.26) week with placebo. Consistent results were achieved in subgroup analyses categorized by baseline splenectomy status (yes/no), concomitant ITP treatment (yes/no), and baseline platelet count (≤ 10 × 109/L, > 10 × 109/L, ≤ 20 × 109/L, > 20 × 109/L, and < 30 × 109/L). The incidence of TEAEs was comparable between the QL0911 and the placebo groups (91.7% and 88.9%, respectively). The most common adverse events overall were ecchymosis (28.5% for QL0911 vs. 37.5% for placebo), upper respiratory tract infections respiratory tract infections (31.9% for QL0911 vs. 27.8% for placebo), and gingival bleeding (17.4% for QL0911 vs. 26.4% for placebo). Conclusion:QL0911 was well-tolerated and increased and maintained platelet counts in adults with ITP. QL0911, a biosimilar to romiplostim (Nplate®), may be a novel treatment option for patients with ITP who have failed or relapsed from first-line treatment in China. Ongoing studies will provide further data on long-term efficacy and safety in such patient populations.

This study is to investigate the role of follicular regulatory T (Tfr) cells/follicular helper T (Tfh) cells imbalance in adult patients with primary immune thrombocytopenia (ITP). Totally, 40 cases of primary ITP patients and 30 healthy controls were enrolled. Blood samples were collected from ITP patients (pre- and post-therapy) and controls. Flow cytometry was used to detect the proportion of Tfr and Tfh cells in peripheral blood. Real-time quantitative polymerase chain reaction (PCR) was performed to detect the mRNA expression levels of FOXP3, BCL-6, and BLIMP-1. Enzyme-linked immunosorbent assay (ELISA) was conducted to detect interleukin (IL)-10 and IL-21 levels. Spearman's correlation was used for correlation analysis. Compared with control, Tfr cell proportion, FOXP3 mRNA, and IL-10 were significantly decreased in the pre-therapy ITP group, but were significantly increased post-therapy. Tfh cell proportion, BCL-6 mRNA, and IL-21 were increased, while BLIMP-1 mRNA was decreased, in the pre-therapy ITP group than the control group. These effects were reversed in the post-therapy ITP group. Moreover, the Tfr/Tfh ratio was decreased in the pre-therapy ITP group than control group, whereas was increased in the post-therapy ITP group than the pre-therapy ITP group. Furthermore, Tfr cell proportion, FOXP3 mRNA, IL-10, and Tfr/Tfh ratio were positively correlated with the platelet count (PLT) in the ITP pre-therapy group. In addition, Tfh cell proportion, BCL-6 mRNA, and IL-21 were negatively correlated with the PLT, while BLIMP-1 mRNA was positively correlated with the PLT. Conclusively, Tfr cell proportion in peripheral blood is decreased and Tfh cell proportion is increased, leading to unbalanced Tfr/Tfh ratio in ITP patients pre-therapy. The imbalance of Tfr/Tfh is recovered post-therapy, suggesting that the Tfr and Tfh cells may be involved in ITP pathogenesis. The abnormal expression of FOXP3, BCL-6, and BLIMP-1 mRNA and the changes in IL-10 and IL-21 levels may be related to the imbalance of Tfr/Tfh.

Objectives: We aimed to investigate relationships of platelet glycoprotein (GP) specific antibody with therapeutic efficacy of high-dose dexamethasone (HD-DXM) and bleeding score in primary immune thrombocytopenia (ITP) adults. Methods: A retrospective study was carried out to analyze relationships of polymorphism of GP specific antibody with initial therapeutic efficacy of HD-DXM and bleeding score of newly diagnosed ITP adults between 1 June, 2016 and 31 January, 2020. Results: 59 patients were involved in the study, with 33 cases of responders and 26 cases of non-responders between June 2016 and January 2020. At admission, there were 31 (52.5%) GP antibody-positive patients. Initial therapy of HD-DXM was effective for 78.6% GP antibody-negative patients and 35.5% GP antibody-positive patients, with a better therapeutic efficacy in patients with anti-GP Ib/IX antibody or anti-GP IIb/IIIa antibody but not in those with anti-GP Ib/IX antibody plus anti-GP IIb/IIIa antibody. Notably, therapeutic efficacy is much worse for minority (Uyghur) patients compared with corresponding Han patients. Similarly, it was much lower in GP antibody-positive patients compared with corresponding negative ones at low and medium bleeding score, with no response in GP antibody-positive patients at high bleeding score. Furthermore, there was a moderate negative correlation between therapeutic efficacy and GP-specific antibody (p < 0.05), but no obvious linear relationship between clinical bleeding degree and GP-specific antibody (p > 0.05). Conclusion: Collectively, the newly diagnosed ITP adults with GP-specific antibody have a poor response to short-term HD-DXM, especially in minority (Uyghur) patients with GP-specific antibody in China.

