Gemcitabine combined with apatinib and toripalimab in recurrent or metastatic nasopharyngeal carcinoma.

BACKGROUND: The role of a triple combination of gemcitabine (chemotherapy) plus apatinib (anti-vascular endothelial growth factor [VEGFR]) and toripalimab (anti-PD-1) (GAT) in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) is unclear. METHODS: Between August 2019 and April 2020, 41 patients with RM-NPC were enrolled and received GAT for up to 6 cycles followed by apatinib and toripalimab. The primary endpoint was the safety. The secondary endpoints included the objective response rate (ORR) and progression-free survival (PFS). Integrated genomic and transcriptional analyses were conducted to identify the patients who benefited in response to this novel combination therapy. FINDINGS: As of April 1, 2022, treatment-related grade 3 or 4 adverse events (AEs) occurred in 23 of 41 patients (56.1%, 95% confidence interval [CI] 41%-70.1%). G3-4 nasopharyngeal necrosis was observed in 9 (9/41, 21.9%) patients. High-risk factors for necrosis included repeated radiotherapy and an interval of less than 12 months from the last radiotherapy. The ORR was 90.2% (95% CI: 76.9%-97.2%). The median PFS was 25.8 months (95% CI: not reached (NR)-NR), and the 24-month PFS rate was 50.7% (95% CI: 34.0%-67.4%). MAS-related GPR family member F (MRGPRF) high expression in tumors correlated with poor PFS from the GAT therapy, characterized by high epithelial mesenchymal transition signatures. Serial circulating tumor DNA (ctDNA) sequencing could predict PFS outcomes to combination therapy. CONCLUSIONS: GAT therapy exhibits a promising antitumor activity and manageable toxicities in patients with RM-NPC. Patients with repeated radiotherapy and an interval of less than 12 months from the last radiotherapy should be carefully selected for antiangiogenic therapies. MRGPRF expression and serial ctDNA monitoring could identify patients that derive benefits from the combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04073784. FUNDING: This research was funded by the National Natural Science Foundation of China (nos. 81772895 and 82002857), the Key-Area Research and Development of Guangdong Province (2020B1111190001), the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project (202103010001), and the National "Ten Thousand Talents Program" Science and Technology Innovation Leading Talents (84000-41180005).

Efficacy of local therapy to metastatic foci in nasopharyngeal carcinoma: large-cohort strictly-matched retrospective study.

Background: Studies of local therapy (LT) to metastatic foci from nasopharyngeal carcinoma (NPC) are inconsistent and controversial. Here, we aimed to explore the survival benefit of LT directed at metastatic foci from NPC. Methods: A retrospective analysis was conducted in NPC patients with liver, lung, and/or bone metastases. The postmetastatic overall survival (OS) rate was analyzed using the Kaplan-Meier method and compared by the log-rank test. Multivariate analysis was performed using the Cox hazard model. Subgroup analyses evaluating the effect of LT were performed for prespecified covariates. Propensity score matching was applied to homogenize the compared arms. Results: Overall, 2041 of 2962 patients were eligible for analysis. At a median follow-up of 43.4 months, the 5-year OS improved by an absolute difference of 14.6%, from 46.2% in the LT group versus 31.6% in the non-LT group, which led to a hazard ratio of 0.634 for death (p < 0.001). Matched-pair analyses confirmed that LT was associated with improved OS (p = 0.003), and the survival benefits of LT remained consistent in the subcohorts of liver and lung metastasis (p = 0.009 and p = 0.007, respectively) but not of bone metastasis (BoM; p = 0.614). Radiotherapy was predominantly used for BoM and biological effective dose (BED) >60 Gy was found to yield more survival benefit than that of BED ⩽ 60 Gy. Conclusions: The addition of LT directed at metastasis has demonstrated an improvement to OS compared with non-LT group in the present matched-pair study, especially for patients with liver and/or lung metastases.

Involvement of long non-coding RNAs in the pathogenesis of rheumatoid arthritis.

