Targeted anti-tumor synergistic effects of Myc decoy oligodeoxynucleotides-loaded selenium nanostructure combined with chemoradiotherapy on LNCaP prostate cancer cells

In the present study,we investigated the synergistic effects of targeted methotrexate-selenium nanostructure containing Myc decoy oligodeoxynucleotides along with X-irradiation exposure as a combination therapy on LNCaP prostate cancer cells.Myc decoy ODNs were designed based on the promoter of Bcl-2 gene and analyzed by molecular docking and molecular dynamics assays.ODNs were loaded on the synthesized Se@BSA@Chi-MTX nanostructure.The physicochemical characteristics of nanostructures were determined by FTIR,DLS,UV-vis,TEM,EDX,in vitro release,and hemolysis tests.Subsequently,the cytotoxicity properties of them with and without X-irradiation were investigated by uptake,MTT,cell cycle,apoptosis,and scratch assays on the LNCaP cell line.The results of DLS and TEM showed negative charge(−9 mV)and nanometer size(40 nm)for Se@BSA@Chi-DEC-MTX NPs,respectively.The results of FTIR,UV-vis,and EDX showed the proper interaction of different parts and the correct synthesis of nanoparticles.The results of hemolysis showed the hemocompatibility of this nanoparticle in concentrations less than 6 mg/mL.The ODNs release from the nanostructures showed a pH-dependent manner,and the release rate was 15%higher in acidic pH.The targeted Se@BSA@Chi-labeled ODN-MTX NPs were efficiently taken up by LNCaP cells by targeting the prostate-specific membrane antigen(PSMA).The significant synergistic effects of nanostructure(containing MTX drug)treatment along with X-irradiation showed cell growth inhibition,apoptosis induction(~57%),cell cycle arrest(G2/M phase),and migration inhibition(up to 90%)compared to the control.The results suggested that the Se@BSA@Chi-DEC-MTX NPs can potentially suppress the cell growth of LNCaP cells.This nanostructure system can be a promising approach for targeted drug delivery and chemoradiotherapy in prostate cancer treatment.

Observation on the Clinical Effect of Applying Venetoclax Combined with Demethylation Drug Therapy in Patients with Acute Myeloid Leukemia

Objective: To investigate the therapeutic effect of applying venetoclax combined with demethylating drugs in treating patients with acute myeloid leukemia (AML). Methods: Eighty cases of AML patients treated with venetoclax combined with demethylating drugs in our hospital were selected from March 2021 to March 2024, including 40 cases of primary treatment patients and 40 cases of relapsed and refractory patients. The efficacy and safety of the combined drug therapy was analyzed. Results: The primary treatment group was presented with a complete remission (CR) rate of 40.5%, partial remission (PR) rate of 47.50%, no response (NR) rate of 12.50%, and a remission rate of 87.50%. The relapsed- refractory group was presented with a CR rate of 37.50%, PR rate of 42.50%, NR rate of 17.50%, and a remission rate of 87.50%. There was no statistical significance between the groups (P > 0.05). The hematological adverse reactions of the combined treatment for AML were leukopenia and the non-hematological adverse reactions were mainly infections, with an incidence rate of 87.50%. Conclusion: The efficacy of venetoclax combined with demethylating drugs in AML was remarkable and the treatment regimen can be adjusted according to the treatment-resistant response.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Update of latest data for combined therapy for esophageal cancer using radiotherapy and immunotherapy:A focus on efficacy,safety,and biomarkers

Esophageal cancer usually has a poor prognosis.Given the significant breakthrough with tumor immunotherapy,an increasing number of clinical studies have demonstrated that the combination of radiotherapy and immune checkpoint inhibitors(ICIs)may have a synergistic effect and good outcome in esophageal cancer.Clinical studies of immunoradiotherapy(iRT)for esophageal cancer have proliferated enormously from 2021 to the present.However,a summary of the efficacy and toxicity of combined therapy to guide esophageal cancer treatment in clinical practice is lacking.For this review,we integrate the latest data to analyze and assess the efficacy and safety of iRT for esophageal cancer.In addition,we discuss better predictive biomarkers,therapeutic options for specific populations,and other challenges to identify directions for future research design.

