Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

Nab-paclitaxel plus capecitabine as first-line treatment for advanced biliary tract cancers:An open-label,non-randomized,phase II clinical trial

BACKGROUND Biliary tract cancers(BTCs)are a heterogeneous group of tumors with high malignancy,poor prognosis,and limited treatment options.AIM To explore the efficacy and safety of nab-paclitaxel plus capecitabine as first-line treatment for advanced and metastatic BTCs.METHODS This open-label,non-randomized,double-center,phase II clinical trial recruited systemic therapy-naive patients with unresectable or metastatic BTCs between April 2019 and June 2022 at Beijing Cancer Hospital and the First Hospital of China Medical University.Eligible patients were administered nab-paclitaxel(150 mg/m2,day 1)and capecitabine(2000 mg/m2,twice daily,days 1-7)in 14-day cycles until experiencing intolerable toxicity or disease progression.The primary outcome was the objective response rate(ORR).The secondary outcomes included the disease control rate(DCR),overall survival(OS),progression-free survival(PFS),and safety.RESULTS A total of 44 patients successfully completed the trial,with a median age of 64.00 years(interquartile range,35.00-76.00),and 26(59.09%)were females.Tumor response assessment was impeded for one patient due to premature demise from tumor hemorrhage.Among the remaining 43 patients undergoing at least one imaging assessment,the ORR was 23.26%[95%confidence interval(CI):11.80%-38.60%],and the DCR was 69.77%(95%CI:53.90%-82.80%).The median OS was 14.1 months(95%CI:8.3-19.9),and the median PFS was 4.4 months(95%CI:2.5-6.3).A total of 41 patients(93.18%)experienced at least one adverse event(AE),with 10 patients(22.73%)encountering grade≥3 AEs,and the most frequent AEs of any grade were alopecia(79.50%),leukopenia(54.55%),neutropenia(52.27%),and liver dysfunction(40.91%),and no treatment-related deaths were documented.CONCLUSION Nab-paclitaxel plus capecitabine may be an effective and safe first-line treatment strategy for patients with advanced or metastatic BTCs.

Factors influencing willingness to participate in ophthalmic clinical trials and strategies for effective recruitment

AIM:To explore the factors influencing individuals’willingness to participate in ophthalmic clinical trials.METHODS:A questionnaire survey was conducted from January to April 2021 among patients and their family members at Zhongshan Ophthalmic Center,Sun Yat-sen University,in Guangzhou,China.The survey gathered data on respondents’willingness,demographic and socioeconomic profiles,as well as their reasons and concerns regarding engagement in clinical trials.RESULTS:Of the 1078 residents surveyed(mean age 31.2±13.1y;65.8%females)in Guangzhou,749(69.5%)expressed a willingness to participate in future ophthalmic clinical trials.Specific characteristics associated with greater willingness included a younger age,lower annual income,higher education,prior participation experience,previous ophthalmic treatment,and a better understanding of clinical trials.With the exception of age,these characteristics were significantly linked to a higher willingness.The primary barrier to participation,expressed by 64.8%of those willing and 54.4%of those unwilling,was“Uncertain efficacy”.In terms of motivations,the willing group ranked“Better therapeutic benefits”(35.0%),“Professional monitoring”(34.3%),and“Trust in healthcare professionals”(33.1%)as their top three reasons,whereas the unwilling participants indicated“Full comprehension of the protocol”(46.2%)as the key facilitator.CONCLUSION:This study reveals a substantial willingness to participate in ophthalmic clinical trials and demonstrates the predictive role of demographic and socioeconomic factors.Variations in motivators and concerns between willing and unwilling participants highlight the significance of tailored recruitment strategies.Importantly,the need for and trust in healthcare professionals stand out as powerful motivations,underscoring the importance of enhancing physician-patient relationships,adopting patient-centered communication approaches,and addressing individualized needs to improve accrual rates.