Long non-coding RNA (lncRNA) plays a contributory role in rheumatoid arthritis (RA). In this review, we summarized the current findings of lncRNAs in RA, including cellular function and the potential mechanisms. Serum lncRNA levels are associated with serum proinflammatory cytokines and disease activity. LncRNAs regulate proliferation, migration, invasion and apoptosis of RA fibroblast-like synoviocytes (FLSs), modulate the differentiation of T lymphocytes and macrophages, and affect bone formation-destruction balance of chondrocytes. Besides, lncRNAs are involved in inflammation and cell motivation signaling pathways. In-depth research on lncRNAs may help elucidate the pathogenesis of RA and provides clues for novel treatment targets.

[Cytokine in synovial monocytic cells from rheumatoid arthritis patients].

OBJECTIVE: To evaluate the inhibitory effect of blockade of Rho kinase upon mediating the secretion of proinflammatory cytokine in monocytic cells from rheumatoid arthritis (RA) patients. METHODS: Synovial fluid (SF) monocytic cells and peripheral blood monocytes (PB) from active RA patients were treated with TNFalpha or LPS respectively in the presence or absence of a specific ROK inhibitor, Y27632. ROK activity was assessed by Western blot and cytokine secretion measured by ELISA. RESULTS: Elevated ROK activity was found in synovial fluid monocytic cells from active RA patients. ROK activity was correlated with DAS, an index of disease activity of RA patients. ROK inhibitor Y27632 reduced the secretion of TNFalpha, IL-1beta and IL-6 in RA SF monocytic cells, but had no effect upon the secretion of IL-10, an anti-inflammatory cytokine. CONCLUSION: The present study provides novel evidence that ROK mediates the secretion of proinflammatory cytokines in monocytic cells from RA synovial fluids, suggesting a critical role of ROK in macrophage-mediated synovial inflammation of RA. Thus inhibition of ROK may be a new therapeutic target for RA.

[Abnormal signaling activity of phosphatidylinositol 3-kinase pathway in peripheral blood T cells from patients with systemic lupus erythematosus].

OBJECTIVE: To investigate the activity of phosphatidylinositol 3-kinase (PI3K) signal pathway, a cytoplasmic signaling pathway known to play an important role in T cell activation, in peripheral blood T cells from systemic lupus erythematosus (SLE) patients. METHODS: T cells were isolated from the peripheral blood samples of 28 SLE patients, 5 males and 23 females, with RosettSep T cell purification kit. PI3K activity was determined by immunoprecipitation and ELISA, and Western blotting was used to measure the Akt and phosphorylated Akt protein expression. T cell proliferation and cytokine production was examined by MTT test and ELISA respectively. Fifteen healthy adults and 8 active rheumatoid arthritis patients were used as controls. The T cells from the SLE patients and normal controls were treated with 10% normal control serum of SLE serum for 24 h ("rest") and then to detect the P13K and Akt activity. Some T cells from the SLE patients were stimulated with CD3/CD28 mono-antibodies or CD3/CD28 mono-antibodies + LY294002, a specific P13K inhibitor, and then the proliferation and secretion of IL-6 and IL-10 were analyzed. RESULTS: Compared with the healthy controls and rheumatoid arthritis patients, the activity levels of PI3K and Akt in the T cells of peripheral blood from the SLE patients were significantly increased. T cells allowed to "rest" for 24 hours in culture medium showed a reversal of the changes in activity of PI3K and Akt. The activity of PI3K pathway was increased in the T cells from healthy controls when cultured with SLE serum. The proliferation and IL-6 and IL-10 secretion of the T cells from SLE patients cultured with LY294002 were inhibited. The P13K and Akt activity levels of the T cells from SLE patients were not related to SLE disease activity index (SLEDAI). CONCLUSION: The T cells from SLE patients show an abnormal activation of PI3K pathway which may be due, at least in part, to their exposure to relevant serum factors.

[Role of gonadotropin releasing hormone analogues for ovarian protection in systemic lupus erythematosus patients treated with cyclophosphamide].

