Efficacy of front-line immunochemotherapy for transplant-ineligible mantle cell lymphoma: A network meta-analysis of randomized controlled trials.

BACKGROUND: There is no standard first-line immunochemotherapy regimen for transplant-ineligible patients with mantle cell lymphoma (MCL) currently, and the efficacy of various treatment remains unclear. METHODS: We conducted a Bayesian network meta-analysis (NMA) of all eligible randomized controlled trials. Pairwise comparisons and ranking of different first-line treatment options were performed. RESULTS: Nine studies were included in the NMA, involving a total of 2897 MCL patients. The BR-Ibrutinib+R regimen showed the best progression-free survival (PFS), with a surface under the cumulative ranking curve (SUCRA) of 0.89 and probability of being the best treatment (PbBT) of 69%. The VR-CAP regimen was the most potential intervention to improve overall survival (OS), with a SUCRA of 0.89 and PbBT of 63%. Compared with the R-CHOP regimen, the BR regimen achieved a better PFS (hazard ratio [HR] 0.45 [95% credible interval 0.2-0.96]). The BR-Ibrutinib+R regimen (HR 0.14 [0.02-0.99]), BR+R regimen (HR 0.19 [0.034-0.99]), and BR regimen (HR 0.3 [0.08-1.03]) were superior to CHOP regimen with better PFS. The R-FC regimen (HR 2.27 [1.01-5.21]) or FC regimen (HR 3.17 [1.15-8.71]) was inferior to the VR-CAP regimen with a worse OS. CONCLUSIONS: Our study presents the most promising first-line treatment strategy for transplant-ineligible MCL patients in terms of PFS and OS, which provides innovative treatment strategy for MCL treatment.

The expression and clinical significance of programmed cell death receptor 1 and its ligand in tumor tissues of patients with extranodal nasal NK/T cell lymphoma.

Appropriate biomarkers may help distinguish the biological behavior of different types of lymphoma and their response to traditional chemotherapy. Extranodal natural killer/T-cell lymphoma (ENKTL) and diffuse large B-cell lymphoma (DLBCL) belong to different subtypes of non-Hodgkin's lymphoma, the biological behavior and prognosis of them are very different, programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) have been investigated in these two types of diseases. However, few studies addressed the difference of PD-1/PD-L1 levels between ENKTL and DLBCL, in order to find out the difference and related clinical application value, the clinical data and tumor tissue paraffin sections of 24 newly diagnosed ENKTL patients and 42 newly diagnosed diffuse large B-cell lymphoma (DLBCL) were collected. PD-1/PD-L1 levels in tumor tissues were detected by immunohistochemical staining. The relationship between the PD-1/PD-L1 levels and clinical data of patients with ENKTL patients was analyzed. Both patient groups showed PD-1 level in tumor tissue of ENKTL patients was significantly lower than that of DLBCL patients (P < 0.05), while the PD-L1 level in tumor tissues of ENKTL patients was not different from DLBCL (P < 0.05). In addition, the ENKTL patients with B symptoms, elevated lactate dehydrogenase (LDH) levels and decreased hemoglobin (HGB) concentrations had lower level of PD-1 in tumor tissue. PD-L1 level in tumor tissues, the LDH level, Epstein-Barr genome (EBV-DNA) copy and Ki-67 index may affect the outcomes of ENKTL patients (P < 0.05), but they were not independent factors. PD-L1 levels in tumor tissues has clinical significance in ENKTL patients, which suggested that the PD-1/PD-L1 signal pathway may be involved in the immune escape of ENKTL and play different roles in different lymphoma subtypes.

Prognostic significance of p53, Sox11, and Pax5 co-expression in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a relatively rare subtype of non-Hodgkin's lymphoma. To identify molecular biomarkers in MCL, we performed immunohistochemistry tissue arrays using biopsies from 64 MCL patients diagnosed in West China Hospital from 2012 to 2016. TP53 mutation status in those patients was also examined by sequencing. The sequencing results showed TP53 mutations were highly heterogeneous in MCL. We identified four novel TP53 mutations in MCL: P151R, G199R, V218E, and G325R. The MCL patients with TP53 mutations had inferior progression-free survival (PFS, p = 0.002) and overall survival (OS, p = 0.011). Tissue array results showed the expression of p53, Sox11, or Pax5 alone did not correlate with the patient PFS and OS. However, the MCL patients with triple-positive expression of p53/Sox11/Pax5 had inferior PFS (p = 0.008) and OS (p = 0.002). Such risk stratification was independent to the mantle cell lymphoma international prognostic index (MIPI), Ki-67 value, and TP53 mutation status of the patients. The triple-positive patients might represent a subtype of high-risk MCL. Our findings might indicate a novel way to stratify MCL and predict patients' prognosis.