Anti-oxidative stress treatment and current clinical trials

Oxidative stress disturbs the balance between the production of reactive oxygen species(ROS)and the detoxification biological process.It plays an important role in the development and progression of many chronic diseases.Upon exposure to oxidative stress or the inducers of ROS,the cellular nucleus undergoes some biological processes via different signaling pathways,such as stress adaption through the forkhead box O signaling pathway,inflammatory response through the IκB kinase/nuclear factor-κB signaling pathway,hypoxic response via the hypoxia-inducible factor/prolyl hydroxylase domain proteins pathway,DNA repair or apoptosis through the p53 signaling pathway,and antioxidant response through the Kelch-like ECH-associated protein 1/nuclear factor E2-related factor 2 signaling pathway.These processes are involved in many diseases.Therefore,oxidative stress has gained more attraction as a targeting process for disease treatment.Meanwhile,anti-oxidative stress agents have been widely explored in pre-clinical trials.However,only limited clinical trials are performed to evaluate the efficacy of anti-oxidative stress agents or antioxidants in diseases.In this letter,we further discuss the current clinical trials related to anti-oxidative stress treatment in different diseases.More pre-clinical studies and clinical trials are expected to use anti-oxidative stress strategies as disease treatment or dietary supplementation to improve disease treatment outcomes.

Pain Efficacy of a Home-Based Low-Intensity Continuous Ultrasound Stimulator for Knee Arthritis: A Single-Arm, Open-Label, Prospective Clinical Trial

1) Background: Osteoarthritis (OA) is defined as a degenerative joint disease that mainly affects the bone. This study aims to evaluate the effect of low-intensity continuous ultrasound (LICUS) treatment on the knee of osteoarthritis patients through home-based intervention using the LICUS medical device. 2) Methods: The clinical trials were designed in a single-arm, open-label, and intervention study. Thirty-five participants, including those who dropped out (12%), were screened and enrolled. The patients received LICUS (1.1 MHz, 1.5 W/cm2, collimated beams) on the knee by the instructions of the investigator at home (5 min/session, 3 times/day, for four-weeks). Outcome measures were assessed using the Visual Analog Scale (VAS) as a primary endpoint and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) as a secondary endpoint to evaluate pain relief and functional recovery of the knee between pre-treatment (baseline) and post-treatment (four-weeks). 3) Results: Knee pain scores measured using the VAS and WOMAC indices were significantly reduced after a four-week treatment with LICUS compared to baseline. Knee stiffness and functional capacity were significantly reduced after the LICUS application. In addition, there were no reports of adverse effects during the study period. 4) Conclusion: Long-term and home-based application of LICUS can be recommended as an alternative option for the treatment of OA patients, as evidenced by the effect of pain relief and knee function recovery.

Knowledge and Attitudes of Oncology Nurses Toward Clinical Trials-A Secondary Publication

Purpose:The purpose of this study was to identify the knowledge and attitudes of oncology nurses toward clinical trials and to provide evidence for the development of clinical trial education programs for oncology nurses.Methods:The study was conducted on 142 nurses who had more than six months of nursing experience working with cancer patients at a tertiary hospital in Seoul,Korea.A structured questionnaire was used to measure the knowledge and attitudes of oncology nurses toward clinical trials.Results:The participants scored an average of 15.03±3.52 out of 19 in terms of knowledge about clinical trials.In terms of attitudes toward clinical trials,the participants scored an average of 5.91±1.37 out of 8.There was a significant positive correlation between the knowledge and attitudes of the participants toward clinical trials(r=0.23,P=0.007).Conclusion:This study found that there was a relationship between the knowledge and attitudes of oncology nurses toward clinical trials.To improve the competency of oncology nurses and provide high-quality care to patients participating in clinical trials,more systematic and sustainable education is required.

Analysis of the Current Situation of Drug Clinical Trial Institutions in Shaanxi Province

To understand the current situation of institutional registration in Shaanxi Province after the implementation ofregistration system management in drug clinical trial institutions.Relevant information was collected on the“Announcement on the Accreditation of Drug Clinical Trial Institutions”issued by the National Medical Products Administration from 2005 to August 2022,the record management information system of drug and medical device clinical trial institutions,and the drug clinical trial registration and information publicity platform.A retrospective analysis was carried out in terms of institutional development,regional distribution,registered majors,principal investigators,and the number of drug clinical trials.After the implementation of institution registration,the number of drug clinical trial institutions in Shaanxi Province increased by 47.4%,884 principal investigators were registered,the number of registered majors expanded from 58 qualified to 117,and the professional scope increased by 50.4%.The policy of institution registration is conducive to promoting the rational use of medical resources and the development of drug clinical trial institutions and improving the healthy development of the pharmaceutical industry in Shaanxi Province.