Plain Language Summary What is the context? Relative thrombopoietin deficiency is implicated in primary immune thrombocytopenia (ITP), which is characterized by increased platelet destruction and impaired megakaryopoiesis. Patients who are innately unresponsive to or have relapsed after glucocorticoid treatment have limited treatment options. Recombinant human thrombopoietin (rhTPO) improves treatment response of primary ITP patients when added to high-dose dexamethasone. What is new? This trial sought to identify an optimal dosing regimen of rhTPO for patients who had failed or relapsed after glucocorticoid therapy. Of the 4 regimens, once daily 15000 U rhTPO for 14 injections yielded the greatest median increase in platelet count (167.5 x 10(9)/L) from baseline and attained the highest total response rate on day 14 (63.2%). 30000 U rhTPO once every other day for 7 injections was effective in rapidly increasing platelet counts in the first 7 days. All 4 regimens were safe and well-tolerated. What is the impact? The 30000 U rhTPO once every other day regimen may offer an effective and safe regimen with less frequent injections, but future trials with longer follow-up are needed. Recombinant human TPO (rhTPO) is effective for refractory/relapsed primary immune thrombocytopenia (ITP), but optimal dosing regimen remains elusive. In this multicenter, randomized, controlled trial, a total of 282 adult ITP patients (mean age 47.3 years; 82 men) with a platelet count <= 30 x 10(9)/L or >30 x 10(9)/L with active bleeding randomly received a once daily (QD) subcutaneous injection of 7500 U (n = 64) or 15000 U rhTPO for 14 injections, or 15000 U or 30000 U rhTPO once every other day (QOD) for 7 injections. The primary outcomes included change from baseline in platelet count and total response rate (TRR) on day 14. On day 14, the median increase of platelet count from baseline was the highest in the 15000-U QD group (167.5 x 10(9)/L, interquartile range [IQR] 23.0-295.0 x 10(9)/L), followed by the 30000-U QOD group (57.5 x 10(9)/L, IQR 9.0-190.0 x 10(9)/L) (ANCOVA P < .001; P = .266 with baseline count as a covariate). The TRR on day 14 was also the highest in the 15000-U QD group (63.2%), followed by the 30000-U QOD group (59.7%). The rate of grade 3 and above adverse events did not differ among the four groups. There were no new safety concerns. All 4 regimens are safe and well-tolerated. The 30000-U QOD regimen is practically indistinguishable in efficacy to the 15000-U QD regimen.

INTRODUCTION:Immune thrombocytopenia (ITP) is an autoimmune disease characterized by thrombocytopenia. Herein, we sought to identify potential immune-related therapeutic targets in ITP.METHODS:The differentially expressed genes (DEGs) between ITP patients and controls in GSE43177 and PRJNA299534 were analyzed. The intersections of the two DEG groups were screened as common genes, and enrichment analysis was performed. Additionally, differential analysis of immune cell levels between ITP and controls was performed. Changes in the proportions of T follicular helper (Tfh) and follicular regulatory T (Tfr) cells in peripheral blood samples from ITP patients, ITP patients responding to therapy, and healthy controls were identified. The expression changes in B-cell lymphoma (Bcl)-6 and interleukin (IL)-21 were further evaluated.RESULTS:A total of 76 common genes were identified, and enrichment analysis found that these genes were mainly associated with neutrophil-mediated immunity, the MAPK signaling pathway, and the FOXO signaling pathway. Furthermore, we found different levels of Tfh cells in patients with ITP and controls. The level of Tfh cells in the peripheral blood is significantly increased in ITP patients and declines after responding to therapy. The Tfr/Tfh ratio was reduced in ITP patients and increased after responding to therapy. IL-21 and Bcl-6 were more highly expressed in ITP patients than in controls.CONCLUSION:We identified abnormally expressed genes in ITP related to immune-related biological functions. We further identified the changes in Tfh and Tfr cells during ITP treatment. This provides a rationale for immunotherapy in ITP patients.