Immunotherapy for esophageal cancer:Where are we now and where can we go

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis,and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma(ESCC)in the past decade.Monoclonal antibodies that selectively inhibit programmed cell death-1(PD-1)activity has now become standard of care in the treatment of ESCC in metastatic settings,and has a high expectation to provide clinical benefit during perioperative period.Further,anti-cytotoxic T-lymphocyte–associated protein 4(CTLA-4)monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody.Well understanding of the existing evidence of immune-based treatments for ESCC,as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant,adjuvant,and metastatic diseases,may provide future prospects of ESCC treatment for better patient outcomes.

CA IX-targeted Ag_(2)S quantum dots bioprobe for NIR-II imaging-guided hypoxia tumor chemo-photothermal therapy

Hypoxia is the common characteristic of almost all solid tumors,which prevents therapeutic drugs from reaching the tumors.Therefore,the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely concerned.As carbonic anhydrase IX(CA IX)is abundantly distributed on the hypoxia tumor cells,it is considered as a potential tumor biomarker.4-(2-Aminoethyl)benzenesulfonamide(ABS)as a CA IX inhibitor has inherent inhibitory activity and good targeting effect.In this study,Ag_(2)S quantum dots(QDs)were used as the carrier to prepare a novel diagnostic and therapeutic bioprobe(Ag_(2)S@polyethylene glycol(PEG)-ABS)through ligand exchange and amide condensation reaction.Ag_(2)S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor imaging by the near infrared-II(NIR-II)fluorescence characteristics of Ag_(2)S QDs.PEG modification of Ag_(2)S QDs greatly improves its water solubility and stability,and therefore achieves high photothermal stability and high photothermal conversion efficiency(PCE)of 45.17%.Under laser irradiation,Ag_(2)S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells(CT-26)in vitro.It also has been proved that Ag_(2)S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good biocompatibility.Therefore,it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

Anti-OX40 Antibody Combined with HBc VLPs Delays Tumor Growth in a Mouse Colon Cancer Model

Objective Combination immunotherapy strategies targeting OX40,a co-stimulatory molecule that can enhance antitumor immunity by modulating the proliferation,differentiation,and effector function of tumor-infiltrating T cells,have attracted much attention for their excellent therapeutic effects.In this study,we aimed to evaluate the antitumor efficacy of combined anti-OX40 and hepatitis B core viruslike particles(HBc VLPs)therapy using a mouse colon cancer model.Methods Humanized B-h OX40 mice were injected subcutaneously with MC38 colon tumor cells and treated with HBc VLPs+anti-h OX40 antibody.Tumor growth was monitored.Flow cytometric analysis was performed to evaluate the populations of T cell subsets in the tumors.Results The combination of anti-OX40 with HBc VLPs resulted in a significant delay in tumor growth,suggesting that a potent antitumor immunity was induced by the combination therapy.Further studies revealed that HBc VLPs+anti-OX40 treatment induced a significant increase in effector T cells(Teffs)and a significant decrease in regulatory T cells(Tregs)in the tumor microenvironment(TME),which accounted for the synergistic antitumor effect of anti-OX40 in combination with HBc VLPs.Conclusion Combination therapy of anti-h OX40 and HBc VLPs provides synergistic antitumor activity in colon cancer-bearing mice,which may represent a potential design strategy for cancer immunotherapy.

Back to the drawing board:Overview of the next generation of combination therapy for inflammatory bowel disease

Inflammatory bowel disease(IBD)is entering a potentially new era of combined therapeutics.Triantafillidis et al provide an insightful review of the current state of combination therapy,with a focus on the use of a combined biologic and immunomodulator,as well as emerging data on the future potential of dual-biologic therapy(DBT).While current evidence for DBT is limited,encouraging safety profiles and ongoing trials suggest a brighter future for this approach.The importance of controlled trials should be stressed in establishing new treatment paradigms.Ongoing prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.

