The Rise of Cell Therapy Trials for Stroke
非含铂双药和非含铂单药治疗老年和_省略_胞肺癌病人疗效_荟萃分析_英文_ca85
Chinese-German Journal of Clinical Oncology March 2011, Vol. 10, No. 3, P134–P139 DOI 10.1007/s10330-011-0745-3Non-small cell lung cancer (NSCLC) creates a large burden on the elderly population; the median age of di-agnosis for lung cancer is 70 years of age, and the me-dian age of death from lung cancer is 71 years of age [1, 2]. Elderly patients are usually grouped with patients of low performance status (PS) in clinical trials [3, 4], though sometimes advanced age does not equal poor PS [5]. How-ever, the optimal treatment for those populations is less-clearly defined [6], since elderly patients are chronically underrepresented in clinical trials; less than 30% patients enrolled in studies of advanced NSCLC have been aged ≥70 years [2]. The consensus among clinicians is that a grad-ual diminution in the physiologic reserve or functional capacity over time is the characteristic hallmark of aging, and this has a direct impact on the choice of therapy and its toxicity profile in elderly cancer patients [7, 8]. Before the 1990s, only one-fourth of patients in the United States over the age of 65 with metastatic lung cancer received chemotherapy, this low proportion partially attributed to the elderly age [9]. Usually, elderly age and poor PS were considered as contraindications to standard surgery, ra-diotherapy and chemotherapy. However, treatments of single non-platinum agents were extensively studied in those populations [10–17], and non-platinum doublets were also investigated or compared with single agents [4, 6, 18–22]. The treatment strategy for those patients as reviewed by Langer [1, 2] notes that weekly cytotoxic treatment with single-agent gemcitabine, vinorelbine, docetaxel, or paclitaxel remains a viable option for elderly individu-Non-platinum doublets versus single agents in non-small cell lung cancer (NSCLC) patients with elderly age and/or poor performance status:a meta-analysis*Huijuan Qiu1, 2, Fang Wang1, 2, Guifang Guo1, 2, Feifei Zhou3, Wenzhuo He1, 2, Liangping Xia1, 21State Key Laboratory of Oncology in South China, Guangzhou 510060, China2VIP Region, Sun Yat-sen Universty Cancer Center, Guangzhou 510060, China3Tumor Center, The Foshan First People’s Hospital, Foshan 510060, ChinaReceived: 24 November 2010 / Revised: 20 January 2011 / Accepted: 15 February 2011© Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2011Abstract Objective: The aim of the study was to compare the efficacies and toxicities of non-platinum doublets (doublets group) with a non-platinum single agent (single-agent group) in previously untreated advanced non-small cell lung cancer (NSCLC) patients with elderly age and/or poor performance status (PS). Methods: The PubMed database was screened.Subsequently, the hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), relative risks (RRs) for overall response rate (ORR) and one-year survival, and odds ratios (ORs) for the different types of toxicities were pooled us-ing the Review Manager 5.0 package. Results: This study comprised of 1427 patients enrolled in four randomized controlled trials. The pooled HR showed that the doublet group could increase ORR (P = 0.002) with no heterogeneity (P = 0.64), and might improve OS (P = 0.01 / P = 0.06) with heterogeneity (P < 0.001). There was no significant difference in PFS (P = 0.16) and one-year survival (P = 0.25) between two treatment groups. The doublet group led to more grade 3/4 neutropenia and thrombocytopenia than the single-agent group (P = 0.02 and P = 0.000, respectively). The incidences of grade 3/4 anemia, vomiting, mucositis, constipation, diarrhea, neurotoxicity, allergy, and fatigue between the two treatment groups were insignifi-cant. Conclusion: Except for neutropenia and thrombocytopenia, the non-platinum doublets could increase ORR, and might improve OS for NSCLC patients with elderly age and/or poor PS without addition of more side effects; however, the doublets showed an increased rate of neutropenia and thrombocytopenia. The addition of doublets may not improve PFS and one-year survival.Key words elderly; non-small cell lung cancer (NSCLC); meta-analysis; doublets; single; non-platinumCorrespondence to: Liangping Xia. Email: xialp@The first author Huijuan Qiu and the second author Fang Wang contrib-uted equally to this paper.* Supported by a grant of Major Science and Technology Project of “Na-tional Significant New Drug Creation” (No. 2008ZX09312-002).135Chinese-German J Clin Oncol, March 2011, Vol. 10, No. 3als who wish for an opportunity for prolonged survival, symptom palliation, and tolerable toxicity; the ultimate role of platinum agent-based combinations remains un-certain, but it is acceptable in selected individuals.Thus, we conducted a meta-analysis focusing on non-platinum doublets versus non-platinum single agents in NSCLC patients with elderly age and/or poor PS, since there were several phase III randomized clinical trials available for evaluation. However, with conflicting clini-cal trial outcomes [4, 6, 18–22], we hoped to clarify the ben-efits of deciding on doublet or single therapy.Patients and methodsSearchingThe PubMed database (/sites/entrez) was searched using keywords: ( [“elderly” or “performance”] and “lung cancer”) in the “title” section, we limited the term to “clinical trial” and collected the relevant trails published before March 31st, 2010. Selection of trialsThe relevant clinical trials were manually selected based on the following criteria: (1) Patients were pathologically confirmed with NSCLC and previously untreated; (2) Pa-tients receiving chemotherapy for NSCLCs were elderly and/or with poor PS; (3) Treatment regimens comprised of a non-platinum single agent compared with non-plati-num doublets regimen with third generation drugs; (4) Studies were peer-reviewed papers; and (5) Study formats were randomized controlled trials (RCTs).Validity assessmentAn open assessment of the trials was performed using the methods according to the references [23, 24].Data abstractionThe baseline information extracted from each trial was listed in Table 1. If a hazard ratio (HR) was not directly reported, estimation of the log HR and variance from the Kaplan-Meier curves was conducted by using the graph-ics software package Grafula 3, Version 2.10 (Wesik Soft-Haus, St. Petersburg, Russia) [24, 25].Only the simultaneous side effects documented in at least three enrolled papers were calculated, which includ-ed anemia, neutropenia, thrombocytopenia, vomiting, mucositis, constipation, diarrhea, neurotoxicity, allergy, and fatigue. Due to more than two treatment groups be-ing involved in some papers, the single-agent treatment arms were merged into one group, and treatment armsNotes: NR: not reported; SCC, squamous cell carcinoma; Adeno-, adenocarcinoma; *, clinical stage; **, week(s), and in papers written by P. Comella / 2004 and John D. Hainsworth / 2007, the weeks was calculated by months multiply 4Table 1 Characteristics of the four trials comparing doublets group versus single-agent group in NSCLC patients with elderly age and/or poor PS Author/yearQuality of scorse Phase Study/armn Medium age (year)Country Female (%)PS 0–1 (%)Giuseppe Frasci / 20011III Gemcitabine + vinorelbine 6075 (71–83)Italy 1273 Gemcitabine 6074 (71–81)878Cesare Gridelli / 20033III Vinorelbine + gemcitabine23274 (69–84)Italy 2181Vinorelbine 23374 (63–83)1281Gemcitabine23374 (70–86)1782P. Comella / 20043NR Gemcitabine + vinorelbine6872 (42–82)Italy 769Gemcitabine + paclitaxel 6573 (53–83)977Gemcitabine6875 (49–86)1672 Paclitaxel 6372 (50–81)1065John D. Hainsworth / 20071III Gemcitabine + docetaxel 17474 (47–91)USA 3862 Docetaxel17174 (45–90)3967Author/yearSCC (n )Adeno-(n )IIIb* (%)IV* (%)Response (%)Medium OS** (95% CI)Medium PFS/TTP**(95% CI)1-yearsurvival (%)Giuseppe Frasci / 2001483840602229 (NR) –30474042581518 (NR) –13Cesare Gridelli / 2003493331692130 (27–36)19 (16–21)30443529711836 (30–45)18 (13–20)38423330701628 (25–34)17 (13–19)28P. Comella / 2004501941592338.8 (31.6–46)16.4 (11.6–21.2)32512538623236.8 (19.2–54.4)18 (11.2–22.4)44403535651820.4 (8.8–32)13.2 (10.4–16)29522925751325.6 (17.6–33.6)14.8 (11.6–18)25John D. Hainsworth / 2007173824762522 (NR)19.2 (15.6–24.8)26223827731720.4 (NR)11.6 (8.0–14.4)24136 /content/1613-9089with doublets were also merged in each paper [4, 18] when analyzing overall response rate (ORR) and adverse events, since gemcitabine, vinorelbine, and docetaxel were equivalently effective and safe for patients with advanced NSCLC who had poor PS and/or who was elderly [10]. Statistical analysisThe relative risks (RRs) for ORR and one-year survival to treatment, the hazard ratios (HRs) for overall surviv-al (OS) and progression-free survival (PFS), odds ratios (ORs) for the different types of toxicities were calculated using the Review Manager package (RevMan) computer program, Version 5.0 (Copenhagen, Denmark: the Nor-dic Cochrane Centre, The Cochrane Collaboration, 2008). Analyses were performed in intent-to-treatment (ITT) groups for ORR, one-year survival, OS and PFS, and in treatment-received analyses for toxicities. A statistical test with a P-value less than 0.05 was considered signifi-cant. A RR > 1 reflected greater ORR or one-year survival in the doublets group, a HR > 1 reflected greater deaths or progression in the doublets group, and OR > 1 indi-cated more toxicities in doublets group; and vice versa. In order to investigate for statistical heterogeneity between trials, the standard chi-squared Q-test was applied (mean-ingful differences between studies indicated by P < 0.10). The results were generated using the fixed-effect model.A random-effect model was employed when there was statistically significant heterogeneity [12, 24]. All P-values were two-sided. All confidence intervals had two-sided probability coverage of 95%.Publication biasThe search strategy was extensive, and funnel plot, and Begg’s test and Egger’ test were performed to examine publication bias.ResultsSelected trialsA total of 176 trials were found, and 7 trials were se-lected for full-text paper review [4, 6, 18–22]. Three trials were discarded since 2 studies were reported repeatedly [20, 21], and another paper compared a first generation NSCLC drug that was now abandoned [22] (Fig. 1). Thus, four stud-ies were ultimately analyzed [4, 6, 18, 19], and all of them were phase III RCTs. Three were conducted in Europe [4, 18, 19] and one in the USA [6]. All the agents adopted in the tri-als were third generation pharmaceuticals: vinorelbine, gemcitabine, paclitaxel, and docetaxel. The quality of the four trials was assessed using the three question instru-ment from the references [23, 24] (Table 1). A total of 1427 patients, 601 patients received combination treatment and 828 patients received single agent treatment, served as data sources for this meta-analysis.Efficacy comparisonThe pooled HR showed that the doublets group might improve OS for NSCLC patients with elderly age and/ or poor PS (HR, 0.80; 95% CI, 0.67–0.96; P = 0.01, if vinorelbine and gemcitabine vs gemcitabine were chosen as in the paper of Gridelli et al[18], Fig. 2a; HR, 0.82; 95% CI, 0.66–1.00, P = 0.06 if vinorelbine and gemcitabine vs vinorelbine were chosen as in the paper of Gridelli et al [18], Fig. 2b), and there was heterogeneity (chi-squared = 348.48; P < 0.001). The pooled RR showed that the dou-blets group could increase ORR in NSCLC (RR, 1.43; 95 % CI, 1.14–1.79; P = 0.002; Fig. 3) with no heterogeneity (chi-squared = 1.70; P = 0.64). There was no significant difference in PFS (HR, 0.83; 95% CI, 0.64–1.08; P = 0.16; chi-squared = 595.19; P < 0.001; Fig. 4) and one-year sur-vival (RR, 1.20; 95% CI, 0.88–1.65; P = 0.25; chi-squared = 7.66; P = 0.05; Fig. 5) between two treatment groups. The above-mentioned PFS and one-year survival was cal-culated under the choice of “vinorelbine and gemcitabine vs gemcitabine” as chosen in the paper of Gridelli et al [18], and the result of “vinorelbine and gemcitabine vs vinorelbine” did not show diversity as chosen in the pa-per of Gridelli et al[18].SafetyAll of the four trials reported grade 3/4 adverse events, with the doublets group leading to greater grade 3/4 neu-tropenia and thrombocytopenia than the single-agent group (OR, 1.40; 95% CI, 1.05–1.87; P = 0.02; OR, 2.23; 95% CI, 1.36–6.64; P = 0.000, respectively; Table 2). NoFig. 1Flow of identifying the trials comparing non-platinum doublets and single agents in patients with previously untreated non-small-cell lungcancer137Chinese-German J Clin Oncol, March 2011, Vol. 10, No. 3statistically significant differences were noted in the inci-dences of grade 3/4 anemia, vomiting, mucositis, constipa-tion, diarrhea, neurotoxicity, allergy, or fatigue between the two treatment groups. There were no significant tox-icity analyses heterogeneities except for anemia and vom-iting (chi-squared =6.63 and 8.43; P = 0.08 and P = 0.04).Publication biasAssessed by funnel plot, Begg’s test (P > 0.10) and Egg-er’s test (P > 0.10), publication bias was not found in these meta-analysis except for the risk ratios (RRs) in one-year survival rate [Begg’s test (P = 0.17) and Egger’s test (P = 0.09)] when using the data of vinorelbine + gemcitabine vs (gemcitabine or vinorelbine) [18].Fig. 2 Meta-analysis of the hazard risks (HRs) be-tween doublets group and single-agent group in OS. (a) if vinorelbine and gemcitabine vs gemcitabine were chosen as in the paper of Gridelli et al [18]; (b) if vinorelbine and gemcitabine vs vinorelbine were chosen as in the paper of Gridelli et al[18]Fig. 3 Meta-analysis of the risk ratios (RRs) between doublets group and single-agent group in overall re-sponse rateFig. 4 Meta-analysis of the hazard risks (HRs) betweendoublets group and single-agent group in PFS/TTPFig. 