Predicting treatment response of patients with extranodal natural killer/T-cell lymphoma based on levels of PD-L1 mRNA and soluble PD-L1.

Appropriate biomarkers may help predict patient response to treatment for extranodal natural killer/T-cell lymphoma (ENKTL), a subtype of non-Hodgkin's lymphoma in China. Programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) have been investigated in various tumors. However, few studies have addressed expression of PD-1/PD-L1 in peripheral blood of ENKTL patients. To identify novel peripheral blood biomarkers for diagnosis and treatment of ENKTL, we retrospectively examined 89 healthy volunteers, 49 patients with ENKTL and 74 patients with diffuse large B-cell lymphoma treated at West China Hospital from September 2017 to September 2018. Both patient groups showed significantly higher expression of PD-1 and PD-L1 on CD4+ T cells, higher levels of PD-L1 mRNA in peripheral blood mononuclear cells (PBMCs) and higher levels of soluble PD-L1 in plasma than healthy volunteers (P < .05). In ENKTL patients, levels of PD-L1 mRNA and soluble PD-L1 were related to disease stage, level of lactate dehydrogenase, lymphocyte count, and copies of Epstein-Barr genome in blood. Levels of PD-L1 mRNA and soluble PD-L1 were similar between healthy volunteers and ENKTL patients who showed complete remission after treatment, and uni- and multivariate analyses identified soluble PD-L1 as a predictor of treatment response in ENKTL patients. Our results suggest that the levels of PD-L1 mRNA in PBMCs and soluble PD-L1 in plasma are useful for ENKTL staging and prediction of treatment response.

[Relationship of Expression Between SOX11 and PAX5 in Pathological Tissue Specimens of Patients with Mantle Cell Lymphoma and Its Clinical Significance].

OBJECTIVE: Investigate the expression of SRY-related HMG box 11 (SOX11) and paired box domain 5 (PAX5) in patients with mantle cell lymphoma (MCL) and analyze the relationship between them and their clinical significance. METHODS: Seventy-six formalin-fixed paraffin-embedded (FFPE) samples of patients who were diagnosed with MCL from January 2012 to August 2017 were collected．Fifty-six FFPE samples from patients with diffuse large B cell lymphoma (DLBCL), thirty-eight FFPE samples from patients with follicular lymphoma (FL) and nine FFPE samples from patients with Burkitt's lymphoma (BL) were used as control groups. Real-time quantitative PCR (qRT-PCR) and immunohistochemistry were used to detect the mRNA and protein expressions of SOX11 and PAX5. The association between expressions of SOX11 and PAX5 in patients with MCL was analyzed. On the basis of the median H score of SOX11 and PAX5 protein expressions in patients with MCL, they were divided into high and low expression group, and the relationship between the different groups and patients' clinical characteristics and prognosis were analyzed. RESULTS: The different mRNA expression levels of SOX11 and PAX5 in different lymphoma tissues were statistically significant ( P<0.01). The mRNA expression levels of SOX11 and PAX5 in MCL group were higher than those of the control groups, and the differences of those between MCL and DLBCL or FL were statistically significant ( P<0.01). However, the differences of those between MCL and BL were not significant ( P>0.05). The expression level of SOX11 protein was also higher than those of the control groups ( P<0.000 1). However, there was no significant difference in PAX5 protein expression level between the MCL group and the control group, nor the expression levels of SOX11 and PAX5 genes and proteins among the control groups ( P>0.05). By analyzing the samples from patients with MCL, we observed a positive relevance between SOX11 and PAX5 both in mRNA expression level ( r s=0.714, P<0.000 1) and protein expression level ( G=0.407, P=0.01). There was no difference in clinical characteristics and overall survival between the high and low expression group. CONCLUSION: In MCL, there was a positive relevance between the expressions of SOX11 and PAX5. The expression of SOX11 or PAX5 alone has no significant effect on the prognostic stratification of MCL patients.

[The Value of Circulating Exsomal miR-451a to Monitor Therapy Response in Diffuse Large B Cell Lymphoma].