Combinational therapy with Myc decoy oligodeoxynucleotides encapsulated in nanocarrier and X-irradiation on breast cancer cells

The Myc gene is the essential oncogene in triple-negative breast cancer(TNBC).This study investigates the synergistic effects of combining Myc decoy oligodeoxynucleotides-encapsulated niosomes-selenium hybrid nanocarriers with X-irradiation exposure on the MDA-MB-468 cell line.Decoy and scramble ODNs for Myc transcription factor were designed and synthesized based on promoter sequences of the Bcl2 gene.The nanocarriers were synthesized by loading Myc ODNs and selenium into chitosan(Chi-Se-DEC),which was then encapsulated in niosome-nanocarriers(NISM@Chi-Se-DEC).FT-IR,DLS,FESEM,and hemolysis tests were applied to confirm its characterization and physicochemical properties.Moreover,cellular uptake,cellular toxicity,apoptosis,cell cycle,and scratch repair assays were performed to evaluate its anticancer effects on cancer cells.All anticancer assessments were repeated under X-ray irradiation conditions(fractionated 2Gy).Physicochemical characteristics of niosomes containing SeNPs and ODNs showed that it is synthesized appropriately.It revealed that the anticancer effect of NISM@Chi-Se-DEC can be significantly improved in combination with X-ray irradiation treatment.It can be concluded that NISM@Chi-Se-DEC nanocarriers have the potential as a therapeutic agent for cancer treatment,particularly in combination with radiation therapy and in-vivo experiments are necessary to confirm the efficacy of this nano-drug.

Enhancing metformin-induced tumor metabolism destruction by glucose oxidase for triple-combination therapy

Despite decades of laboratory and clinical trials,breast cancer remains the main cause of cancer-related disease burden in women.Considering the metabolism destruction effect of metformin(Met)and cancer cell starvation induced by glucose oxidase(GOx),after their efficient delivery to tumor sites,GOx and Met may consume a large amount of glucose and produce sufficient hydrogen peroxide in situ.Herein,a pH-responsive epigallocatechin gallate(EGCG)-conjugated low-molecular-weight chitosan(LC-EGCG,LE)nanoparticle(Met–GOx/Fe@LE NPs)was constructed.The coordination between iron ions(Fe3+)and EGCG in this nanoplatform can enhance the efficacy of chemodynamic therapy via the Fenton reaction.Met–GOx/Fe@LE NPs allow GOx to retain its enzymatic activity while simultaneously improving its stability.Moreover,this pH-responsive nanoplatform presents controllable drug release behavior.An in vivo biodistribution study showed that the intracranial accumulation of GOx delivered by this nanoplatform was 3.6-fold higher than that of the free drug.The in vivo anticancer results indicated that this metabolism destruction/starvation/chemodynamic triple-combination therapy could induce increased apoptosis/death of tumor cells and reduce their proliferation.This triple-combination therapy approach is promising for efficient and targeted cancer treatment.

Lenvatinib combined with sintilimab plus transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma

BACKGROUND Recently,combination therapy has shown a better trend towards improved tumour response and survival outcomes than monotherapy in patients with hepatocellular carcinoma(HCC).However,research on triple therapy[lenvatinib+sintilimab+transarterial chemoembolization(TACE)]as a first-line treatment for advanced HCC is limited.AIM To evaluate the safety and efficacy of triple therapy as a first-line treatment for advanced HCC.METHODS HCC patients with Barcelona Clinic Liver Cancer stage C treated with triple therapy were enrolled.All patients were treated with lenvatinib every day and sintilimab once every 3 wk.Moreover,TACE was performed every 4-6 wk if necessary.The primary outcome of the study was overall survival(OS).The secondary outcomes were the objective response rate(ORR),disease control rate(DCR),and incidence of adverse events.RESULTS Forty HCC patients who underwent triple therapy were retrospectively analysed from January 2019 to January 2022.With a median follow-up of 8.5 months,the 3-,6-,and 12-mo OS rates were 100%,88.5%,and 22.5%,respectively.The ORR and DCR were 45%and 90%,respectively.The median progressive free survival and median OS were not reached.Common complications were observed in 76%of the patients(grade 3,15%;grade 4,2.5%).CONCLUSION Combination therapy comprising lenvatinib,sintilimab and TACE achieved promising outcomes in advanced HCC patients and had manageable effects.

