Minimally invasive surgery (MIS) has shown satisfactory surgical results for the treatment of thoracic myelopathy (TM) caused by ossification of the ligamentum flavum (OLF). This study investigated the prognostic factors following MIS and was based on the retrospective analysis of OLF patients who underwent percutaneous full endoscopic posterior decompression (PEPD). Thirty single-segment OLF patients with an average age of 60.4 years were treated with PEPD under local anaesthesia. Clinical data were collected from the medical and operative records. The surgical results were assessed by the recovery rate (RR) calculated from the modified Japanese Orthopaedic Association (mJOA) score. Correlations between the RR and various factors were analysed. Patients' neurological status improved from a preoperative mJOA score of 6.0 ± 1.3 to a postoperative mJOA score of 8.5 ± 2.0 (P < 0.001) at an average follow-up of 21.3 months. The average RR was 53.8%. Dural tears in two patients (6.7%, 2/30) were the only observed complications. Multiple linear regression analysis showed that a longer duration of preoperative symptoms and the presence of a high intramedullary signal on T2-weighted MRI (T2HIS) were significantly associated with poor surgical results. PEPD is feasible for the treatment of TM patients with a particular type of OLF. Patients without T2HIS could achieve a good recovery if they received PEPD early. Thoracic myelopathy (TM) is less common than cervical myelopathy and lumbar spinal stenosis 1 , and TM is mainly caused by ossification of the ligamentum flavum (OLF) in East Asian countries, such as Japan, Korea, and China 2. As the number of reported cases has increased, OLF has been studied not only in East Asia but also worldwide 3-5. Although much of its pathophysiology has been determined, the exact pathogenetic mechanism and the epidemiology of OLF remain poorly understood 6,7. Therefore, making an appropriate and timely therapeutic decision for the treatment of OLF may be hindered by the paucity of knowledge. TM caused by OLF remains a challenge for spine surgeons. OLF generally requires posterior surgical decompression due to its progressive nature and poor response to conservative therapy 8,9. Decompression procedures include traditional open surgeries, such as laminectomy with or without posterior fusion 10,11 , and minimally invasive surgery (MIS), such as microendoscopic decompression 12,13 and percutaneous endoscopic decompression 14-17. However, the prognostic guidelines are still unclear, and the surgical results vary widely despite complete decompression 3,18 .
There is mounting evidence that metastasis-associated in colon cancer-1 (MACC1) plays pivotal roles in development and progression of many tumors, particularly in osteosarcoma (OS). However, its precise roles and molecular mechanisms remain to be delineated in OS. In the current study, we found that the levels of MACC1 mRNA and protein in four OS cell lines (MG-63, HOS, SaOS-2 and U2OS) were significantly higher than that in hFOB1.19 osteoblast (P < 0.05). The vector pcDNA-MACC1 contributed to the increase of MACC1 level in MG-63 cells, whereas MACC1 siRNA evoked the decrease of MACC1 level in U2OS cells. In addition, MACC1 downregualtion caused the inhibition of cell proliferation in vitro, colony formation, invasion and tumor growth in vivo, arrested cell cycle in G0/G1 phase and induced cell apoptosis in U2OS cells, and reversed effects were observed in MG-63 cells by MACC1 upregulation. Most notably, MACC1 depletion markedly inactivated Akt signaling pathway in U2OS cells, conversely, MACC1 upregulation evidently activated Akt signaling pathway in MG-63 cells. Collectively, our data presented herein suggest that biological implications triggered by MACC1 may be tightly associated with the status of Akt signaling pathway in OS.