5 Meta-analysis of the risk ratios (RRs) between doublets group and single-agent group in one-year sur-vival rate138 /content/1613-9089DiscussionAll papers in PubMed database are peer-reviewed, pro-viding higher quality of details than the studies present-ed in meetings, so, only those articles were screened for this meta-analysis. There were four papers [4, 6, 18, 19] with a total of 1427 patients entered in this study, and all of them were highly homologous when analyzing both the efficacy and side effects. Due to platinum-based regimens and targeted agents were not fully compared in phase III clinical trails, so, they were excluded from this analysis. Thus, we only focused on the non-platinum chemo-therapeutic agents studies in NSCLC patients with either elderly age or poor PS. The elderly age criteria was ≥ 70 years old in two studies [4, 20], and one study, it was ≥ 65 years old [6], however, in the study of Comella [4], there were 17% patients with less than 70 years of age enrolled because of their poor PS. Therefore, all the patients met our eligibility criteria. The median OS of the combina-tion group was either better than [4, 19] or equal to [6, 18] the single agent group as shown in the original four papers. After meta-analysis, the pooled HR showed that dou-blets group might improve OS for NSCLC patients (P = 0.01) if vinorelbine and gemcitabine vs gemcitabine were chosen in the paper of Gridelli et al[18]; however, they were equal (P = 0.06) when vinorelbine and gemcitabine vs vinorelbine were chosen in the paper of Gridelli et al [18]. The real reasons that caused this difference were un-known, but we think that this may be associated with the second line or greater than second line setting that were unknown in all the patients; it also may relate to the het-erogeneity (P < 0.001) of the data when OS was calculated. It was hard to judge whether vinorelbine and gemcitabine was better for those populations since a comparison of the two drugs was lacking, but vinorelbine, gemcitabine, and docetaxel were demonstrated to be equally effective [10]. We also analyzed the one-year survival rate with the hope of focusing more attention on this issue, however, there was no significant difference between the doublets group and single-agent group. The PFS may be more suit-able to judge the effect of the drugs applied. Unfortu-nately, we did not find a significant improvement in PFS (P = 0.16) if a doublet regimen was administered. This may be associated with the unavailable PFS in Frasci et al [19], which might be longer in doublets group, because the time to symptom deterioration in the gemcitabine and vinorelbine group reported in another paper [21] was 21 weeks, which was significantly longer than 13 weeks in the single-agent group (P = 0.002). Absolutely, the ORR was significantly improved in the doublets group, and we can speculate that the tumor shrinkage may help to relieve the tumor burden-related symptoms, which will benefit patients more.The side effects were the main consideration when the chemotherapy regimen was designed in NSCLC patients with elderly age and/or poor PS. In this study, only the grade 3/4 adverse events and simultaneous reports in at least three of the four chosen papers were compared. It was easy to understand that the doublets group led to more grade 3/4 neutropenia and thrombocytopenia than the single agent group (P = 0.02 and P = 0.000, respective-ly), and there were no statistically significant differences in the remaining side effects between the two treatment groups. Thus, the tolerability of non-platinum agents in those populations was as good as those reported in each original paper. Thus, we believe the combination of non-platinum doublets can be considered in certain patients. ConclusionFor NSCLC patients with elderly age and/or poor PS, non-platinum doublet regimens could increase ORR (P = 0.002) and might improve OS (P = 0.01; P = 0.06), how-ever, didn’t increased PFS (P = 0.16) and one-year sur-vival (P = 0.25) than single agent. In addition, the doublet regimens led to more grade 3/4 neutropenia (P = 0.02) and thrombocytopenia (P = 0.00). The prospective RCTs needTable 2Summary of toxicity compared in doublets group versus single-agent group Trials Doublets (n)Single (n)P OR (95% CI)P for homogeneityAnaemia 438/58330/8070.42 1.44(0.60–3.44)0.08#Neutropenia 4112/583120/8070.02 1.40(1.05–1.87)0.10 Thrombocytopenia 449/58327/8070.00 2.23(1.36–6.64)0.31 Vomiting 421/58324/8070.75 1.22(0.37–3.98)0.04#Mucositis 45/5834/8070.45 1.66(0.45–6.12)0.44 Constipation 413/58310/8070.12 2.00(0.84–4.74)0.31 Diarrhea 314/52310/7470.32 1.52(0.67–3.48)0.69 Neurotoxicity 36/5234/7470.48 1.81(0.51–6.39)0.36 Allergy 31/5233/747–0.32(0.03–3.14)0.33 Fatigue 356/46560/6880.63 1.25(0.84–1.86)0.63 Notes: the number in column “trails” meant how many papers reported this kind of side effects; the fraction in column “doublets” and “single” meant thetotal of patients suffered this kind of side effects (numerator), and total number of patients in the papers to analyze this kind of side effects (denomina-tor); #: there were significant heterogeneity for those toxicities and the pooled OR were performed using random-effort model139 Chinese-German J Clin Oncol, March 2011, Vol. 10, No. 3more large sample sizes and good design.Conflict of interest statementWe declare that we have no conflict of interests. Authors’ contributionsAll authors have contributed substantially to the study. Huijuan Qiu and Liangping Xia contributed to the design of the study, to the recruitment the data, to writing of manuscript. Fang Wang and Guifang Guo contributed to the conception and design of the study. Feifei Zhou and Wenzhuo He have contributed the data analysis. All au-thors read and approved the final manuscript. AcknowledgementsWe wish to thank Professor Yuantao Hao and Yechun Yang, the statisticians, who helped conduct all of the sta-tistical analysis. We would also like to thank Professor Li Zhang and Likun Chen for giving us the idea for this paper.ReferencesAvery EJ, Kessinger A, Ganti AK. Therapeutic options for elderly pa-1.tients with advanced non-small cell lung cancer. Cancer Treat Rev, 2009, 35: 340–344.Langer CJ. Neglected and underrepresented subpopulations: elderly 2.and performance status 2 patients with advanced-stage non-small-cell lung cancer. Clin Lung Cancer, 2006, 7 Suppl 4: S126–137.Beretta GD, Michetti G, Belometti MO,3. et al. Gemcitabine plusvinorelbine in elderly or unfit patients with non-small cell lung cancer.Br J Cancer, 2000, 83: 573–576.Comella P, Frasci G, Carnicelli P,4. et al. Gemcitabine with eitherpaclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients. Br J Cancer, 2004, 91: 489–497.Hesketh PJ, Chansky K, Lau DH,5. et al. Sequential vinorelbine anddocetaxel in advanced non-small cell lung cancer patients age 70 and older and/or with a performance status of 2: a phase II trial of the Southwest Oncology Group (S0027). J Thorac Oncol, 2006, 1: 537–544.Hainsworth JD, Spigel DR, Farley C,6. et al. Weekly docetaxel versusdocetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a random-ized phase 3 trial of the Minnie Pearl Cancer Research Network. Can-cer, 2007, 110: 2027–2034.Sawhney R, Sehl M, Naeim A. Physiologic aspects of aging: impact 7.on cancer management and decision making, part I. Cancer J, 2005, 11: 449–460.Sehl M, Sawhney R, Naeim A. Physiologic aspects of aging: impact 8.on cancer management and decision making, part II. Cancer J, 2005, 11: 461–473.Earle CC, Neumann PJ, Gelber RD,9. et al. Impact of referral patternson the use of chemotherapy for lung cancer. J Clin Oncol, 2002, 20: 1786–1792.Leong SS, Toh CK, Lim WT,10. et al. A randomized phase II trial of sin-gle-agent gemcitabine, vinorelbine, or docetaxel in patients with ad-vanced non-small cell lung cancer who have poor performance status and/or are elderly. J Thorac Oncol, 2007, 2: 230–236.Kudoh S, Takeda K, Nakagawa K,11. et al. Phase III study of docetaxelcompared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol, 2006, 24: 3657–3663.Gridelli C, De Maio E, Barbera S,12. et al. The MILES-2G phase 2 studyof single-agent gemcitabine with prolonged constant