在现代生物-心理-社会医学模式下,心理-社会因素在疾病诊疗过程中越来越重要,良好的医患沟通能力对于医学生来说非常重要,而扎实的医学理论基础及专业技术则是良好的医患沟通的前提.本文针对本科实习医师目前的医患沟通现状进行了分析,并对我院血液病中心在强化实习医师医患沟通能力培养方面进行了经验总结,进一步阐明其突出问题及相应的解决办法及策略,为临床实习带教提供一定的指导作用.

目的 探讨程序性死亡受体-1(programmed cell death-1,PD-1)、淋巴细胞活化基因-3(lym-phocyte activation gene-3,LAG-3)在弥漫大 B 细胞淋巴瘤(Diffuse Large B-cell Lymphoma,DLBCL)患者外周血CD8+T细胞上的表达及临床意义.方法 纳入17例初治DLBCL患者作为病例组,10例健康体检者作为对照组,采用流式细胞术检测病例组治疗前后及对照组外周血CD8+T细胞上LAG-3、PD-1的表达,同时收集初治DLBCL患者的临床指标,分析DLBCL患者CD8+T细胞上PD-1、LAG-3的表达与临床指标之间的关系.结果 病例组PD-1+LAG-3-、PD-1-LAG-3+及PD-1+LAG-3+CD8+T细胞比例均较对照组高(P＜0.05),治疗后与治疗前相比,上述指标均下降(P＜0.05);PD-1+CD8+T细胞比例与DLBCL患者B症状具有显著相关性(r=0.598,P＜0.05).结论 DLBCL患者CD8+T细胞上PD-1、LAG-3的比例较高,经治疗后表达降低;DLBCL患者CD8+T细胞上PD-1的表达水平与患者的B症状具有一定相关性,提示PD-1、LAG-3参与了 DLBCL疾病的发展.

Background. Diffuse large B-cell lymphoma (DLBCL) is a clinically and genetically heterogeneous lymphoid malignancy. The unsatisfactory outcome for refractory patients has prompted efforts to explore new therapeutic approaches for DLBCL. However, the mechanisms involved in treatment associated with immune checkpoints remain unclear. This study is aimed at investigating the potential roles of programmed cell death protein 1 (PD1) and lymphocyte activation gene 3 (LAG3) in CD8+ T cells for treatment in DLBCL. Methods. Utilizing flow cytometry, we examined the content of T cells, the levels of cytokines, and the expression of PD1 and LAG3 in patients with DLBCL as well as in healthy controls. Levels of cytokines in CD8+ T cells from DLBCL patients before and after treatment were compared by blocking of PD1 and LAG3 in magnetic bead-sorted CD8+ T cells. Results. We found that the proportion of CD4+ T cells and CD8+ T cells was increased in DLBCL patients after treatment. The levels of cytokines trended toward those of healthy controls in treatment. PD1 (+), LAG3 (+), or PD1 (+) LAG3 (+) were all expressed in lower amounts in CD4+ T cells and CD8+ T cells after treatment than in untreated DLBCL patients. In addition, blockade of PD1 and LAG3 in sorted CD8+ T cells markedly inhibited cytokine production in response to treatment. Conclusion. PD1 and LAG3 in CD8+ T cells may be important targets of therapy and play therapeutic role in patients with DLBCL.