Therapeutic effect of San Bi Tang combined with glucosamine sulfate capsules in cold-dampness-type knee osteoarthritis

BACKGROUND Cold-dampness-type knee osteoarthritis is a common middle-aged and elderly disease,but its pathogenesis is not fully understood,and its clinical treatment has limitations.Glucosamine sulfate capsules are commonly used for treating arthritis,and San Bi Tang is a classic formula of traditional Chinese medicine(TCM)that has the effects of warming yang,dispelling dampness,relaxing muscles,and activating collaterals.This research hypothesized that the combination of modified San Bi Tang and glucosamine sulfate capsules could enhance the clinical efficacy of treating cold-dampness-type knee osteoarthritis through complementary effects.AIM To analyze the clinical efficacy of San Bi Tang combined with glucosamine sulfate capsules when treating cold-dampness-type knee osteoarthritis.METHODS A total of 110 patients with cold-dampness-type knee osteoarthritis were selected as research subjects and randomly divided into a control group and an experimental group of 55 cases each.The control group received only treatment with glucosamine sulfate capsules,while the experimental group received additional treatment with modified San Bi Tang for a duration of 5 wk.The patients’knee joint functions,liver and kidney function indicators,adverse reactions,and vital signs were evaluated and analyzed using SPSS 26.0 software.RESULTS Before treatment,the two groups’genders,ages,and scores were not significantly different,indicating comparability.Both groups’scores improved after treatment,which could indicate pain and knee joint function improvement,but the test group had better scores.The TCM-specific symptoms and the clinical efficacy of the treatment in the test group were higher.Before and after treatment,there were no abnormalities in the patients’liver and kidney function indicators.CONCLUSION The combination of modified San Bi Tang and glucosamine sulfate capsules is superior to treatment with sulfated glucosamine alone and has high safety.

Tumor-infiltrating T-Lymphocyte immunity-related immune tolerance and anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy for advanced hepatocellular carcinoma

Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma(HCC)whose treatment options are limited.However,the long-term patient response to drugs and the survival outcomes remain a concern.With increasing exploration of the HCC microenvironment,particularly in terms of T lymphocyte immunity,a new era of immunomolecular targeted therapy,based on molecular signaling,has arrived for advanced HCC.In the study of immune tolerance of the intrinsic HCC microenvironment,we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors,such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy,have improved clinical outcomes in some patients with advanced HCC.Furthermore,various combination therapies have been investigated,and HCC types have been categorized into different types based on anti–programmed cell death protein 1(PD-1)/ligand of programmed cell death protein 1(PD-L1)treatment.In this paper,we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC.We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy.Thereafter,we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors,anti–T lymphocyte–related signaling pathways in HCC,and other anti-CD8+T cell immune checkpoints.In this way,this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC,in order to provide better individualized treatments for patients with advanced HCC.

A Clinical Study to Assess the Effectiveness of Oral Combination Kit Therapy in Syndromic Management of Abnormal Vaginal Discharge (FEMINE Study) in Kinshasa, Democratic Republic of Congo

Background: Vaginal discharge is one of most common and nagging problems that women face. About 20% - 25% of women who visit gynecology department complain of vaginal discharge and leucorrhoea. An orally administered combination kit, containing 2 g secnidazole, 1 g azithromycin and 150 mg fluconazole (Azimyn FS Kit), has been successfully evaluated in clinical trials and used in several countries for management syndromic vaginal discharge due to infections. Methods: This is a longitudinal study which aimed to verify the clinical efficacy of the combined oral kit containing secnidazole, azithromycin and fluconazole (Azimyn FS Kit®) in the syndromic treatment of abnormal vaginal discharge in patients received in outpatient consultations in Kinshasa/DR Congo from March to September 2023. Results: Majority of patients had whitish vaginal discharge (51.6%) of average abundance (56.2%), accompanied by pruritus in 72.1% of cases, and dyspareunia in 23.5% of cases and hypogastralgia in 40.2% of cases. One week after treatment with the Azimyn FS® combined kit, at the greatest majority of patients (97.3%), abnormal vaginal discharge had decreased by more than 50% (84.1%). Two weeks after treatment with the Azimyn FS® combined kit, almost all patients (97.3%) no longer had abnormal vaginal discharge which had completely disappeared. Conclusion: A single dose of secnidazole, azithromycin and fluconazole in the form of an oral combi-kit (Azimyn FS Kit) has shown excellent therapeutic effectiveness in the syndromic treatment of abnormal vaginal discharge wherein patients were treated without diagnostic confirmation.