infusion in ad-vanced non-small cell lung cancer elderly patients. Lung Cancer, 2008, 61: 67–72.Lilenbaum R, Rubin M, Samuel J,13. et al. A randomized phase II trialof two schedules of docetaxel in elderly or poor performance status patients with advanced non-small cell lung cancer. J Thorac Oncol, 2007, 2: 306–311.Quoix E, Breton JL, Ducoloné A,14. et al. First line chemotherapy withgemcitabine in advanced non-small cell lung cancer elderly patients:a randomized phase II study of 3-week versus 4-week schedule.Lung Cancer, 2005, 47: 405–412.Baka S, Ashcroft L, Anderson H,15. et al. Randomized phase II study oftwo gemcitabine schedules for patients with impaired performance status (Karnofsky performance status </= 70) and advanced non-small-cell lung cancer. J Clin Oncol, 2005, 23: 2136–2144.Rossi D, Dennetta D, Ugolini M,16. et al. Weekly paclitaxel in elderlypatients (aged > or = 70 years) with advanced non-small-cell lung cancer: an alternative choice? Results of a phase II study. Clin Lung Cancer, 2008, 9: 280–284.Fidias P, Supko JG, Martins R,17. et al. A phase II study of weeklypaclitaxel in elderly patients with advanced non-small cell lung can-cer. Clin Cancer Res, 2001, 7: 3942–3949.Gridelli C, Perrone F, Gallo C,18. et al. Chemotherapy for elderly patientswith advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst, 2003, 95: 362–372.Frasci G, Lorusso V, Panza N,19. et al. Gemcitabine plus vinorelbineyields better survival outcome than vinorelbine alone in elderly pa-tients with advanced non-small cell lung cancer. A Southern Italy Cooperative Oncology Group (SICOG) phase III trial. Lung Cancer, 2001, 34 Suppl 4: S65–69.Gridelli C, Cigolari S, Gallo C,20. et al. Activity and toxicity of gemcitabineand gemcitabine + vinorelbine in advanced non-small-cell lung can-cer elderly patients: Phase II data from the Multicenter Italian Lung Cancer in the Elderly Study (MILES) randomized trial. Lung Cancer, 2001, 31: 277–284.Frasci G, Lorusso V, Panza N,21. et al. Gemcitabine plus vinorelbineversus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol, 2000, 18: 2529–2536.De Marinis F, Rinaldi M, Ardizzoni A,22. et al. The role of vindesine andlonidamine in the treatment of elderly patients with advanced non-small cell lung cancer: a phase III randomized FONICAP trial. Italian Lung Cancer Task Force. Tumori, 1999, 85: 177–182.Jadad AR, Moore RA, Carroll D,23. et al. Assessing the quality of reportsof randomized clinical trials: is blinding necessary? Control Clin Tri-als, 1996, 17: 1–12.Lin H, Jiang J, Liang X,24. et al. Chemotherapy with cetuximab or che-motherapy alone for untreated advanced non-small-cell lung cancer:a systematic review and meta-analysis. Lung Cancer, 2010, 70:57–62.Parmar MK, Torri V, Stewart L. Extracting summary statistics to per-25.form meta-analyses of the published literature for survival endpoints.Stat Med, 1998, 17: 2815–2834.。
2016年04月急性冠脉综合征治疗新药临床研究指导原则.(英文版)
30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom1 April 2016 1 EMA/CHMP/207892/20152 Committee for medicinal products for human use (CHMP)3 Guideline on clinical investigation of new medicinal 4products for the treatment of acute coronary syndrome 5(CPMP/EWP/570/98) 6Draft7 Draft agreed by Cardiovascular Working PartyFebruary 2016 Adopted by CHMP for release for consultation1 April 2016 Start of public consultation 27 April 2016 End of consultation (deadline for comments)31 October 2016 8 This guideline replaces 'Points to consider on the clinical investigation of new medicinal products for the 9 treatment of acute coronary syndrome (ACS) without persistent ST segment elevation' 10 (CPMP/EWP/570/98). 1112 Comments should be provided using this template . The completed comments form should be sent to CVSWPSecretariat@ema.europa.eu .13Keywords Acute coronary syndrome, STE-ACS, NSTE-ACS, guideline, CHMP1415Table of contents16Executive summary (4)171. Introduction (background) (4)182. Scope (5)193. Legal basis and relevant guidelines (5)204. Choice of efficacy criteria (endpoints) (6)214.1. All-cause mortality and CV mortality (6)224.2. New myocardial infarction (6)234.3. Revascularisation (6)244.4. Unstable angina pectoris necessitating hospitalisation (6)254.5. Stent thrombosis (6)264.6. Stroke (7)274.7. Left ventricular function and heart failure (7)284.8. Composite endpoints (7)294.9. Endpoints in fibrinolysis studies (7)305. Methods to assess efficacy (how to measure the endpoints) (8)315.1. Mortality (8)325.2. New myocardial infarction (8)335.3. Revascularisation (8)345.4. Unstable angina pectoris necessitating hospitalisation (8)355.5. Stent thrombosis (8)365.6. Ventricular function and heart failure (9)375.7. Angiographic endpoints (9)386. Selection of patients (9)396.1. Study population (9)406.1.1. STE-ACS (ST elevation acute coronary syndrome) (9)416.1.2. NSTE-ACS (Non-ST elevation acute coronary syndrome) (9)426.1.3. Unstable angina (9)436.2. Inclusion criteria for the therapeutic studies (10)446.3. Exclusion criteria for the therapeutic studies (10)456.4. Risk Stratification (10)466.5. Special populations (11)476.5.1. Older patients (11)487. Strategy and design of clinical trials (11)497.1. Clinical pharmacology (11)507.2. Therapeutic exploratory studies (12)517.2.1. Objectives (12)527.2.2. Design (12)537.3. Confirmatory Therapeutic Studies (12)547.3.1. Objectives (12)557.3.2. Background therapy (12)567.3.3. Choice of comparator (13)577.3.4. Duration of clinical studies (13)587.3.5. Analyses and subgroup analysis (13)598. Safety aspects (14)608.1. Bleedings (14)618.2. All-cause mortality (15)628.3. Thrombocytopenia (15)638.4. Rebound effect (15)648.5. Effects on laboratory variables (15)658.6. Effects on concomitant diseases (15)66References (16)6768Executive summary6970Two CHMP Guidelines have been previously developed to address clinical investigations of new71medicinal products for the treatment of acute coronary syndrome (ACS): (I) the CHMP points toconsider (PtC) on the clinical investigation of new medicinal products for the treatment of acute7273coronary syndrome without persistent ST-segment elevation (CPMP/EWP/570/98), published in 2000 74[1], and (II) the CHMP PtC on the clinical development of fibrinolytic products in the treatment of75patients with ST segment elevation myocardial infarction (CPMP/EWP/967/01), published in 2003 [2].76Since their finalisation, major developments have taken place in the definitions, diagnosis,77interventions and management of ACS, as reflected in the relevant European Society of Cardiology78(ESC) clinical practice guidelines (3, 4). Currently, an update of the above mentioned CHMP Guidelines 79is considered necessary to take these new developments into consideration based on literature review 80and experience gained with medicinal products intended for treatment during the acute phase and81beyond. The present update includes the following changes: 1) guidance addressing both ST-segment 82elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction83(NSTEMI), as well as unstable angina (UA), 2) update in their definitions, 3) risk stratification using84different scoring systems, 4) investigated endpoints, and 5) clinical developments of new medicinal85products beyond the acute stage, including agents other than antiplatelets and anticoagulants.1. Introduction (background)8687Cardiovascular