This study investigates the regulatory effect of plasmacytoid dendritic cells (pDC)/myeloid dendritic cells (mDC) imbalance on balance of Th1/Th2 and Th17/Treg in primary immune thrombocytopenia (ITP). A total of 30 untreated ITP patients and 20 healthy controls were recruited. Compared with healthy control, the pDC proportion of ITP patients was significantly reduced (P = 0.004), while the mDC proportion was not significantly changed (P = 0.681), resulting in a decrease in the pDC/mDC ratio (P = 0.001). Additionally, compared with controls, serum levels of interleukin (IL)-6, IL-12, and IL-23 were increased in ITP patients (P < 0.001), and mRNA levels of IL-12p40, IL-12p35, and IL-23p19 were also increased (P =0.014, P = 0.043, P < 0.001). Compared with the healthy control, the proportion of Th1 and Th17 cells in ITP patients increased (P = 0.001, P = 0.031). Serum levels of interferon gamma (IFN-gamma) and IL-17 in ITP patients also increased (P = 0.025, P = 0.005). Furthermore, T-bet and ROR gamma t mRNA levels were increased in peripheral blood of ITP patients (P = 0.018, P < 0.001). Correspondingly, the proportion of Th2 and Treg cells decreased (P = 0.007, P < 0.001), along with a decrease in serum IL-4 and transforming growth factor beta (TGF-beta) (P = 0.028, P = 0.042), and an increase in GATA-3 mRNA (P < 0.001). However, there was no significant difference in Foxp3 mRNA levels (P = 0.587). Pearson correlation analysis showed that the proportion of total dendritic cells (DCs) was positively correlated with IL-12 (r = 0.526, P = 0.003) and IL-23 (r = 0.501, P = 0.005) in ITP patients. Th1/Th2 ratio, IFN-gamma, and IL-12 levels were negatively correlated with platelet counts (r = -0.494, P = 0.009; r = -0.415, P = 0.028; r = -0.492, P = 0.032). However, IL-23 was positively correlated with IL-17 (r = 0.489, P = 0.006) and negatively correlated with platelet count (r = -0.564, P = 0.001). The ratio of IL-6 and Th17 cells was negatively correlated with platelet count (r = -0.443, P = 0.014; r = -0.471, P = 0.011). The imbalance of pDC/mDC and the increase of IL-6, IL-12, and IL-23 lead to the increased differentiation of CD4+ T cells into Th1 and Th17 cells, which might be the important mechanisms underlying the imbalance of Th1/Th2 and Th17/Treg in ITP patients.

We conducted a prospective, multicenter, randomized, controlled clinical trial to compare the efficacy and safety of high-dose dexamethasone (HD-DXM) plus recombinant human thrombopoietin (rhTPO), vs HD-DXM alone in newly diagnosed adult immune thrombocytopenia (ITP) patients. Enrolled patients were randomly assigned to receive DXM plus rhTPO or DXM monotherapy. Another 4-day course of DXM was repeated if response was not achieved by day 10 in both arms. One hundred patients in the HD-DXM plus rhTPO arm and 96 patients in the HD-DXM monotherapy arm were included in the full analysis set. So, HD-DXM plus rhTPO resulted in a higher incidence of initial response (89.0% vs 66.7%, P < .001) and complete response (CR, 75.0% vs 42.7%, P < .001) compared with HD-DXM monotherapy. Response rate at 6 months was also higher in the HD-DXM plus rhTPO arm than that in the HD-DXM monotherapy arm (51.0% vs 36.5%, P = .02; sustained CR: 46.0% vs 32.3%, P = .043). Throughout the follow-up period, the overall duration of response was greater in the HD-DXM plus rhTPO arm compared to the HD-DXM monotherapy arm (P = .04), as estimated by the Kaplan-Meier analysis. The study drugs were generally well tolerated. In conclusion, the combination of HD-DXM with rhTPO significantly improved the initial response and yielded favorable SR in newly diagnosed ITP patients, thus could be further validated as a frontline treatment for ITP. This study is registered as clinicaltrials.gov identifier: NCT01734044.

目的 探讨弥漫大B细胞淋巴瘤(DLBCL)患者Toll样受体4(TLR4)、核因子κB(NF-κB)蛋白的表达及临床意义.方法 选取2015年4月至2017年1月该院诊治的118例DLBCL患者作为观察组,118例体检健康者作为健康对照组,对比2组研究对象TLR4、NF-κB蛋白的表达水平及与不同病理学特征的关系,并分析与DLBCL患者预后的关系.结果 观察组的TLR4、NF-κB蛋白阳性表达率明显高于健康对照组(P<0.05);DLBCL患者的临床分期、乳酸脱氢酶(LDH)及国际预后指数(IPI)与TLR4及NF-κB蛋白阳性表达率有关(P<0.05),年龄、性别、结外累及、B症状等指标均与TLR4、NF-κB蛋白阳性表达率无关(P>0.05);TLR4、NF-κB蛋白表达为阳性的患者生存率显著低于阴性表达的患者(P<0.05).结论 TLR4及NF-κB蛋白在DLBCL患者中高表达,且与DLBCL患者的临床分期、LDH及IPI相关,可作为DLBCL发展及预后的评定指标之一.

