Abstract

BACKGROUND To evaluate the efficacy and safety of recombinant human serum albumin /granulocyte colony-stimulating factor (rHSA/G-CSF) in breast cancer following receipt of cytotoxic agents. METHODS The phase 1b trial assessed the pharmacokinetics, pharmacodynamics, and safety of dose-escalation, ranging from rHSA/G-CSF 1800 μg, 2100 μg, and 2400 μg. Randomized controlled phase 2b trial was further conducted to ensure the comparative efficacy and safety of rHSA/G-CSF 2400 μg and rhG-CSF 5 μg/kg. In multicenter, randomized, open-label, parallel, phase 2 study, participants treated with anthracycline-containing chemotherapy were assigned in a ratio 1:1:1 to receive double delivery of rHSA/G-CSF 1200 μg, 1500 μg, and continuous rhG-CSF 5 μg/kg. RESULTS Between December 16, 2014, to July 23, 2018, a total of 320 patients were enrolled, including 25 individuals in phase 1b trial, 80 patients in phase 2b trial, and 215 participants in phase 2 study. The mean duration of agranulocytosis during the first chemotherapeutic intermission was observed as 1.14 ± 1.35 days in rHSA/G-CSF 1500 μg, which was comparable with that of 1.07 ± 0.97 days obtained in rhG-CSF control (P = 0.71). Safety profiles were assessed to be acceptable ranging from rHSA/G-CSF 1800 μg to 2400 μg, while the double delivery of HSA/G-CSF 2400 μg failed to meet the noninferiority in comparison with rhG-CSF. CONCLUSION The prospective randomized controlled trials demonstrated that rHSA/G-CSF was efficacious and well-tolerated with an approachable frequency and expense of application for prophylactic management of agranulocytosis. The double delivery of rHSA/G-CSF 1500 μg in comparisons with paralleling G-CSF preparations is warranted in the phase 3 trial. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT02465801 (11/17/2014), NCT03246009 (08/08/2017), NCT03251768 (08/07/2017).

Abstract

OBJECTIVE To explore the clinical efficacy and mechanism of compound Shenlu granule (SLG) treatment in patients with aplastic anemia (AA). METHODS A total of 89 AA patients were randomly divided into an SLG supportive group (group A, n = 44) and a control group (group B, n = 45) while continuing Western medical management. After 6 months, hemograms, traditional Chinese medicine (TCM) syndrome scores, and overall clinical efficacy rate were assessed. Serum metabolomics characteristics were observed using ultraperformance liquid chromatography-mass spectrometry after SLG intervention. RESULTS The levels of red blood cell (RBC), hemoglobin (Hb), and platelet (PLT) were increased in both groups after treatment for 6 months (P < 0.05), and in group A, the elevation of PLT became much more significant (P < 0.01). The TCM syndrome score was lower in group A than in group B after treatment (P < 0.05). Metabolomics data showed a significant difference in the patients using SLG after 6 months, and 14 biomarkers were identified. CONCLUSION SLG supportive treatment showed positive results in patients with AA, and metabolomics data indicated that SLG influenced aminoacyl-tRNA biosynthesis and glycerophospholipid metabolism to gradually return to normal.

Abstract

PURPOSE The decision regarding the optimal secondary prophylactic treatment for esophageal variceal bleeding (EVB) in hepatic cirrhosis is controversial. A network meta-analysis was conducted to assess the benefits of various treatments for the secondary prophylaxis of EVB in patients with cirrhosis. METHODS A thorough examination of databases, including EMBASE, PubMed, and Cochrane Database of Controlled Trials, was conducted to identify relevant randomized controlled trials up to December 2019. Key primary outcomes included mortality and rebleeding. Within the identified databases, a network meta-analysis was performed. Results were expressed by using a 95% credible interval (CrI) and odds ratios (ORs). The quality of results was assessed by using the Grading of Recommendations, Assessment, Development and Evaluation approach. FINDINGS Forty-eight trials with 4415 participants with cirrhosis and portal hypertension who had a history of recent variceal bleeding were included. Carvedilol ranked first (surface under the cumulative ranking curve [SUCRA], 87.4%) in overall survival, and some advantage was suggested; however, the findings were not statistically significant, compared with endoscopic variceal ligation + nonselective beta-blockers (NSBB) (OR, 0.59; CrI, 0.28, 1.3), NSBB + isosorbide mononitrate (OR, 0.67; CrI, 0.33, 1.4), and transjugular intrahepatic portosystemic shunt (TIPS) (OR, 0.52; CrI, 0.24, 1.1). NSBB + isosorbide mononitrate (SUCRA, 63.9%) ranked higher than NSBB + endoscopic variceal ligation (SUCRA, 49.6%) in reducing mortality. TIPS (SUCRA, 98.8%) ranked higher than other treatments in reducing rebleeding but did not confer any survival benefit. IMPLICATIONS TIPS ranks first in preventing rebleeding of secondary prophylaxis of EVB and carvedilol shows outstanding efficacy in improving survival. International Prospective Register of Systematic Reviews: identifier CRD42019131814.