diseases are currently the leading cause of death in industrialized countries and also 88expected to become so in emerging countries by 2020 [3, 4]. Among these, coronary artery disease 89(CAD) is the most prevalent manifestation and is associated with high mortality and morbidity. ACS 90has evolved as a useful operational term to refer to any constellation of clinical symptoms that are91compatible with acute myocardial ischemia. It encompasses (STEMI), NSTEMI, and UA.92ACS represents a life-threatening manifestation of atherosclerosis. It is usually precipitated by acute 93thrombosis induced by a ruptured or eroded atherosclerotic coronary plaque, with or without94concomitant vasoconstriction, causing a sudden and critical reduction in blood flow. In the complex95process of plaque disruption, inflammation was revealed as a key pathophysiological element. Non-96atherosclerotic aetiologies are rare e.g. such as arteritis and dissection.97The leading symptom of ACS is typically chest pain. Patients with acute chest pain and persistent (>20 min) ST-segment elevation have ST-elevation ACS (STE-ACS) that generally reflect an acute total9899coronary occlusion. Patients with acute chest pain but without persistent ST-segment elevation have 100rather persistent or transient ST-segment depression or T-wave inversion, flat T waves, pseudo-101normalization of T waves, or no ECG changes. At presentation, based on the measurement of102troponins, it is possible to further discriminate between the working diagnosis of non-ST-elevation ACS 103(NSTE-ACS) and unstable angina.104NSTE-ACS is more frequent than STE-ACS [5] with an annual incidence around 3 per 1000 inhabitants, 105but varying between countries [6]. Hospital mortality is higher in patients with STEMI than among 106those with NSTEMI (7% vs. 3–5%, respectively), but at 6 months the mortality rates are very similar 107in both conditions (12% and 13%, respectively) [5,7,8]. Long term follow-up shows that death rates 108were higher among patients with NSTE-ACS than with STE-ACS, with a two-fold difference at 4 years[8]. This difference in mid- and long-term evolution may be due to different patient profiles, since 109110NSTE-ACS patients tend to be older with more co-morbidities, especially diabetes and renal failure.2. Scope111112The aim of this guideline is to provide guidance when performing trials to develop medicinal products 113in the management of ACS. The primary goals of therapy for patients with ACS are to:1. Treat acute, life-threatening complications of ACS, such as serious arrhythmias, pulmonary 114115oedema, cardiogenic shock and mechanical complications of acute myocardial infarction (AMI). [9] 1162. Reduce the amount of myocardial necrosis that occurs in patients with AMI, thus preserving 117left ventricular (LV) function, preventing heart failure (HF), and limiting other cardiovascular118complications.1193. Prevent major adverse cardiac events like death, non-fatal myocardial infarction (MI), andneed for urgent revascularization.120121The focus in this Guideline concerns mainly the medical treatment of ACS (treatment goals 2 and 3). 122The choice of interventional procedures [percutaneous coronary intervention (PCI) or coronary artery 123bypass graft CABG)] falls outside the scope of this guideline.3. Legal basis and relevant guidelines124125This guideline has to be read in conjunction with the introduction and general principles and parts I 126and II of the Annex I to Directive 2001/83 as amended.127Pertinent elements outlined in current and future EU and ICH guidelines, should also be taken into 128account, especially those listed below:129•Dose-Response Information to Support Drug Registration (ICH E4; CPMP/ICH/378/95).130•Statistical Principles for Clinical Trials (ICH E9; CPMP/ICH/363/96).131•Choice of Control Group and Related Issues in Clinical Trials (ICH E10; CPMP/ICH/364/96).132•Points to consider on an Application with 1) Meta-analyses 2) One pivotal study133(CPMP/EWP/2330/99).134•Points to consider on multiplicity issues in clinical trials (CPMP/EWP/908/99).135•Investigation of subgroups in confirmatory clinical trials (EMA/CHMP/539146/2013).136•The Extent of Population Exposure to Assess Clinical Safety for Drugs (ICH E1A;137CPMP/ICH/375/95).138•Pharmacokinetic Studies in Man (3CC3A).139•Studies in Support of Special Populations: Geriatrics (ICH E7 CHMP/ICH/379/95) and related Q&A 140document (EMA/CHMP/ICH/604661/2009).141•Note for Guidance on the Investigation of Drug Interactions (CPMP/EWP/560/95).142•Reporting the Results of Population Pharmacokinetic Analyses (CHMP/EWP/185990/06).143•Reflection paper on the extrapolation of results from clinical studies conducted outside the EU to 144the EU-population (EMEA/CHMP/EWP/692702/2008).145•Draft Guideline on clinical investigation of medicinal products for the treatment of chronic heart 146failure (EMA/392958/2015 )•Guideline on clinical investigation of medicinal products for the treatment of acute heart failure147148(CPMP/EWP/2986/03 Rev. 1)4. Choice of efficacy criteria (endpoints)149150Definitions of clinical endpoints in confirmatory trials should be in line with the relevant clinical151guidelines to facilitate interpretation of the results, to allow comparisons across clinical studies and to 152extrapolate to clinical practice. Endpoints should be centrally adjudicated by a blinded committee. The 153following endpoints are relevant to the investigation of efficacy in patients with ACS.4.1. All-cause mortality and CV mortality154155As one of the goals of treatment of ACS is reduction of mortality, this is an important endpoint to156measure. There is an ongoing debate around the use of all-cause versus cardiovascular mortality in 157cardiovascular (CV) trials. All cause mortality is the most important endpoint in clinical trials for the 158estimation of the benefit-risk balance of a drug, in particular when investigating newer medicinal159products with possible safety issues. On the other hand, CV mortality is more specifically linked to the 160mode of action of CV medicinal products/intervention and is especially relevant when the earliest part 161of the follow up is assessed. The choice is also dependent on the objective of the study i.e. in non-162inferiority trials, CVmortality may be preferred while in superiority trials all cause mortality is usually 163used. In fibrinolysis studies, all cause mortality is preferred (see section 4.9).164As such, one of the two mortality endpoints should be included as a component of the primary165endpoint, with the other investigated as a key secondary endpoint.4.2. New myocardial infarction166167New onset MIis a relevant endpoint in studies of ACS and should always be investigated. The definition 168of MI has evolved through the years; at the time of drafting of this Guideline, the third universal169definition of MI is applicable [10]. Criteria of MI are the same as those used to define the index event 170(see below).4.3. Revascularisation171172Some clinical trials have included revascularization endpoints (PCI or CABG) as part of the primary 173composite with conflicting results [11, 12]. Such endpoints are considered more relevant tointerventional studies, and in the scope of this Guideline, their inclusion as a primary endpoint should 174175be clearly justified and their