Advances in locoregional therapy for hepatocellular carcinoma combined with immunotherapy and targeted therapy

Locoregional therapies(LRTs)of hepatocellular carcinoma(HCC)represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC.Among these,TACE is used throughout the stageⅠb toⅢb of HCC treatment.In recent years,immunotherapy led by immune checkpoint inhibitors has become a hot direction in clinical research.At the same time,targeted drugs such as Sorafenib and Apatinib have played an important role in the treatment and complementary therapy of advanced HCC,and their clinical application has been quite mature.HCC is the sixth most common malignant tumor in the world.When it comes to its treatment,different therapies have different indications,and their individual efficacies are not satisfactory,which makes the exploration of the use of combination therapy in HCC treatment become a new trend.In this paper,the status of the three therapies and the progress of their combined application are briefly reviewed.

Comparison of therapeutic effectiveness of combined interventional therapy for 1126 cases of primary liver cancer

AIM： To verify the effect of combined interventiona therapy for hepatocellular carcinoma （HCC）. METHODS： The clinical data of 1126 HCC patients who received combined interventional therapy for transcatheter arterial chemoembolization （TACE） before or after hepatectomy, TACE and radio-frequency ablation （RFA）, Chinese medicine treatment and biotherapy after TACE or transcatheter arterial infusion （TAI）, were reviewed according to the results of their liver function, alpha-fetoprotein, image data, color-ultrosonography finding and survival rate. RESULTS： A total of 874 patients were followed up for a period of 2 to 63 mo. The overall 1-, 3- and 5- year survival rates were 67.8%, 28.7% and 18.8% respectively. The 1- 3- and 5- year survival rates of patients who received TACE were 74.7%, 41.4%, 36.9% before hepatectomy and 78.9%, 40.4%, 37.5% after hepatectomy. The effective rate （PR ＋ NC） after TACE and RFA was 93.4%, the 1- and 3- year survival rates were 74.5% and 36.8% after TACE and RFA. The effective rate of PR ＋ NC after TACE was 83.2%. The 1-, 3- and 5- year survival rates were 69.3%, 21.7%, 8.4% after TACE. The effective rate of PR ＋ NC after TAI was 27.5%, the 1- and 2- year survival rates were 11.6% and 0% after TAI. The liver function, color-ultrosonography finding and alpha-fetoprotein after TACE ＋ RFA, TACE and TAI were compared. There was no significant difference in each index between TACE and RFA or TACE as well as in liver function between TACE and RFA or between TACE and TAI. CONCLUSION： The therapeutic effectiveness of TACE before or after hepatectomy is most significant, while the effect of TACE and RFA is better than that of TACE, and the effect of TAI is minimal.

Combined therapy with bevacizumab and photodynamic therapy for myopic choroidal neovascularization: A oneyear follow-up controlled study

AIMTo evaluate the efficacy and safety of a combined treatment for myopic choroidal neovascularization (CNV) using photodynamic therapy (PDT) and intravitreal bevacizumab and to compare it with intravitreal bevacizumab monotherapy.

Effective combined therapy for pulmonary epithelioid hemangioendothelioma: A case report

BACKGROUND Pulmonary epithelioid hemangioendothelioma(P-EHE)is a rare disease.Thus far,consensus on a standard treatment for P-EHE has not been established given its low incidence worldwide.Apatinib combined with chemotherapy with doxorubicin/cyclophosphamide has been used as an effective combination treatment for human malignancies.However,the efficacy of this combination has not been reported in P-EHE cases.CASE SUMMARY We present the case of a 64-year-old woman with chest tightness,cough,and chest pain.Computed tomography showed multiple unresectable pulmonary nodules.She had been misdiagnosed with lung carcinoma and underwent gefitinib treatment at a hospital.Subsequently,the patient underwent a cardiothoracic surgery for further disease investigation.CD31,CD34,and Vimentin expression were detected in the resected nodule specimens by immunohistochemical analyses,and pathological analyses confirmed the diagnosis of P-EHE.Following this,four cycles of apatinib combined with chemotherapy with doxorubicin/cyclophosphamide were initiated.The patient demonstrated stabilization of multiple bilateral nodules and showed a dramatic improvement in the clinical presentation after combination treatment.The patient could not tolerate the side effects of chemotherapy.Therefore,she then continued apatinib monotherapy,which is ongoing to date.The patient was stable at the last follow-up after 24 mo.CONCLUSION Apatinib combined with chemotherapy with doxorubicin/cyclophosphamide may be an effective therapeutic option for P-EHE treatment.