An Overview of Quality Management of Therapeutic Vaccines in Clinical Trials in China

Objective To provide suggestions and a reference for improving the quality management system of clinical trials of therapeutic vaccines and promoting the development of therapeutic vaccines in China.Methods Literature research,case study and comparative study were used to analyze the quality management system of clinical trials of therapeutic vaccines.Results and Conclusion From the perspective of the sponsor,investigators and the thirdparty technical service company,the problems such as the low efficiency of clinical trial sample preparation and the lax implementation of the protocol by hospital departments in the quality management of clinical trials of therapeutic vaccines in China were found.Then,the optimization plan for the quality management of clinical trials of therapeutic vaccines is proposed,including optimizing the preparation process of therapeutic vaccines and strengthening the training of hospital department personnel.

Problems and Countermeasures to Improve Clinical Trial Participants’Compensation Rights in China

Objective To discuss the problems existing in the compensation of Chinese clinical trial participants and propose some suggestions for improving their rights.Methods The literature related to the participants’right to compensation at home and abroad was searched to study the inadequacy of the compensation right for clinical trial participants in China from four aspects:insurance system,principle of attribution,legal relationship and compensation regulations.Then,some suggestions to improve the participants’right to compensation were proposed.Results and Conclusion China lacks clear legal norms for participants’right to compensation.There are problems such as unclear insurance rules and compensation rules,unclear contractual relationships between parties to clinical trials,and no laws and regulations to rely on for attribution and compensation.China should issue regulatory guidelines related to the right to compensation of participants in clinical trials,so that all parties in clinical trials can have rules to follow if there is the occurrence of injury,which can better protect the rights and interests of the participants.

Comparative Study on the Policy of Multiplicity Issues in Clinical Trials at Home and Abroad

Objective To study the content of China’s guiding principles on multiplicity issues in clinical trials,and to provide reference for the revision of China’s relevant guiding principles.Methods Based on ICH E9,the similarities and differences of the guiding principles of US Food and Drug Administration(FDA),European Medicines Agency(EMA),and National Medical Products Administration(NMPA)on the multiplicity issues in clinical trials were compared one by one.Results and Conclusion In general,NMPA guidelines are based on ICH E9,but in detail,the guidelines of FDA and EMA focus differently on the multiplicity issues.Therefore,NMPA guidelines need to be detailed and comprehensive.NMPA guidelines can be refined by referring to foreign guidelines to improve the practical guiding significance for clinical research and promote the level of domestic clinical trials in line with international standards.

Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review(1999-2023)

BACKGROUND Gastric cancer(GC)is the sixth most common cancer and third leading cause of cancer-related deaths worldwide.Current treatments mainly rely on surgery-and chemotherapy-based systemic;however,the prognosis remains poor for advanced disease.Recent studies have suggested that immunotherapy has significant potential in cancer therapy;thus,GC immunotherapy may improve quality of life and survival for patients with this disease.AIM To provide a comprehensive overview of the knowledge structure and research hotspots of GC immunotherapy.METHODS We conducted a bibliometric analysis of publications on immunotherapy related to GC in the Web of Science Core Collection database.We analyzed 2013 publications from 1999 to February 1,2023,using the VOSviewer and CiteSpace software.We assessed publication and citation distributions using the WoS platform and explored research countries,institutions,journals,authors,references,and keywords(co-occurrence,timeline view,and burst analysis).In addition,we examined 228 trials on immunotherapy,137 on adoptive cell therapy,274 on immune checkpoint inhibitors(ICIs),and 23 on vaccines from ClinicalTrials.gov and the International Clinical Trials Registry Platform.The Impact Index Per Article for the top ten high-cited papers collected from Reference Citation Analysis(RCA)are presented.RESULTS Our bibliometric analysis revealed that the study of immunotherapy in GC has developed rapidly in recent years.China accounted for almost half the publications,followed by the United States.The number of publications in recent years has been growing continuously,and most institutions and authors with the most publications are from China.The main keywords or clusters identified were“tumor microenvironment”,“adoptive immunotherapy”,“dendritic therapy”,and“microsatellite instability”.CONCLUSION Our analysis of 2013 publications indicated that immunotherapy for GC has led to several new developments in recent years.Considerable progress has been made in vaccinations,immune checkpoint therapy,and adoptive cellular therapy.In particular,ICIs and chimeric antigen receptor T-cells are novel options for the treatment of GC.We suggest that the combination of ICIs,chemotherapy,targeted therapy,and other immunotherapies should be the primary research direction in the future.