BackgroundTreatment of rheumatoid arthritis (RA) patients by anti-tumour necrosis factors (anti-TNFs), such as golimumab, has substantially improved patient outcomes. However, unmet therapeutic needs exist for the significant proportion of patients who do not respond to current biologics treatment. Mavrilimumab is a fully human monoclonal antibody which inhibits the granulocyte-macrophage colony-stimulating factor receptor α (GM–CSFR-α). Recently, a Phase IIb study has been completed to evaluate the efficacy and safety of mavrilimumab and golimumab in both disease-modifying antirheumatic drug (DMARD)-inadequate responder (IR) and anti-tumor necrosis factor-inadequate responders (anti-TNF-IR) patients (EARTH EXPLORER 2, NCT01715896).ObjectivesTo assess peripheral biomarkers and pathophysiological pathways modulated by mavrilimumab in comparison with golimumab in both DMARD-IR and anti-TNF-IR RA patients.MethodsIn total, 75 DMARD-IR and 63 anti-TNF-IR patients were randomized in a 1:1 ratio to receive subcutaneous 100 mg mavrilimumab (n=70) every other week (Q2W) or 50 mg golimumab (n=68) Q2W alternating with placebo, in combination with methotrexate (7.5–25.0 mg/week) for 24 weeks. Serum levels of 18 RA-associated proteins as well as 3 protease-derived protein fragments were measured in 71 DMARD-IR and 61 anti-TNF-IR RA patients at baseline and 4 time points post-administration. Transcriptome sequencing was used to measure gene expression changes in whole blood of RA patients at baseline and day 169 post-administration.ResultsSerum levels of CCL22 and CCL17 were suppressed by mavrilimumab but not golimumab, while CXCL13 and ICAM1 levels were suppressed by golimumab but not mavrilimumab. Those four proteins may be specific pharmacodynamic markers for the two biologics respectively. More interestingly, both mavrilimumab and golimumab demonstrated early and sustained suppression of multiple inflammatory markers in DMARD-IR patients, including CRP, SAA, MMP1, MMP3, IL6, VEGF, IL2R, and CD163. However, golimumab-induced early changes rapidly returned towards baseline levels in anti-TNF-IR patients, while serum protein suppression by mavrilimumab was maintained through day 169 in anti-TNF-IR patients. Similarly, mavrilimumab administration was associated with durable suppression of extracellular matrix markers, C1M, C3M, and P4NP7S, while golimumab only induced a transient change of the three markers in anti-TNF-IR patients. Furthermore, RNA sequencing results demonstrated significant regulation of 1547 transcripts at day 169 after mavrilimumab administration while golimumab had no impact on whole blood gene expression in anti-TNF-IR patients. In contrast, significant changes of 1042 and 2058 transcripts were observed in DMARD-IR patients at day 169 after mavrilimumab and golimumab administration respectively.ConclusionsOur study demonstrated sustained suppression of RA disease markers by mavrilimumab but not golimumab in anti-TNF-IR patients, suggesting the potential of greater long-term disease control by mavrilimumab ...
BackgroundBiologic products, such as rituximab and adalimumab, have revolutionized the treatment for chronic inflammatory disorders, providing an option to patients who were non-responsive to conventional systemic therapies. In China, rituximab is only approved for the treatment of certain haematologic malignancies. At present, there are several approved biosimilar drugs in Europe but none in China. HLX01, a China-manufactured proposed rituximab biosimilar, was first developed for patients with non-Hodgkin’s lymphoma later as a new drug for the treatment for autoimmune diseases. Currently, HLX01’s biosimilar NDA for the treatment of non-Hodgkin’s lymphoma is being reviewed by authorities in China.ObjectivesEvaluation of clinical PK, safety and exploratory efficacy in RA patients to support the development of HLX01 for the treatment of autoimmune diseaseMethodsWe conducted a multi-centre, randomised, double-blind, parallel active-controlled clinical trial to compare the PK, PD safety and exploratory efficacy (ACR20 and DAS28-CRP) between HLX01 and Europe sourced rituximab (EU-RTX) as two-1000 mg intravenous infusions (Days 1 and 15) in moderately to severely active RA patients who have had inadequate response to treatment with disease-modifying antirheumatic drugs (DMARDs). The PK equivalence was achieved if 90% confidence intervals (CIs) for the test-to-reference ratios of area under the curve from time zero to infinity (AUC(0-inf)) and maximum observed concentration (Cmax) fall within the pre-defined 80-125% equivalence margin.ResultsIn