OBJECTIVE: To evaluate the effectiveness of gonadotropin releasing hormone analogues (GnRH-a) in protection against premature ovarian failure during cyclophosphamide (CTX) therapy for systemic lupus erythematosus (SLE). METHODS: 28 female patients with SLE, aged 35.3 +/- 2.4 (30-39) were treated with prednisone orally 1 mg/kg daily for 8 weeks, and then the dose was decreased by 10% every 10 days. CTX 200 mg with normal saline 200 ml was intravenously injection every other day for 4 months. Peripheral white blood cell (WBC) count was made every week. If the WBC count was less than 3.5 x 10(9)/L, the use of CTX should be stopped temporarily until the WBC count became normal. And then, the CTX administration should be adjusted to 400 mg intravenously every week. All patients were offered treatment with Hypodermic injection of GnRH-a 3.75 mg was given monthly just at the beginning of the standard CTX regimen for 3 months. Follow-up was conducted for 6 months after the last prescription of GnRH-a. RESULTS: All patients developed amenorrhea after treated by GnRH-a. Menstruation recovered 73 days (69-82 days) after the last subcutaneous injection in 25 patients. Among these 25 patients, one developed amenorrhea again after two normal menses periods. The other 3 patients were in persistent amenorrhea during the following 6 months after the GnRH-a treatment. The levels of plasma estradiol (E2) was 998 +/- 308 pmol/L before GnRH-a treatment, and decreased significantly 1, 2, and 3 months after the last injection of GnRH-a (132 +/- 44 pmol/L, 88 +/- 37 pmol/L and 81 +/- 29 pmol/L respectively, all P < 0.05). The level of plasma E2 increased 2 months after the last injection of GnRH-a in the 25 patients with return of menses, and the level of plasma E2 returned to the normal baseline level after 6 months in 24 patients. CONCLUSION: Treatment with GnRH-a during CTX therapy is associated with a significant reduction of premature ovarian failure in most women with SLE.

[Clinical study of etanercept for treating ankylosing spondylitis].

OBJECTIVE: To evaluate the efficacy and safety of etanercept, a tumor necrosis factor (TNF)-alpha inhibitor, in the treatment of ankylosing spondylitis (AS), and investigate its effect on serum levels of matrix metalloproteinase-3 (MMP-3). METHODS: Forty-eight patients with AS received etanercept 25 mg twice a week for a treatment course of 12 weeks. The patients' symptoms, signs, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels and side effects were observed before and after the treatment. The serum levels of MMP-3 was determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: All the patients completed the treatment. The degree of spinal pain and pain at night, the duration of morning stiffness, the finger-to-floor distance, BASDAI and BASFI were significantly improved after the treatment (P<0.05). Etanercept treatment resulted in a significant reduction in serum MMP-3 level in the AS patients to 31.22-/+10.26 ng/ml as compared with the level before treatment (46.17-/+25.74 ng/ml, P<0.05). The reduction of serum MMP-3 was positively correlated to decrement of ESR and CRP (r=0.397 and 0.474, respectively, P<0.05). The most common adverse events of etanercept included injection site reaction and upper respiratory infection. CONCLUSION: Etanercept treatment has obvious therapeutic effects on AS without serious adverse effects. MMP-3 may be a potentially useful indicator to assess the effect of anti-TNF-alpha treatment in AS patients.

[Significance of calcineurin activation and CD40L expression in patients with active lupus nephritis].

AIM: To investigate the significance of the calcineurin (CaN) activation in active lupus nephritis patient. METHODS: Peripheral blood mononuclear cells (PBMCs) were separated from twenty-one active LN patients and 12 healthy controls. Phosphatase activity of CaN was determined using the CaN assay kit by measuring the content of released PO4. Reverse transcription-PCR was used to detect the expression of CD40L mRNA. Flow cytometry analysis was used to detect the expression of CD40L in LN PBMC. RESULTS: (1) Increased activation of CaN in spontaneous cultured PBMC in active LN group was found as compared with control group (46.08 +/- 5.58 vs 8.81 +/- 3.61, P < 0.01). In stimulated by PMA/Ionomycin , activity of CaN in active LN group was also higher than that of control (69.34 +/- 12.59 vs 37.12 +/- 11.57, P < 0.01). (2) Relative content of CD40L in PBMC in active LN groups increased significantly as compared with the control groups under spontaneous and PMA/Ionomycin-induced culture, respectively (P < 0.01). (3) FK506 reduced significantly production of CD40L in spontaneous and PMA/Ionomycin-induced PBMC of LN. CONCLUSION: Elevated activation of CaN in active LN may participate in regulation overexpression of CD40L in PBMC of LN. Through inhibiting CaN activity, FK506 may prevent abnormal activation of CD40-CD40L costimulatory pathway in lupus nephritis.