Probiotics supplementation for management of type Ⅱ diabetes risk factors in adults with polycystic ovarian syndrome: a meta-analysis of randomized clinical trial

This meta-analysis of randomized controlled trials aimed to evaluate the effects of probiotic supplementation on glucose homeostasis in patients with polycystic ovary syndrome(PCOS).The meta-analysis was performed in accordance with the Cochrane Handbook guidelines and relevant the preferred reporting items for systematic reviews and meta-analyses(PRISMA)statement criteria.Of 825 identified reports,11 randomized clinical trials were included in the meta-analysis.An analysis of pooled extracted data revealed that supplementation with probiotics significantly decreased fasting blood glucose(FBG,n=7;standardized mean difference(SMD)=−0.40;95%confidence interval(CI):−2.02,−0.02;P=0.04)and insulin levels(n=6;SMD=−0.57;95%CI:−0.89,−0.25;P=0.0004)and the homeostatic model assessment of insulin resistance(n=7;SMD=−0.64;95%CI:−0.96,−0.31;P=0.0001)while increasing the quantitative insulin sensitivity check index(QUICKI,n=5;SMD=0.58;95%CI:0.08,1.09;P=0.02)in patients with PCOS.The FBG-reducing effect decreased as the baseline body mass index(BMI)and mean age of the participants increased.Indeed,a greater number of bacterial species and a higher bacterial dose were shown to reduce QUICKI effectively.The systematic review indicated that probiotic supplementation may help to control glucose homeostasis in adults with polycystic ovarian syndrome.

Injectable collagen scaffold with human umbilical cordderived mesenchymal stem cells promotes functional recovery in patients with spontaneous intracerebral hemorrhage:phase Ⅰ clinical trial

Animal expe riments have shown that injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can promote recovery from spinal cord injury.To investigate whether injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can be used to treat spontaneous intracerebral hemorrhage,this non-randomized phase I clinical trial recruited patients who met the inclusion criteria and did not meet the exclusion crite ria of spontaneous intracerebral hemorrhage treated in the Characteristic Medical Center of Chinese People’s Armed Police Force from May 2016 to December 2020.Patients were divided into three groups according to the clinical situation and patient benefit:control(n=18),human umbilical cord-derived mesenchymal stem cells(n=4),and combination(n=8).The control group did not receive any transplantation.The human umbilical cord-derived mesenchymal stem cells group received human umbilical cord-derived mesenchymal stem cell transplantation.The combination group received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells.Patients who received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells had more remarkable improvements in activities of daily living and cognitive function and smaller foci of intra cerebral hemorrhage-related encephalomalacia.Severe adve rse events associated with cell transplantation were not observed.Injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells appears to have great potential treating spontaneous intracerebral hemorrhage.

A randomized clinical trial assessing the efficacy of single and multiple intralesional collagenase injections for treating contracted scars

Background:Scar contractions caused by trauma or burns can cause secondary physical dysfunction and disfigurement.Many minimally invasive methods for scar contraction have shown limited applicability and efficacy.This study investigated the feasibility and efficacy of intralesional collagenase injections for scar contraction treatment.Methods:Patients with contracted scars who had limited joint movement and physical disfiguration for>1 year were enrolled in this single-blind,randomized clinical trial from July 2017 to February 2018 at Shanghai Ninth People’s Hospital.Collagenase was injected into the firm-contracted scar(15 U/cm^(2))three times at 4-week intervals in the multiple treatment group and once in the single treatment group,and a placebo injection was performed in the control group.Scar length and skin texture were documented at the 4-and 12-week follow-ups.The safety of the collagenase treatment was also evaluated.Results:The contracted scar was significantly elongated after both single and multiple collagenase treatments.The results showed that,compared to a one-time treatment,repeated injections were more effective at 12 weeks,with an average improvement of 26.83(15.79%).At 12 weeks,78.9% of the patients in the multiple group and 52.9%in the single group achieved significant improvement at 12 weeks.No severe adverse events were observed.Conclusion:Intralesional collagenase injection showed promising results in improving scar contraction and provides an alternative treatment for patients.

Patient Recruitment in Clinical Trials: Areas of Challenges and Success, a Practical Aspect at the Private Research Site

Enrolling in clinical trials could be time-sensitive and time-demanding tasks for the research site, especially if it is a private research organization compared to the research conducted at an academic or medical center. Every study differs in various aspects, such as phases, study indication, eligibility criteria, etc. In terms of meeting the enrollment deadline, typically, the study indication and availability of the patient’s population at the geographical area of the research site would decide if the trial could be time-consuming. Patient recruitment and retention are critical for the success of every clinical trial;however, worldwide, this area is facing tremendous pressure and challenges. Globally 55% of clinical trials terminated due to low recruitment, with an average enrollment success rate of 40% for Phase III and IV trials. Over 80% of clinical trial attempts fail to enroll, extending the study and adding new study sites. In the United States, more than 80% of clinical trials fail to achieve targeted patient enrollment, and 30% of study participants discontinue participation. This article reviewed various factors hindering clinical trial recruitment and retention and suggested strategies to make the research site successful.