the study, a total of 196 patients randomised at 1:1 ratio to HLX01 and EU-RTX and 179 subjects (88 in HLX01 group; 91 subjects in EU-RTX group) were included in the PK pre-protocol set (PPS). The 90% confidence intervals (CI) for the ratio of geometric means for the pairwise comparisons of the primary PK endpoint AUC (0-inf) (Figure 1), as well as AUC(0-14d), AUC(0-t,1), AUC(15d-t), Cmax,1, Cmax,2, Cmin were within the pre-specified limits of 80-125% (Table 1). Based on the ACR20 and DAS28-CRP results at week 24, HLX01 group and EU-RTX group are similar. In addition to the efficacy similarity, there was also no statistical difference in safety and immunogenicity between the two treatment groups.ConclusionWe report successful demonstration of similarity in PK, safety and initial efficacy between first China-manufactured biosimilar of rituximab, HLX01, and Europe-sourced rituximab in patients with moderately to severely active rheumatoid arthritis. These results support the Phase 3 confirmatory clinical trial for the development of HLX01 for the treatment of rheumatoid arthritis.Disclosure of InterestsXiaofeng Zeng: None declared, Yongfu Wang: None declared, Zhenyu Jiang: None declared, Zhuoli Zhang: None declared, Lan He: None declared, Xiao Zhang: None declared, Xin Lu: None declared, Xiumei Liu: None declared, Jian Xu: None declared, Cibo Huang: None declared, Rui Liu: None declared, Xiaoxia Zuo: None declared, Baozeng Zhao Employee of: Employee of Shanghai Henlius Biotech Inc.,...
BackgroundAdalimumab first launched in China in August 2010 with now more than 10 million people have its indications.1, 2 However, the relative high cost of the biologic drug limits the treatment accessibility and reduces the quality of life in patients living with the chronic inflammatory disease like rheumatoid arthritis and psoriasis. In accordance with the China National Medical Product Administration (NMPA) biosimilar regulatory development pathway, biosimilar products require to demonstrate similarity in pharmacokinetics (PK) and safety profile compared to its reference drug, which could further address the unmet medical needs of adalimumab. HLX03 was developed as a proposed biosimilar to adalimumab with the potential to increase affordable treatment options for access.ObjectivesThe study was aiming to compare the pharmacokinetics (PK), safety and immunogenicity of the proposed adalimumab biosimilar HLX03 with reference product.MethodsWe conducted a randomised, double-blind, parallel-controlled clinical trial (NCT03357939) in China to compare the PK, safety and immunogenicity of HLX03 and China sourced adalimumab (CN-adalimumab). In this study, 211 healthy volunteers were randomised 1:1 to receive a single (40 mg) subcutaneous injection of HLX03 or CN-adalimumab. The primary PK endpoints were area under the curve (AUC) from time zero to the last quantifiable concentration (AUC0-t) and maximum observed concentration (Cmax), secondary endpoint was AUC from time zero to infinity (AUC0-inf). PK equivalence was established if the 90% confidence interval (CI) for the test-to-reference ratio fall within the 80-125% equivalence margin.ResultsBased on the analysis of 210 subjects in the per protocol population (PPS) and 211 subjects in the full analysis set (FAS), HLX03 demonstrated PK equivalence to CN-adalimumab for all primary endpoints (Table 1). The incidents of adverse events (AEs) between two treatment groups were similar, with treatment-emergent AEs (TEAEs) noted by a total of 149 (70.0%), 79 (73.8%) in HLX03 and 70 (66.0%) in CN-adalimumab group, respectively. One subject suffered non-drug-related severe AE (tuberculosis) in the HLX03 arm, and one subject occurred grade 4 AE (elevated creatine phosphokinase) in the CN-adalimumab arm. In the group of CN-adalimumab, 6 more incidents of positive anti-drug antibodies (ADA) recorded at day 7 and no further significant difference observed. Based on the established clinical PK equivalence and safety similarities, 262 patients with moderate-to-severe chronic plaque psoriasis were randomized in 21 centers at 1:1 ratio to conduct a double-blind, parallel-controlled phase 3 study (NCT03316781) to further evaluate the efficacy and safety profiles of HLX03 and reference adalimumab. The primary efficacy endpoint was the improvement rate of Psoriasis Area and Severity Index (PASI) over the baseline at week 16.ConclusionPK equivalence and safety similarities between HLX03 and CN-adalimumab were demonstrated which leads to a multi-center, randomised, double-blind, parallel-...
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