[Role of Akt/NF-kappa B signal transduction pathway in murine glomerular mesangial cell proliferation induced by immune complex].

AIM: To explore whether immune complex (IC) can directly induce glomerular mesangial cells(MCs) proliferation and the role of Akt/NF-kappa B signal pathway in the proliferation. METHODS: The mice were divided into control, stimulation and oligodeoxynucleotide(ODN) groups. In ODN group, MCs isolated from mice were transfected with Akt1 sense, mismatched or antisense ODN for 8 h, respectively, by using lipofectin, control and stimulation groups were incubated with lipofectin for 8 h. Then stimulation and ODN groups were incubated with aggregated IgG(AIgG)(a standard IC model), while the control group with monomeric IgG. MTT colorimetry was used to detect MCs proliferation. Distribution of MCs in cell cycle was analyzed by flow cytometry. Cyclin D1 mRNA and its protein expression were determined by RT-PCR and Western blot, respectively.The activity of NF-kappa B in MCs was determined by EMSA. RESULTS: AIgG activated NF-kappa B, upregulated cyclin D1 mRNA and its protein expression, and induced majority of MCs to enter S-phase in cell cycle. Akt1 antisense ODN specifically decreased AIgG-induced NF-kappa B activation, cyclin D1 mRNA and its protein expression, and then inhibited MCs to progress to S-phase and cell proliferation. Sense ODN and mismatched ODN had no such effects. CONCLUSION: IC can directly stimulate MCs proliferation through Akt/NF-kappa B signal pathway, suggesting that NF-kappa B probably be a useful molecule for targeted therapy in IC-mediated MC overproliferation.

[Efficacy of oral bromocriptine in protecting the postpartum systemic lupus erythematosus patients from disease relapse].

OBJECTIVE: To explore the efficacy of oral bromocriptine in protecting the postpartum patients with systemic lupus erythematosus (SLE) from disease relapse. METHODS: The research strategy was a randomized controlled trial. 68 consecutive pregnancy patients with SLE from July 1995 to June 2002 followed up in the teaching hospital were included in the study. The patients were randomly divided into the treatment group and the control group according to their expected date of confinement. The patients in the treatment group had bromocriptine (2.5 mg bid) for 14 days started within 12 hours of postpartum and didn't nurse their infants. The patients in the controlled group didn't have any treatment of influence on prolactin or other sexual hormones. 21 patients nursed and 13 didn't nurse their infants in the controlled group. All patients were followed up for 12 months. RESULTS: The serum prolactin and estradiol levels in treatment group were lower than in nursing controlled group and in non nursing controlled groups, at second week and second month after delivery. The relapse rate in the treatment group was lower than in nursing controlled group and in non nursing controlled groups. The result of Log-rank test was chi(2) = 8.90, P = 0.007 5 comparing three group data of following up with SLEDAI increase 3 as endpoint. The number needed treatment was 3.1, 95% CI (1.9-8.5). Accumulative doses of prednisone within the 12 months were (3.90 +/- 1.82) g in the treatment group and (8.92 +/- 3.36) g in the controlled group, P < 0.001, and cyclophosphamide were (1.41 +/- 0.83) g in the treatment group and (4.27 +/- 2.38) g in the controlled group, P < 0.001. CONCLUSIONS: Oral bromocriptine for 2 weeks in postpartum patients with SLE may relieve the disease from hyperprolactinemia and hyperestrogenemia, and may be beneficial in protecting the patients from disease relapse and in reducing the usage of steroid and immunosuppressant.