Detachable string magnetically controlled capsule endoscopy for the noninvasive diagnosis of esophageal diseases:A prospective,blind clinical study

BACKGROUND Traditional esophagogastroduodenoscopy(EGD),an invasive examination method,can cause discomfort and pain in patients.In contrast,magnetically controlled capsule endoscopy(MCE),a noninvasive method,is being applied for the detection of stomach and small intestinal diseases,but its application in treating esophageal diseases is not widespread.AIM To evaluate the safety and efficacy of detachable string MCE(ds-MCE)for the diagnosis of esophageal diseases.METHODS Fifty patients who had been diagnosed with esophageal diseases were pros-pectively recruited for this clinical study and underwent ds-MCE and conven-tional EGD.The primary endpoints included the sensitivity,specificity,positive predictive value,negative predictive value,and diagnostic accuracy of ds-MCE for patients with esophageal diseases.The secondary endpoints consisted of visualizing the esophageal and dentate lines,as well as the subjects'tolerance of the procedure.RESULTS Using EGD as the gold standard,the sensitivity,specificity,positive predictive value,negative predictive value,and diagnostic accuracy of ds-MCE for esophageal disease detection were 85.71%,86.21%,81.82%,89.29%,and 86%,respectively.ds-MCE was more comfortable and convenient than EGD was,with 80%of patients feeling that ds-MCE examination was very comfortable or comfortable and 50%of patients believing that detachable string v examination was very convenient.CONCLUSION This study revealed that ds-MCE has the same diagnostic effects as traditional EGD for esophageal diseases and is more comfortable and convenient than EGD,providing a novel noninvasive method for treating esophageal diseases.

The Status Quo and Enlightenment of the Foreign Extended Clinical Trial System

Objective To study the extended clinical trial systems in the United States,the European Union and Australia,and to provide a reference for the improvement of China’s extended clinical trial system.Methods Literature research method,risk management analysis method and comparative research were used in this paper to analyze the development history,scope of use,status quo of the extended clinical trial systems in the United States,the European Union,and Australia.Then,the current situation and shortcomings of China’s extended clinical trial system were compare with these foreign countries so as to put forward some suggestions for improvement.Results and Conclusion China should improve existing laws and regulations by establishing a fast application procedure,increasing application channels,and providing an information disclosure platform to meet the needs of patients in extended clinical trials.

Coronary artery disease and heart failure:Late-breaking trials presented at American Heart Association scientific session 2023

The late-breaking science presented at the 2023 scientific session of the American Heart Association paves the way for future pragmatic trials and provides meaningful information to guide management strategies in coronary artery disease and heart failure(HF).The dapagliflozin in patient with acute myocardial infarction(DAPA-MI)trial showed that dapagliflozin use among patients with acute MI without a history of diabetes mellitus or chronic HF has better cardiometabolic outcomes compared with placebo,with no difference in cardiovascular outcomes.The MINT trial showed that in patients with acute MI and anemia(Hgb<10 g/dL),a liberal transfusion goal(Hgb≥10 g/dL)was not superior to a restrictive strategy(Hgb 7-8 g/dL)with respect to 30-day all-cause death and recurrent MI.The ORBITA-2 trial showed that among patients with stable angina and coronary stenoses causing ischemia on little or no antianginal therapy,percutaneous coronary intervention results in greater improvements in anginal frequency and exercise times compared with a sham procedure.The ARIES-HM3 trial showed that in patients with advanced HF who received a HeartMate 3 levitated left ventricular assist device and were anticoagulated with a vitamin K antagonist,placebo was noninferior to daily aspirin with respect to the composite endpoint of bleeding and thrombotic events at 1 year.The TEAMMATE trial showed that everolimus with low-dose tacrolimus is safe in children and young adults when given≥6 months after cardiac transplantation.Providing patients being treated for HF with reduced ejection fraction(HFrEF)with specific out-of-pocket(OOP)costs for multiple medication options at the time of the clinical encounter may reduce‘contingency planning’and increase the extent to which patients are taking the medications decided upon.The primary outcome,which was cost-informed decisionmaking,defined as the clinician or patient mentioning costs of HFrEF medication,occurred in 49%of encounters with the checklist only control group compared with 68%of encounters in the OOP cost group.