OBJECTIVE: To investigate the expression level of circulating exsomal miR-451a and its significances in therapy monitoring in diffuse large B cell patients. METHODS: We isolated exsomal RNAs fractions from serum of 56 DLBCL patients before treatment,during treatment and after treatment. The serum of 56 healthy controls was collected at the same time. Quantitative real time polymerase chain reaction (qRT-PCR) were performed to detected the expression level of circulating exsomal miR-451a. Receive operater characteristic (ROC) curve was performed to comfirm the diagnostic efficiency of miR-451a. Chemotherapy effect corresponding with miR-451a was analyzed. RESULTS: Circulating exsomal miR-451a was down-expression in DLBCL compared with healthy controls (P<0.000 1), and the area under the ROC curve (AUC) was 0.737 (95%CI0.645-0.816) . In 43 patients who had complete follow-up information,the patients who obtained remission,including complete remission (CR) and partial remission (PR) ,had the levels of circulating exsomal miR-451a gradually increased. While in patients who did not get remission, including stable disease (SD) and progression disease (PD) ,had no significant changes of circulating exsomal miR-451a. CONCLUSION: Circulating exsomal miR-451a may be an potential indicator for therapy response monitoring in DLBCL.

Isolation, identification and characterization of the nematophagous fungus Arthrobotrys (Monacrosporium) sinense from China.

With the development of anthelmintic resistance of parastic nematodes, it is necessary to isolate and study nematophagous fungi to screen out the native isolates for their potential in the biocontrol of domestic animal nematodosis. This study aimed to isolate the Arthrobotrys sinense (Monacrosporium sinense) of nematophagous fungus, to characterize representative molecular isolates using scanning electron microscope (SEM), and to determine the effect of the temperature and pH values on radial growth of the isolate. Five isolates were isolated from 1532 samples of different types, and their occurrence frequencies were 0.32% of the total samples. They were identified as A. sinense by means of morphology and the sequence of the 5.8S, 18S, and 28S rDNA, as well as internal transcribed spacers 1 and 2. The isolate NBS003 could grow from 11°C to 35°C and had optimal growth at 30°C. The isolate could grow at pH 4 to 11, and its optimal value was obtained at pH 9. SEM results showed that 6 h after their addition, the second stage larvae (L2) and the third stage infective larvae (L3) of Haemonchus contortus were captured. L2 and L3 were penetrated by the fungus at 18 and 24 h post-capture, respectively. L2 and L3 were completely digested at 84 and 90 h post-capture, respectively. The NBS003 of the A. sinense should have a certain potential to be used for capturing the free-living stage of nematodes in sheep.

Observational Study of Surgical Treatment of Sagittal Fractures of Mandibular Condyle.

OBJECTIVE: This study was conducted to investigate the complications that occur after surgical treatment of sagittal fracture of the mandibular condyle (SFMC). METHODS: A retrospective study was conducted on patients in whom SFMC was treated using surgical methods (87 patients, 105 sides) between January 1995 and December 2011 (79 sides were treated by rigid internal fixation and the remaining 26 sides were removed the condylar fragments). The longest follow-up was 17 years, and the shortest was 2 years. Follow-ups were conducted to assess mandibular activity, mouth opening, and computed tomography scans of condylar morphologic alterations. The postoperative complications were evaluated and the causes were analyzed. RESULTS: We observed 3 patients with joint ankylosis (all of them were removed the condylar fragments); 8, mouth opening less than 30 mm; 23, deviation on mouth opening at 6 months. At 4 weeks, 19 patients had facial nerve weakness, which was resolved within 6 months. The radiological investigation showed complete remodeling in 56.2% of the condyles (in the 59 sides, 57 sides were treated by rigid internal fixation and 2 sides were removed the condylar fragments); partial remodeling 27.6% condyles (in the 29 sides, 20 sides were treated by rigid internal fixation and 9 sides were removed the condylar fragments); poor remodeling, 16.2% condyles (in the 17 sides, 2 sides were treated by rigid internal fixation and 15 sides were removed the condylar fragments). CONCLUSIONS: Surgical treatment of SFMC is not perfect. There were some complications that occurred after the surgical treatment of SFMC. The findings also indicate that condylar anatomic reduction is the basis for functional recovery and, therefore, rigid fixation should be implemented. Furthermore, the removal of condylar fragments should be performed with caution, and if used, the fragments should be removed entirely.

[An experimental study on segmental defects reconstruction of canine mandible with allogenic bone marrow mesenchymal stem cells combined with lyophilized bone].