Real world effectiveness of PCSK-9 inhibitors combined with statins versus statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease in China(RWE-PCSK study)

BACKGROUND The efficacy and safety of proprotein convertase subtilisin/kexin type 9(PCSK-9) inhibitors were confirmed by several clinical trials, but its effectiveness in routine clinical practice in China has not been evaluated. This study aims to describe the real world effectiveness of PCSK-9 inhibitors combined with statins compared with statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease(ASCVD).METHODS This is a multi-center observational study, enrolled patients from 32 hospitals who underwent percutaneous coronary intervention(PCI) from January to June in 2019. There are 453 patients treated with PCSK-9 inhibitors combined with statins in PCSK-9 inhibitor group and 2,610 patients treated with statins-based lipid lowering therapies in statins-based group. The lipid control rate and incidence of major adverse cardiovascular events(MACE) over six months were compared between two groups.A propensity score-matched(PSM) analysis was used to balance two groups on confounding factors. Survival analysis using Kaplan-Meier methods was applied for MACE.RESULTS In a total of 3,063 patients, 89.91% of patients had received moderate or high-intensity statins-based therapy before PCI, but only 9.47% of patients had low-density lipoprotein cholesterol(LDL-C) levels below 1.4 mmol/L at baseline. In the PSM selected patients, LDL-C level was reduced by 42.57% in PCSK-9 inhibitor group and 30.81%(P < 0.001) in statins-based group after six months. The proportion of LDL-C ≤ 1.0 mmol/L increased from 5.29% to 29.26% in PCSK-9 inhibitor group and 0.23% to 6.11% in statins-based group, and the proportion of LDL-C ≤ 1.4 mmol/L increased from 10.36% to 47.69% in PCSK-9 inhibitor group and 2.99% to 18.43% in statins-based group(P < 0.001 for both). There was no significant difference between PCSK-9 inhibitor and statins-based treatment in reducing the risk of MACE(hazard ratio = 2.52, 95% CI: 0.49-12.97, P = 0.250).CONCLUSIONS In the real world, PCSK-9 inhibitors combined with statins could significantly reduce LDL-C levels among patients with very high risk of ASCVD in China. The long-term clinical benefits for patients received PCSK-9 inhibitor to reduce the risk of MACE is still unclear and requires further study.

Evaluation of modified hemodilution combined therapy in the treatment of acute ischemic stroke in the elderly