assessment pre-defined and systematically assessed.4.4. Unstable angina pectoris necessitating hospitalisation176177Unstable angina has been investigated in ACS clinical trials. Due to the varying definitions used, the 178associated subjectivity and the influence of local clinical practice, this endpoint is not encouraged to be 179included in the composite primary endpoint.4.5. Stent thrombosis180181Stent thrombosis (ST) is a rare event that can have fatal consequences. ST has been captured in some 182registration studies, but not consistently in the primary endpoint (PEP). The investigation of ST as part 183of the primary endpoint is not encouraged due to the uncertainty of the clinical relevance of all184captured events, except for the "definite" subcategory. Another category identified by the timing isintra-procedural stent thrombosis (IPST), which is a rare event indicating the development of occlusive 185186or non-occlusive new thrombus in or adjacent to a recently implanted stent before the PCI procedure is187completed. Some recent studies [13,14] show that these events may be of prognostic value. As such they should also be collected and presented as secondary endpoint but not included in the analysis of 188189ST.4.6. Stroke190191Stroke should be defined by a generally accepted definition [15]. Clinical studies in ACS have used192non-fatal stroke in the primary endpoint , including any types of strokes. However it is preferred to193include only ischemic strokes in the primary endpoint, as this is the true measure of efficacy;194haemorrhagic stroke should be included as a safety endpoint. An ischaemic stroke with haemorrhagic195conversion should be considered as “primary ischaemic”. The subgroup of “undefined strokes” should196be as small as possible in order to be able to properly assess the effect of the study treatment. In case 197all types of strokes are included in the primary endpoint, a sensitivity analysis including only ischemic198stroke should be submitted.4.7. Left ventricular function and heart failure199Some medicinal products such as modulators of reperfusion injury or inflammation, or gene/cell200201therapy are developed to improve myocardial function and reduce the occurrence of HF. In these202cases, measurement of myocardial function could be a relevant endpoint to investigate the mechanismof action. In phase III studies, these endpoints can be investigated as secondary endpoints to support 203204the clinical endpoints. Occurrence of HF should be considered as a clinical endpoint in phase III studies205aimed at showing benefit in long-term cardiovascular outcome. All-cause mortality and long term206follow-up are mandatory in studies with novel interventions.4.8. Composite endpoints207Due to the rather low incidence of cardiovascular events during the follow-up period after the acute 208209phase of the ACS, composite endpoints consisting of relevant components are acceptable, both as210primary and secondary endpoints. The composite of CV death, non-fatal MI and non-fatal stroke (Major211Adverse Cardiovascular Events, [MACE]) has commonly been used in registration studies, with non-212fatal strokes showing limited contribution to the results. As such, it is preferred to investigate the213composite of death and non-fatal MI in confirmatory studies; non-fatal ischaemic stroke could beincluded in the composite if justified. Sometimes different definitions of MACE are being used with214215novel therapies [16], that should be justified when used in place of MACE. The inclusion of less216objective and clinically derived outcomes in the same composite is generally not encouraged, as they217may either drive the efficacy or dilute the results. In case these endpoints are included they have to be218stringently defined, and adjudicated. Each component of the primary composite endpoint should be219analysed as secondary endpoint.220The net clinical benefit that includes both benefit and safety issues of the studied drug may be used as221a secondary endpoint to be evaluated if it contributes to the discussion on the benefit-risk balance of222the studied drug.4.9. Endpoints in fibrinolysis studies223224In fibrinolysis studies, angiographic studies using the TIMI (Thrombolysisi in Myocardial Infarction)perfusion grades as evaluation criteria are often used. However, complete recanalization cannot be 225226considered as a surrogate for survival when assessing fibrinolytic drugs, as some medicinal productsproviding higher complete recanalization rates than alteplase, failed to demonstrate additional survival 227228benefit. For this reason, all cause mortality is the most relevant endpoint or a combined endpoint as 229previously discussed (see 4.1). Secondary endpoints such as heart failure hospitalisations, left230ventricular function, ventricular arrhythmias, the need for rescue recanalization (emergent and/or231planned) should also be considered and justified.5. Methods to assess efficacy (how to measure the232endpoints)2335.1. Mortality234235Definition of CV death should be clearly defined, in line with acceptable standards [17]. It is mandatory 236to report and centrally adjudicate all mortality data where survival is an endpoint of the study.237Assessment of cardiovascular mortality will require censoring of other “types” of mortality, which may 238complicate its interpretation, in particular when non-CV deaths are in high proportion.5.2. New myocardial infarction239240The diagnostic of MI is based on the detection of a rise and/or fall of cardiac biomarker values241[preferably cardiac troponin (cTn)] with at least one value above the 99th percentile upper reference 242limit (URL). All MIs should be collected and also classified by their different sub types (i.e,243spontaneous, secondary to an ischemic imbalance, related to PCI, related to ST or CABG) [10]. This is 244particularly important considering the different prognostic values of each type of MI. For the same 245reason and to support the clinical relevance of post procedural MIs, these events should be presented 246with higher cut-off values (≥ 5 and ≥10x upper level of normal ULN, in case of CK-MB or ≥70x ULN of 247cTn) [18]. These higher cut-off values can also help in diagnosing MIs in the setting of elevated248baseline biomarkers, which is a problematic situation. In such cases, serial measurements of the249biomarkers are necessary, in addition to new ECG changes or signs of worsening of cardiac function, 250e.g. HFor hypotension [18].5.3. Revascularisation251252The underlying cause of revascularization should be identified: restenosis, ST or disease progression. 