Abstract

BACKGROUND Transfusion-Transmitted Zika virus (TT-ZIKV) has become an emerging threat to world blood banks due to the fast spread of ZIKV epidemics and high rate of asymptomatic infections. For the risk assessment of ZIKV infection in blood products, relevant studies in blood donations or blood donors tested for ZIKV were collected and analyzed systematically. The overall prevalence of ZIKV infection were estimated through meta-analysis and potential risk factors were detected. The results will provide important clues for the protocol design of blood screening tests. METHODS Relevant articles about the rate of ZIKV detected in blood samples were identified from PubMed, Scopus and Web Of Science using key terms search strategy until October 7, 2017. Eligible articles were screened following inclusion and exclusion criteria. Meta-analysis and subgroup analyses were performed by software R3.4.1. Overall postdonation and posttransfusion follow-ups were analyzed. RESULTS Ten literatures (528,947 blood samples) were included for meta-analysis. The overall pooled prevalence of ZIKV (RNA and antibody) in blood donations was 1.02% (95%CI 0.36-1.99). The pooled prevalence of ZIKV RNA in blood donations was 0.85% (95%CI 0.21-1.88) less than the pooled prevalence of anti-ZIKV antibodies 1.61% (95%CI 0.03-5.21), however the difference was not statistically significant (p = 0.52). The prevalence varied significantly in different geographical regions (p < 0.001). Blood donations were more than two times likely to be infected by ZIKV in Zika epidemic period (1.37, 95%CI 0.91-1.91) than in non-epidemic period (0.61, 95%CI 0-2.55). The prevalence of anti-ZIKV antibodies (1.61, 95%CI 0.03-5.21) was almost twice as much as ZIKV nucleic acid detected in blood donations (0.85, 95%CI 0.21-1.88). However, statistically significant differences were not observed. A total of 122 ZIKV positive blood donors were followed, of which 48 (39%) reported symptoms postdonation, but none of the 13 followed recipients reported any clinical symptoms related to Zika infection posttransfusion. CONCLUSION The pooled prevalence of Zika infection in blood donations was 1.02%. The prevalence varied greatly and reached to high-risk level in most of the situations. The results suggest that nucleic acid tests (NAT) for blood screening and pathogen reduction/inactivation technology (PRT) should be implemented in Zika-endemic areas and appropriate strategies should be designed according to different conditions. More studies are needed in the future to provide more evidence.

Abstract

BACKGROUND Primary immune thrombocytopenia is a severe bleeding disorder. About 50-85% of patients achieve initial remission from first-line therapies, but optimal second-line treatment remains a challenge. All-trans retinoic acid (ATRA) has an immunomodulatory effect on haemopoiesis, making it a possible treatment option. We aimed to evaluate the efficacy and safety of ATRA plus danazol versus danazol in non-splenectomised patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. METHODS We did a multicentre, randomised, open-label, phase 2 study of adult patients (≥18 years) with primary immune thrombocytopenia from five different tertiary medical centres in China. Those eligible were non-splenectomised, resistant to corticosteroid treatment or relapsed, and had a platelet count less than 30 x 109 per L. Masked statisticians used simple randomisation to assign patients (1:1) to receive oral ATRA (10 mg twice daily) plus oral danazol (200 mg twice daily) or oral danazol monotherapy (200 mg twice daily) for 16 weeks. Neither clinicians nor patients were masked to group assignments. All patients were assessed every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. The primary endpoint was 12-month sustained response defined as platelet count of 30 x 109 per L or more and at least a doubling of baseline platelet count (partial response), or a platelet count of 100 x 109 per L or more (complete response) and the absence of bleeding without rescue medication at the 12-month follow-up. All randomly allocated patients, except for those who withdrew consent, were included in the modified intention-to-treat population and efficacy assessment, and all patients who received at least one dose of the study agents were included in the safety analysis. Study enrolment was stopped early because the trial results crossed the interim analysis efficacy boundary for sustained response. This trial is registered with ClinicalTrials.gov, number NCT01667263. FINDINGS From June 1, 2012, to July 1, 2016, we screened 130 patients for eligibility; 34 were excluded and 96 were randomly assigned. 93 patients were included in the modified intention-to-treat analysis: 45 in the ATRA plus danazol group and 48 in the danazol group. At the 12-month follow-up, sustained response was achieved more frequently in patients receiving ATRA plus danazol than in those receiving danazol monotherapy (28 [62%] of 45 vs 12 [25%] of 48; odds ratio 4.94, 95% CI 2.03-12.02, p=0.00037). Only two grade 3 adverse events were reported: one (2%) patient receiving ATRA plus danazol with dry skin, and one (2%) patient receiving danazol monotherapy with liver injury. There was no grade 4 or worse adverse event or treatment-related death in either group. INTERPRETATION Patients with primary immune thrombocytopenia given ATRA plus danazol had a rapid and sustained response compared with danazol monotherapy. This finding suggests that ATRA represents a promising candidate for patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. FUNDING National Natural Science Foundation of China, Beijing Natural Science Foundation, Beijing Municipal Science and Technology Commission, and the National Key Research and Development Program of China.