Progress in clinical trials of cell transplantation for the treatment of spinal cord injury:how many questions remain unanswered?

Spinal cord injury can lead to severe motor,sensory and autonomic nervous dysfunctions.However,there is currently no effective treatment for spinal cord injury.Neural stem cells and progenitor cells,bone marrow mesenchymal stem cells,olfactory ensheathing cells,umbilical cord blood stem cells,adipose stem cells,hematopoietic stem cells,oligodendrocyte precursor cells,macrophages and Schwann cells have been studied as potential treatments for spinal cord injury.These treatments were mainly performed in animals.However,subtle changes in sensory function,nerve root movement and pain cannot be fully investigated with animal studies.Although these cell types have shown excellent safety and effectiveness in various animal models,sufficient evidence of efficacy for clinical translation is still lacking.Cell transplantation should be combined with tissue engineering scaffolds,local drug delivery systems,postoperative adjuvant therapy and physical rehabilitation training as part of a comprehensive treatment plan to provide the possibility for patients with SCI to return to normal life.This review summarizes and analyzes the clinical trials of cell transplantation therapy in spinal cord injury,with the aim of providing a rational foundation for the development of clinical treatments for spinal cord injury.

A 3-year clinical trial of lamivudine in treatment of patients with chronic hepatitis B

BACKGROUND: Lamivudine was approved for the treat- ment of chronic hepatitis B in China in 1999; however the long-term result has not yet been reported in detail. This clinical trial was to evaluate the long-term efficacy and safe- ty of 3-year lamivudine treatment for chronic hepatitis B and the impact of emergence of YMDD mutation of hepa- titis B virus (HBV). METHODS: This multi-center, randomized, double-blind, placebo controlled trial began from 1996 to 1999. A total of 429 patients with serum HBsAg, HBeAg and HBV DNA positive were randomized to receive either lamivudine 100 mg daily (322 patients) or placebo (107) for the first 12 weeks. All patients were given subsequently open labelled lamivudine 100 mg/d for a total of 156 weeks. RESULTS: After 12-week lamivudine therapy, the levels of serum HBV DNA decreased rapidly. The negativity of HBV DNA (<1.6 pg/ml) at week 12 was 92.2% in the lamivudine group, whereas it was only 14.1% in the place- bo group (P<0.01). After 1-year lamivudine treatment, 72.7% of the patients showed undetectable serum HBV DNA (<1.6 pg/ml). At the end of 3 years, serum HBV DNA continued to be substantially suppressed with a me- dian level below a detectable level in patients with non-YM- DD variant HBV, which was increased to 86 mEq/ml (bD- NA method, equivalent hybridization method 10 pg/ml) in patients with YMDD mutation. At the end of 1, 2 and 3 years, the rates of HBeAg loss were 9.5%, 16.8% and 20.0% respectively and the rates of HBeAg/anti-HBe sero- conversion were 8.3%, 11.5% and 17.3%. The rates of HBeAg loss and seroconversion were correlated with the baseline level of ALT. In patients with a baseline level of alanine transaminase (ALT)>2 × upper limit of normal (ULN) and ALT >5×ULN, the rates of HBeAg loss were 42.2% and 66.7%, and the rates of seroconversion were34.4% and 61.1% respectively (P<0.01) at the end of year 3. The levels of ALT at year 3 remained normal in 58.8% of patients whose baseline level of ALT was elevated, and in 79.1% of patients whose level of ALT was normal before treatment. YMDD mutations occurred in 12.1%, 49.7% and 70.5% of patients respectively at year 1, 2 and 3. In pa- tients with YMDD mutation, the levels of HBV DNA were increased slightly with mild to moderate elevation of ALT level. HBeAg loss and seroconversion were 20.0% and 15.1% in patients with YMDD mutation at the end of year 3, which were lower than those in non-variant patients (P<0.01). Adverse drug reactions or events varied gene- rally from mild to moderate. In 2 patients serious adverse events (fatigue and abdominal distension) were related to medication. ALT flares (ALT>5×ULN) occurred in 17 patients: 10 were YMDD mutants and 7 were non-mutants; all of them were relieved. No death occurred in the period of 3 years. CONCLUSION: Sustained inhibition of HBV replication and clinical improvement could be obtained after 3-year lamivudine therapy of good tolerance and safety.