253In the latter case target vessel revascularization (TVR) could be included. Early target lesion eventsafter revascularization (before 30 days) are more likely to be caused by an angiographic complication 254255and should preferably be included as safety endpoint (see ST).5.4. Unstable angina pectoris necessitating hospitalisation256257When investigated, robust definitions should be employed. In order to support the seriousness of the 258event it should also be shown that it has led to a revascularisation procedure. Since a medicinalproduct that prevents death and/or new MI might result in more patients suffering from UA, the259260analysis of this endpoint should take into account censoring issues as well.5.5. Stent thrombosis261262ST should be collected and classified as definite, probable and possible in line with acceptable263definitions [19]. In addition, the timing of ST should be documented (acute, sub-acute, late and very 264late), as risk factors and clinical sequels differ with timing.5.6. Ventricular function and heart failure265266Investigation of cardiac function should follow state of the art methods. This can include among others 267measurement of ventricular function by isotopic method and/or by cardiac magnetic resonance imaging 268and/or echocardiography. Investigation of HFshould follow the relevant CHMP guidelines.5.7. Angiographic endpoints269270Angiograms should undergo central blinded reading. In principle, the rate of TIMI 3 flow (complete 271revascularization) of the infarct related artery at 90 minutes is considered the most relevant272angiographic endpoint, as it has been shown to correlate with an improved outcome in terms of273mortality and left ventricular function. An earlier evaluation of the patency pattern (i.e. 30 and 60274minutes) may provide important information on the speed of recanalization. Whatever is the time-point 275selected as primary outcome, it must be properly justified and pre-specified in the clinical trial.6. Selection of patients2766.1. Study population277The definition of the different ACS subtypes should be based on current guidelines/universal definition 278279of MI including STEMI and NSTEMI as well as UA [3, 4, 10].6.1.1. STE-ACS (ST elevation acute coronary syndrome)280281In patients with acute chest pain and persistent (>20 min) ST-segment elevation on ECG the282diagnostic of STE-ACS is made [3]. This condition generally reflects an acute total coronary occlusion.Most patients will ultimately develop an ST-elevation myocardial infarction (STEMI) with the criteria of 283284acute myocardial infarction described before [see 5.2].6.1.2. NSTE-ACS (Non-ST elevation acute coronary syndrome)285286In patients with acute chest pain but no persistent ST-segment elevation the diagnostic of NSTE-ACS is 287made [4]. ECG changes may include transient ST-segment elevation, persistent or transient ST-288segment depression, T-wave inversion, flat T waves or pseudo-normalization of T waves or the ECG 289may be normal. The clinical spectrum of non-ST-elevation ACS (NSTE-ACS) may range from patients 290free of symptoms at presentation to individuals with ongoing ischaemia, electrical or haemodynamic 291instability or cardiac arrest. The pathological correlate at the myocardial level is cardiomyocyte292necrosis (NSTEMI) or, less frequently, myocardial ischaemia without cell loss (UA). Currently, cardiac 293troponins play a central role in establishing a diagnosis and stratifying risk, and make it possible to 294distinguish between NSTEMI and UA[4].6.1.3. Unstable angina295296Unstable angina (UA) is defined as myocardial ischemia at rest or minimal exertion in the absence of 297cardiomyocytes necrosis, i.e. without troponin elevation. Among NSTE-ACS population, the higher298sensitivity of troponin has resulted in an increase in the detection of MI [4]; the diagnosis of UAis less 299frequently made.6.2. Inclusion criteria for the therapeutic studies300301Inclusion of both STEMI and NSTEMI and/or NSTE-ACS patients in the same clinical trial (or not)302should be justified based on the mechanism of action of the investigated product and the proposed 303time of intervention. If both subgroups are investigated in the same trial, both subgroups should be 304well represented. For interventions aimed at post-acute and longer term phases (secondary305prevention or plaque stabilisation) it may be justified to address both conditions in the same clinical 306trial. Time of inclusion of the patients in relation to the index event should be set and adequately307discussed a priori.308Patients with unstable angina represent a different risk category and prognosis that necessitates309different interventions than NSTEMI patients. However, during the acute presentation of NSTE-ACS it may be difficult to discriminate NSTEMI from UA so both groups have been included in some clinical 310311studies. In general, the investigation of interventions in these patients is encouraged, but preferably in 312separate clinical trials.If fibrinolysis is considered, inclusion criteria should be in line with the current treatment guidelines 313314concerning the inclusion for fibrinolysis [3].6.3. Exclusion criteria for the therapeutic studies315316If the patients do not fulfil the above criteria for ACS they should be excluded from the ACS studies. 317Other life-threatening conditions presenting with chest pain, such as dissecting aneurysm,318myopericarditis or pulmonary embolism may also result in elevated troponins and should always be 319considered as differential diagnoses [4].320If drugs interfering with the haemostatic system are tested, patients with a significant risk of bleeding 321(e.g. recent stroke, recent bleeding, major trauma or surgical intervention) and/or a propensity to 322bleed (e.g. thrombocytopenia, clotting disturbances, intracranial vascular diseases, peptic ulcers,323haemophilia) should be excluded from participation in the clinical studies.324Attention should be paid to the time elapsed between a previous application of antiplatelet or325anticoagulant acting agent beforehand and the administration of study drug (e.g. the pharmacokinetic 326[PK] and even more importantly, the pharmacodynamic [PD] half-life of these previously administered 327drugs).328For reasons of generalisability of the study results to the future target population it is strongly advised 329not to define the exclusion criteria too narrow, i.e. polymorbid patients (e.g. renal and/or hepatic330impairment, heart failure), should not automatically be excluded from the main therapeutic clinical 331trials.332When fibrinolysis is considered, exclusion criteria for fibrinolysis should be strictly respected [3].6.4. Risk Stratification333334In clinical trials, the ability of the therapy to demonstrate a treatment effect may depend on the335underlying risk and expected event rates. Enrichment strategies are sometimes used in trials to obtain 336the required number of events with a reasonable time in specific subgroups who are likely to exhibit a 337higher event rate than the overall target population and potentially larger treatment effect. In thatcase, it has to be shown that the results of this enriched study population can be extrapolated to the 338339general population.。
塞来昔布对去卵巢骨质疏松症的保护机制研究
ｄｏｉ：１０．１１６５９／ｊｊｓｓｘ．１１Ｅ０２１１２８·基础研究·塞来昔布对去卵巢骨质疏松症的保护机制研究王 ，阿尖措，王德元 （青海红十字医院骨科二病区，青海西宁８１００００）［摘 要］ 目的 探讨塞来昔布对骨代谢稳态和骨质疏松症的作用。
方法 体外培养骨髓来源巨噬细胞（ＢＭＤＭ）、ＲＡＷ２６４．７和ＭＣ３Ｔ３ Ｅ１。
采用ＣＣＫ ８试剂盒检测不同浓度塞来昔布对ＢＭＤＭ和ＭＣ３Ｔ３ Ｅ１细胞活力的影响；采用抗酒石酸酸性磷酸酶（ＴＲＡＣＰ）染色检测塞来昔布对破骨细胞分化形成的影响；采用实时聚合酶链反应（ＲＴ ＰＣＲ）检测ＢＭＤＭ和ＭＣ３Ｔ３ Ｅ１细胞中活化Ｔ 细胞核因子１（ＮＦＡＴｃ１）、ＴＲＡＣＰ、组织蛋白酶Ｋ（ＣＴＳＫ）、降钙素受体（ＣＴＲ）、ＢＭＰ ２、Ｒｕｎｘ２和碱性磷酸酶（ＡＬＰ）ｍＲＮＡ水平；采用Ｗｅｓｔｅｒｎｂｌｏｔ检测细胞ｐ ＮＦ κＢ、ＮＦ κＢ、ＮＦＡＴ和ＧＡＰＤＨ的表达水平。
采用荧光素酶报告基因试验检测ＢＭＤＭ中ＮＦ κＢ和ＮＦＡＴ活性。
采用卵巢切除术构建骨质疏松症小鼠模型，雌性Ｃ５７ＢＬ／６Ｊ小鼠３０只随机分为对照组、模型组、塞来昔布低剂量（１２．５ｍｇ／ｋｇ）组、塞来昔布中剂量（２５ｍｇ／ｋｇ）组和塞来昔布高剂量（５０ｍｇ／ｋｇ）组，每组６只，分别以相应剂量的溶剂或药物灌胃进行干预处理。
采用微计算机断层扫描（ｍｉｃｒｏ ＣＴ）扫描各组小鼠胫骨，分析骨微结构参数变化。
结果 塞来昔布可抑制破骨细胞分化，但并不影响细胞活力。
塞来昔布可抑制ＲＮＡＮＫＬ诱导的ＮＦＡＴｃ１、ＴＲＡＣＰ、ＣＴＳＫ和ＣＴＲｍＲＮＡ表达，并抑制ｐ ＮＦ κＢ和ＮＦＡＴ蛋白表达及ＮＦ κＢ和ＮＦＡＴ活性。
塞来昔布可促进成骨细胞增殖，并促进ＢＭＰ ２、Ｒｕｎｘ２和ＡＬＰｍＲＮＡ表达。