Abstract

BACKGROUND Excessive postoperative blood loss after cardiopulmonary bypass is a common problem, especially in patients suffering from congenital heart diseases. The efficacy of epsilon aminocaproic acid (EACA) as a prophylactic treatment for postoperative bleeding after pediatric open-heart surgery has not been determined. This meta-analysis investigates the efficacy of EACA in the minimization of bleeding and blood transfusion and the maintenance of coagulation tests after pediatric open-heart surgery. METHODS A comprehensive literature search was performed to identify all randomized clinical trials on the subject. PubMed, Embase, the Cochrane Library, and the Chinese Medical Journal Network were screened. The primary outcome used for the analysis was postoperative blood loss. Secondary outcomes included postoperative blood transfusion, re-exploration rate and postoperative coagulation tests. The mean difference (MD) and risk ratio (RR) with 95% confidence intervals (CI) were used as summary statistics. RESULTS Five trials were included in this meta-analysis of 515 patients. Prophylactic EACA was associated with a reduction in postoperative blood loss, but this difference did not reach statistical significance (MD: -7.08; 95% CI: -16.11 to 1.95; P = 0.12). Patients treated with EACA received fewer postoperative blood transfusions, including packed red blood cells (MD: -8.36; 95% CI: -12.63 to -4.09; P = 0.0001), fresh frozen plasma (MD: -3.85; 95% CI: -5.63 to -2.08; P < 0.0001), and platelet concentrate (MD: -10.66; 95% CI: -18.45 to -2.87; P = 0.007), and had a lower re-exploration rate (RR: 0.46; 95% CI: 0.23 to 0.92; P = 0.03). Prophylactic EACA also improved coagulation tests 6 hours after open-heart surgery. CONCLUSIONS Prophylactic EACA minimizes postoperative blood transfusion and helps maintain coagulation in pediatric patients undergoing open-heart surgery. Therefore, the results of this study indicate that adjunctive EACA is a good choice for the prevention of postoperative blood transfusion following pediatric cardiac surgery.

Abstract

BACKGROUND Severe acute pancreatitis is a life-threatening disease. Patients with peripancreatic necrotic infection often require surgical removal of necrotic infected tissue and a wide debridement will cause blood loss and worsen the condition. AIM: To assess whether treatment with NovoSeven, a recombinant activated FVII (rFVIIa), could improve coagulation function and therefore reduce blood loss, blood transfusion and all-cause mortality during necrosectomy in patients with infected necrosis secondary to severe acute pancreatitis. MATERIALS AND METHODS Severe acute pancreatitis patients admitted to Nanjing Jinling Hospital for necrosectomy were enrolled and randomized to receive either standard treatment or standard treatment plus an intravenous infusion of rFVIIa (40mug per kilogram of body weight per hour) before operation. The prospectively defined primary end points were perioperative coagulation parameters (prothrombin time, activated partial thromboplastin time), blood transfusion unit and blood loss. The secondary end points were operation time, ICU stay and all-cause mortality at 28days after the operation. RESULTS A total of 64 patients were enrolled (31 in the rFVIIa group and 33 in the control group). Treatment with rFVIIa was associated with a reduction in operation time, red blood cell and fresh froze plasma transfusion, blood loss and prothrombin time compared to the control group (p<0.05 for all). Activated partial thromboplastin time and mortality were similar between the two groups (P>0.05). CONCLUSION Treatment with rFVIIa significantly improved the extrinsic coagulation function in patients with severe acute pancreatitis and was associated with decreased risk of bleeding. However, rFVIIa did not improve intrinsic coagulation or reduce over-cause mortality. Clinical Trial Registration Number: ChiCTR-TRC-1300389. Copyright 2014 Elsevier Ltd. All rights reserved.

Abstract

Double filtration plasmapheresis (DFPP) is used to treat myasthenia gravis (MG). However, the definite mechanism is unclear. This study investigated whether DFPP improves MG through an immunomodulatory action. Thirty-five MG patients were randomly divided into two treatment groups: Group A (DFPP combined with oral methylprednisolone) and Group B (oral methylprednisolone alone). Their antibody levels, clinical scores, cytokine levels, and CD4(+)CD25(high)Foxp3(+) (regulatory T cell [Treg]) levels were then determined. Anti-titin antibody levels were significantly lower in Group A compared with Group B after treatment. The clinical remission rate in Group A was significantly higher than in Group B. The changes in cytokine levels (interleukin [IL]-2, IL-4, IL-10, and interferon-) in sera and the peripheral blood mononuclear cell culture supernatants did not significantly differ before and after the treatments in both groups (p<0.05). The soluble intercellular adhesion molecule-1 (sICAM-1) levels were lower in Group A than in Group B (p<0.05). MG patients exhibited a lower percentage of Treg cells than normal patients. DFPP combined with methylprednisolone treatment increased the Treg cell percentage more than treatment with methylprednisolone alone (p<0.05). DFPP treatment more effectively lowers sICAM-1 and increases Treg cell expression, consequently benefiting MG patients. Copyright 2014 Elsevier Ltd. All rights reserved.