树突状细胞是重要的专职抗原呈递细胞,具有桥接先天性和适应性免疫反应的作用,可以诱导幼稚的初始T细胞分化为效应CD4+T细胞,介导CD8+T细胞的交叉启动以及促进B细胞的抗体反应.DC在维持免疫稳态和免疫耐受中起着关键作用.DC-T细胞的相互作用是原发免疫性血小板减少症(ITP)中免疫反应的基础.本文就DC的功能异常、亚群失衡、相关细胞因子在ITP发病机制中的研究进展进行综述.

目的:探讨钙离子通道A1C(calcium voltage-gated channel subunit alpha1 C,CACNA1C)基因表达水平对弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者利妥昔单抗耐药的预测价值.方法:选取我院在2015年3月至2017年5月收治的DLBCL患者93例,均采用利妥昔单抗+CHOP方案化疗,随访2年,根据淋巴瘤化疗疗效评定标准,分为利妥昔单抗耐药组和敏感组;免疫组化法检测所有患者肿瘤组织的钙调蛋白CACNA1C基因、B淋巴细胞瘤-2(B-cell lymphoma-2,BCL-2)基因、PRDM1基因表达情况;绘制受试者工作曲线(receiver operating characteristic curve,ROC),分析CACNA1 C基因、BCL-2基因、PRDM1基因水平在预测DLBCL利妥昔单抗耐药中的效能.结果:93例患者中共出现利妥昔单抗耐药病例26例,耐药率为27.96％;在一般资料方面耐药与敏感病例比较差异无统计学意义(P>0.05);耐药组患者CACNA1C着色细胞比例(40.12±15.44)％vs(69.62±17.65)％低于敏感组,BCL-2着色细胞比例(66.31±15.92)％vs(47.43±14.66)％高于敏感组,PRDM1着色细胞比例(73.42±21.64)％vs(56.73±18.59)％高于敏感组,差异具有统计学意义(P<0.05);ROC曲线显示,CACNA1C基因(AUC=0.848,95％CI=0.765～0.932)曲线下面积大于BCL-2基因(AUC=0.777,95％CI=0.673～0.881)和PRDM1基因(AUC=0.615,95％CI=0.486～0.744);CACNA1C与BCL-2基因表达联合预测的曲线下面积(AUC=0.915,95％CI=0.854～0.976)显著高于三种基因表达水平单独预测,其中CACNA1C基因的最佳截点值为58.61％,BCL-2的最佳截点值为48.33％,此时联合预测在预测利妥昔单抗耐药的敏感性和特异性分别为80.77％和89.55％.结论:CACNA1 C基因表达水平在预测DLBCL患者利妥昔单抗耐药方面具有较好的价值,其中CACNA1 C与BCL-2联合预测利妥昔单抗耐药价值更高.

Th9细胞作为一类新发现的CD4+辅助T细胞,以PU.1为其标志性转录因子,通过表达细胞因子IL-9在炎症免疫疾病、肿瘤疾病及寄生虫疾病中发挥多样作用.包括在炎症免疫疾病中发挥促炎、促组织纤维化等作用;在肿瘤疾病中,在不同的肿瘤组织、甚至不同部位的肿瘤组织中Th9及IL-9的表达均不同,发现其既有抗瘤作用,又有原瘤作用,但IL-9发挥不同作用的机制尚不完全清楚,受到多种信息调控,对Th9及IL-9的研究有助于揭示新的治疗靶点.

目的观察可溶性ST2（sST2）和白细胞介素（IL）-33在原发免疫性血小板减少症（ITP）中的表达水平变化及其对Th17/Treg细胞平衡的调节机制。方法 30例ITP患者作为ITP组,选取同期健康体检者20例作为对照组,采用酶联免疫吸附试验（ELISA）检测2组外周血血清中IL-33、sST-2、IL-17和转化生长因子-β（TGF-β）的水平。结果与对照组比较,ITP组血清sST2及IL-17水平均升高（P＜0.01）,TGF-β表达水平降低（P＜0.01）,而IL-33的表达水平差异无统计学意义（P＞0.05）;在ITP组中sST2与TGF-β呈负相关（r=-0.471,P＜0.01）,与IL-17无相关性（r=0.189,P＞0.05）。结论 sST2表达水平增加和Th17/Treg细胞失衡可能是导致ITP发病的免疫机制之一。