OBJECTIVE: To investigate the effect of segmental defects reconstruction of canine mandible with allogenenic bone marrow mesenchymal stem cells (BMSC) combined with lyophilized bone. METHODS: A 30 mm segmental defect was created on the left mandibles of beagles. Beagles were randomly divided into three groups. Allogeneic bone marrow mesenchymal stem cells with lyophilized bone were used for segmental defects reconstruction in group A. Autologous bone marrow mesenchymal stem cells with freeze- dried bone were used for segmental defects reconstruction in group B. The defects of group C were repaired with lyophilized bone only. Every three beagles were sacrificed 4, 12, 24, and 48 weeks after surgery respectively. The reconstruction effect was evaluated by CT and histopathological examination. RESULTS: CT examination showed that new bones formed in group A and group B 12 weeks after surgery, but not in group C. The form of the reconstructed mandibles in the three groups recovered in 48 weeks. The small pores on the bone graft were filled with new bones in group A and group B. In group C, the pores were still evident. Histopathological examination showed that bone trabecula between allogeneic bone and autogenous bone was completely joined in group A and group B. A large number of fibrous tissue appeared around the implanted bone and new bones were formed. In group C, the lyophilized bone resorption was still not obvious, the new bone formation was significantly slower than the other two groups. There was no difference between group A and group B. CONCLUSIONS: Both allogeneic bone marrow mesenchymal stem cells and autologous mesenchymal stem cells could accelerate the bone formation.

[Construction of the eukaryotic expression plasmid containing lvgA gene flanked with CpG motifs of Legionella pneumophila and its expression in NIH3T3 cells].

OBJECTIVE: To construct the eukaryotic expression plasmid containing lvgA gene flanked with CpG motifs of Legionella pneumophila for its expression in NIH3T3 cells. METHODS: lvgA gene flanked with CpG motifs of Legionella pneumophila was amplified by PCR. The PCR products was inserted into the eukaryotic expression plasmid pcDNA3.1/myc-his(+) to construct the recombinant plasmid pclvgA/CpG, which was subsequently transfected into NIH3T3 cells via lipofection. Immunofluorescence analysis was carried out to detect the transient expression of the plasmid in the cells. RESULTS: Sequence analysis showed that the recombinant plasmid pclvgA/CpG contained the lvgA/CpG fragment with a length of 657 bp, encoding a protein of 27.7 Ku. Immunofluorescence analysis identified the transient expression of the recombinant plasmid pclvgA/CpG in NIH3T3 cells. CONCLUSION: The lvgA gene flanked with CpG motifs of Legionella pneumophila has been constructed successfully, and the transient expression of the recombinant plasmid pclvgA/CpG can be detected in NIH3T3 cells.

[Determination of GATA-4 in the testis of the mouse].

OBJECTIVE: To explore the characteristics and distribution of GATA-4 in the testis of male mice. METHODS: Paraffin sections were obtained from the testes of 24 male B6SJLF1/J mice, aged 0 day (n = 6), 2 weeks (n = 6), 4 weeks (n = 6) and 6 weeks (n = 6), and the expressions of GATA-4 in the testis were observed by the immunohistochemical ABC method and DAB visualization at different times. RESULTS: Positive expressions of GATA4 were found in the Sertoli cells and Leydig cells of all the mice, but significantly higher in the 4- and 6-week-old than in the 0-day and 2-week-old groups (P < 0.01). And they were also observed in the germ cells of the 4- and 6-week-old mice, significantly higher in the latter than in the former (P < 0.01). CONCLUSION: GATA-4 exists in the testis of male mice, which has provided a morphological base for sex determination and differentiation and hormone regulation in the testis.

[The GATA family in reproduction].

The GATA family proteins are a group of zinc finger transcription factors that are expressed in human and mammalian animals and play an important role in mammalian organ morphogenesis, cell proliferation and sex differentiation. GATA-4 and GATA-6 have been identified in the ovaries and testes of humans, mice, pigs and chickens. GATA-4 contributes to fetal male gonadal development by regulating the genes that mediate Müllerian duct regression and the onset of testosterone production. GATA-4 and GATA-6 are localized in and regulate the function of the ovarian and testicular somatic cells of fetal mice, especially granulosa cells, thecal cells, Sertoli cells and Leydig cells. GATA-4 is also present in the germ cells of fetal and prepubertal mice.