BACKGROUND： Thrombolysis therapy is not suitable for the elderly patients with acute ischemic stroke who delayed to be diagnosed for more than 3 hours, but traditional medicine is also not very ideal. OBJECTIVE： To observe the clinical therapeutic effect of modified hemodilution combined therapy applied in elderly patients with acute cerebral thrombosis and analyze the mechanism of this therapeutic method. DESIGN： 1：1 paired grouping according to gender and controlled observation SETTING： Department of Internal Medicine, Chengzhanyuan District, First Hospital Affiliated to Zhejiang University. PARTICIPANTS： Totally 90 elderly patients with acute ischemic stroke who received the treatment in the Cadre Ward and Mental Ward, Department of Internal Medicine, Chengzhanyuan District, First Hospital Affiliated to Zhejiang University from March 1996 to June 2004 were recruited. They all met the diagnosis criteria revised by the Fourth Academic Conference of National Cerebrovascular Diseases in 1995 and were diagnosed as acute ischemic stroke by skull CT. They were informed of therapeutic plan and detected items. According to 1：1 paired principle in gender, 90 enrolled patients were assigned into treated group （n=45） and control group （n=45）. There were 39 male and 6 female in the treatment group, and they were aged （76±6）years, ranging from 71 to 84 years, and hospitalized at the 14^th to 76^th hours after onset. There were 39 male and 6 female in the control group, and they were aged （76±6）years , ranging from 70 to 82 years, and hospitalized at the 16^th to 72^th hours after onset. METHODS： Therapeutic method： Patients of treated group received modified hemodilution combined therapy. 200 mL whole blood of patients was exchanged with 500 mL dextran-40 （including 20 mL danshen parenteral solution and 32 mg heparin） at the beginning of therapy; From the 2^nd day, compound huangqi tea bag （Huangqi mainly, including danshen, honghua, chuanxiong, shishao and a little acetyl salicylic acid） was made, twice a day, 1 bag once. At the same time, the above-mentioned dextran-40 liquid of 500 mL was intravenously injected, once a day, 14 days in total; On the 6^th day after therapy, the above-mentioned aseptic autoblood stored in refrigerator at 4℃ was transfused back into the patients following pre-treatment of high-concentration oxygenation and ultraviolet irradiation by light quantum instrument. Patients of control group were intravenously injected of 0.4 g venoruton（Traditional Chinese medicine compound parenteral solution for promoting blood circulation and removing blood stasis ） and 50 g/L glucose of 500 mL, 75 mg acetosal was taken orally, once a day, 14 days in total. ② Measurement and observation of index： Blood coagulation index, change of platelet aggregation rate and change of hemorrheology of patients in two groups were monitored before and after therapy. The level of blood lipid of patients in two groups was measured with American Beckman automatic biochemistry analyzer. Blood flow rate of middle cerebral artery of resting electrocardiogram were measured with American HP SONOS 2500 sonoscope. Neuro-dysfunction score revised in the national conference （1995） was used to evaluate the recovery of neurological function of the patients in two groups at the 3rd, 5^th, 7^th and 14^th days after therapy. ③Therapeutic effect and adverse effect were observed at the same time. MAIN OUTCOME MEASURES ： ① Changes of coagulation index, blood lipid level and hemorheology; ② Blood flow rate of middle cerebral artery and NDS of patients with acute ischemic stroke in two groups; ③Adverse effect of drug. RESULTS： Totally 90 patients were enrolled in the experiment. One patient from treated group died of hyperosmolar nonketotic diabetic coma of complicated diabetes mellitus. One patient from control group died of severe pulmonary infection. The rest 88 patients entered the stage of result analysis. ① Change of coagulation index and platelet aggregation rate： prothrombin time （PT）, activated partial thromboplastin time （APTT） and thrombin time （TT） of patients after therapy were significantly longer than those before therapy in the treated group and those after therapy in control group [After therapy in treated group： （18.4±1.9）, （41.8±2.1）, （19.7±1.7） s, Before therapy in treated group： （13.4±1.3）, （35.8±1.3）, （12.5±0.9） s, After therapy in control group： （16.9±1.5）, （39.1±1.1）, （11.9±2.1） s, P〈 0.05]：Concentration of fibrinogen （Fbg） after therapy was significantly lower than that before therapy in the treated group and that after therapy in control group[After therapy in treated group： （3.4±0.4） g/L; Before therapy in treated group： （4.3±0.7） g/L; After therapy in control group：（4.0±0.6） g/L; P 〈 0.05]. Platelet aggregation rate decreased from （37.92 ±0.85）% before therapy to （26.42±1.01）% after therapy （P 〈 0.01）. ②Change of blood lipid level： Levels of total cholesterol （TC）, triacylglycerol（TG） and low density lipoprotein cholesterol （LDL-C） of patients after therapy were significantly lower than those before therapy in treated group and those after therapy in control group [After therapy in treated group： （5.2±0.9）, （1.9±0.9）, （2.08±1.1） mmol/L, before therapy in treated group： （5.9±1.2）, （2.8±0.9）, （3.94±0.5） mmol/L, After therapy in control group： （6.0±1.1）, （2.6±0.8）, （3.84±0.9） mmol/L, P 〈 0.05]. ③Change of hemorheology index： Hematocrit of patients of treated group was significantly lower after therapy than before therapy [Before therapy： （43.84±4.55）% ;After therapy： （40.48±4.02）%;P 〈 0.05]. Blood flow rate of middle cerebral artery of patients of treated group was significantly lower before therapy than after therapy [（90±1.2）, （97±2.1） cm/s,P〈 0.01]. ⑤NDS of patients in treated group was significantly lower than of control group 14 days after therapy. The total effective rate after therapy was significantly higher in the treated group than in the control group （93%,78%, P 〈 0.05）. ⑥There was no obvious adverse effect. CONCLUSION： Modified hemodilution combined therapy can improve hemorheology, decrease hematocrit, increase blood flow rate of middle cerebral artery, so as to improve the impaired clinical neurological function of elderly patients with acute cerebral thrombosis through anticoagulation and antiplatelet aggregative activity as well as regulating blood lipid.