与模型组比较，塞来昔布低剂量组、塞来昔布中剂量组和塞来昔布高剂量组小鼠骨体积／总体积（ＢＶ／ＴＶ）和骨小梁数目（Ｔｂ．Ｎ）显著增加（Ｐ＜０．０１），骨小梁分离度（Ｔｂ．Ｓｐ）显著减小（Ｐ＜０．０１）。
癌症临床试验(英文版
• Phase 4: From hundreds to thousands of people
– Usually takes place after drug is approved – Used to further evaluate long-term safety and
12
Clinical Trial Design
• Eligibility criteria: Can range from general (age, sex, type of cancer) to specific (prior treatment, tumor characteristics, blood cell counts, organ function); eligibility criteria also vary with trial phase
radioactive substances
7
Diagnostic Trials
• Develop better tools for classifying types and phases of cancer and managing patient care
• Possible benefits:
• Institutional review boards (IRBs) • Data and safety monitoring boards
(DSMBs)
– Minimize risks – Ensure integrity of data – Can stop study if necessary
– New technology may be better and less invasive – Earlier detection of recurrences
国际垂体协会《库欣病的诊断和管理共识(更新版)》解读——药物篇
·4483··指南解读·【编者按】 库欣病的临床症状复杂多样，其诊断和治疗极具挑战性，需要准确诊断、选择恰当的治疗方案和长期管理以优化患者结局。
国际垂体协会于2020年10月召开了库欣病的临床共识研讨会，并于2021年12月在柳叶刀子刊Lancet Diabetes Endocrinology 上发表了2021年版《库欣病的诊断和管理共识（更新版）》，该共识是以2008年和2015年国际内分泌协会发布的库欣综合征临床指南为基础，更新了临床实践证据和建议，包括库欣病的诊断和鉴别诊断、并发症的管理、药物治疗等。
本刊特邀请四川大学华西医院内分泌代谢科谭惠文等学者基于该共识并结合国内临床实践，对库欣病的诊断和药物使用进行详细阐述，使广大全科及专科医生对库欣病的诊疗更加规范化。
国际垂体协会《库欣病的诊断和管理共识（更新版）》解读——药物篇唐宇1，谭惠文1，2*，李建薇1，2，余叶蓉1，2【摘要】 库欣病是内源性库欣综合征最常见的病因，是垂体促肾上腺皮质激素腺瘤导致高皮质醇血症的临床综合征。
由于高皮质醇血症的持续存在，库欣病患者可以出现满月脸、水牛背、向心性肥胖、代谢障碍等临床表现。
对于库欣病，准确地诊断、恰当地治疗以及后续随访都极为重要。
国际垂体协会根据新近研究证据，于2021年12月发布了《库欣病的诊断和管理共识（更新版）》，对于库欣病的筛查和诊断流程、术后监测、药物和放射治疗、并发症管理均有更新。
本文重点对该共识中库欣病药物治疗部分进行解读，希望促进全科及专科医生对库欣病的规范化诊治。
【关键词】 库欣综合征；库欣病；诊疗指南； 药物疗法管理；垂体协会【中图分类号】 R 586.2 【文献标识码】 A DOI：10.12114/j.issn.1007-9572.2022.0469唐宇，谭惠文，李建薇，等. 国际垂体协会《库欣病的诊断和管理共识（更新版）》解读——药物篇［J］. 中国全科医学，2022，25（36）：4483-4490. ［］TANG Y，TAN H W，LI J W，et al. Interpretation of Consensus on Diagnosis and Management of Cushing 's Disease ：a Guideline Update from the pituitary society——medical therapies［J］. Chinese General Practice，2022，25（36）：4483-4490.Interpretation of Consensus on Diagnosis and Management of Cushing 's Disease ：a Guideline Update from the Pituitary Society ——Medical Therapies TANG Yu 1，TAN Huiwen 1，2*，LI Jianwei 1，2，YU Yerong 1，21.Department of Endocrinology and Metabolism ，West China Hospital ，Sichuan University ，Chengdu 610041，China2.Medical Center of Pituitary Adenomas and Related Diseases ，West China Hospital ，Sichuan University ，Chengdu 610041，China*Corresponding author ：TAN Huiwen ，Associate chief physician ；E-mail ：【Abstract 】 Cushing 's disease，the most common cause of endogenous Cushing 's syndrome，is hypercortisolemiacaused by adrenocorticotropic hormone-secreting pituitary adenoma. Patients may present clinical symptoms such as moon face，buffalo back，central obesity and metabolic disorders due to the persistence of hypercortisolemia. Accurate diagnosis，appropriate treatment and follow-up of Cushing 's disease are vitally important. Based on recent evidence，the Pituitary Society published the Consensus on Diagnosis and Management of Cushing 's Disease ：a Guideline Update in December 2021，with updates in screening and diagnosis procedures，postoperative monitoring，medical therapies and radiotherapy，and complication management. This article interprets the medical therapies recommended in the consensus，which will be helpful for general practitioners and specialists to standardize the diagnosis and treatment of Cushing 's disease.【Key words 】 Cushing syndrome；Cushing disease；Diagnostic and treatment guideline；Pituitary adenoma；Medication therapy management基金项目：四川大学华西医院学科卓越发展1·3·5工程临床研究孵化项目（2020HXFH034）；四川省卫生健康委员会项目（20PJ046）1. 610041四川省成都市，四川大学华西医院内分泌代谢科2. 610041四川省成都市，四川大学华西医院垂体瘤及相关疾病诊疗中心*本文数字出版日期：2022-08-18扫描二维码查看原文·4484·E-mail:******************.cn临床实践指南）提到，如有证据倾向于明显的周期性高皮质醇血症，推荐选用阻断替代方案。
医学英语口语：艾滋病英语词汇
以下是⽆忧考整理的《医学英语⼝语：艾滋病英语词汇》，希望⼤家喜欢！艾滋病 AIDS 艾滋病毒 HIV 艾滋病毒案例 HIV cases 艾滋病毒带原者 HIV carriers 艾滋病毒和肝炎病毒重叠感染 hepatitis c/co-infection with HIV 艾滋病毒急性感染 primary HIV infection 艾滋病服务组织 AIDS service organization （ASO） 艾滋病感染者 AIDS－infected patient 艾滋病⼯作者 AIDS Worker 艾滋病患者 HIV sufferers 艾滋病教育培训中⼼ AIDS education and training centers （AETC） 艾滋病快速诊断试剂 quick AIDS tests 艾滋病⽂献资料库 AIDS hotline 艾滋病相关癌症 AIDS-related cancers 艾滋病相关症群期 AIDS-related complex （ARC） 艾滋病携带者 HIV patients 艾滋病宣傳員 AIDS activist 艾滋病药物数据库 AIDSDRUGS 艾滋病药物协助计划 AIDS drug assistance program （ADAP） 艾滋病，后天免疫缺乏症候群 HIV disease 艾滋村 AIDS village（s） 艾滋村 HIV/AIDS villages 艾滋消瘦症候群 AIDS wasting syndrome ⽩⾎球 leukocytes ⽩⾎球 white blood cells 伴随药物 concomitant drugs 保守估計 conservative projections 爆炸性的⽔平 explosive level 被动免疫 passive immunity B细胞淋巴瘤 B cell lymphoma 病毒讀數实验 viral load test 病毒学 virology 丙种球蛋⽩ gamma globulin 不安全的集⾎系统 unsafe blood collection system 补药，滋补品 tonic（s） 参加者不知情的研究 blinded study 成⼈艾滋病临床研究协作组 adult AIDS clinical trials group （AACTG） 重新复活的性产业 resurgent sex industry 丑化与歧视 stigma and discrimination 雏妓 underage prostitute 传媒 press/media/mass media 传染/传播 transmission 传染⽅式/ 流⾏⽅式 spread path 传染途径 mechanisms for transmission 传染途径 routes of infection 垂直传播 vertical transmission 耸⼈听闻 sensational/ frightening ⼤相径庭 to stand in stark contrast to ⼤众宣传 public education 蛋⽩分解抑制剂 protease inhibitors 蛋⽩酶 protease 盗汗 night sweats 问题最为严重 has been hit the hardest 地⽅病 endemic 低估数据 an underestimate 地位的象征 status symbol 第⼀阶段⼈体试验 phase I trials 定时炸弹 time bomb 对疫情不予重视 downplay the epidemic 鹅⼝疮 thrush 遏⽌其扩散 to stem the spread of （HIV/AIDS） ⼉科艾滋病临床试验联盟 pediatric AIDS clinical trials group （PACTG） 发⽣频率出现的范围、程度或频率 incidence 贩毒者 traffickers 防治此传染病 to contain the epidemic ⾮何杰⾦淋巴瘤 non-Hodgkin‘s lymphoma （NHL） 肺结核 tuberculosis （TB） 复苏的 resurgent 腹泻 diarrhea 辅助疗法 complementary therapy 副作⽤ side effects 改⾰开放 reform and opening 感染 contract/infect 感染 infection 感染HIV病毒 to carry HIV 肝炎 hepatitis 告诫 to exhort ⾼危险群 high-risk populations ⾼效抗逆转录病毒疗法 highly active antiretroviral therapy （HAART） 个体户 self-employed entrepreneurs 公共保健 public health care ⾻髓抑制 bone marrow suppression 管不著 beyond the reach of officialdom 官场；官僚作风 officialdom 毫升 milliliter （ml） 合⽤针头 sharing of needles HIV 急性期感染 acute HIV infection HIV 菌种 HIV strains/ strains of HIV HIV阳性 HIV positive 患上/染上 to suffer from/ to be infected with/ to be afflicted with/ contract （the virus/AIDS） 黄疸 jaundice 黄⾦時段 in prime time 婚前性⾏为 premarital sex 机会性感染 opportunistic infections 机能障碍 lesion [遗传]基因 gene 基因组，染⾊体组 genome 结核菌素⽪下测试 tuberculin skin test （TST） 接种 inoculation 接种疫苗 vaccination 静脉内的；静脉注射物 intravenous （IV） 静脉注射 intravenous injection 静脉注射使⽤者是中国艾滋病主要⼈⼝ IV users constitute the largest proportion of HIV cases in China 静脉注射药物 intravenous （IV） drug 精神病 psychiatric disorders 惊险的经济发展 breakneck economic development 巨⼤的危险 titanic peril 卡波⽒⾁瘤 Kaposi‘s sarcoma （KS） 开矿 mine exploration 抗⽣素 antibiotic 抗体 antibody 抗体媒介免疫 antibody-mediated immunity 抗原呈递 antigen presentation 可归咎于 be attributable to 劳动⼒流动 labor mobility 联合国艾滋病计划 U.N. AIDS program， the 联合国艾滋病特别⼤会 United Nations General Assembly Special Session on HIV/AIDS 淋巴 lymph 淋巴结 lymph nodes 淋病 gonorrhea 临床潜伏期 clinical latency 临床实验 clinical trial 流动⼈⼝ transient population 流⾏病 epidemic 流⾏病学 epidemiology 流⾏病学家 epidemiologist 乱交与婚前性关系 casual and premarital sex 乱交，性乱⾏为 promiscuity 梅毒 syphilis 美国疾病控制预防中⼼ CDC （ US Centers for Disease Control and Prevention） 免疫反应 immune response 免疫疗法 immunotherapy 免疫缺乏 immunodeficiency 免疫缺陷 immune deficiency 免疫系统 immune system 免疫作⽤ immunization 男⼥婴每年出⽣⾃然⽐率 natural ratio of males to females born each year 男性继承⼈ male heirs 脑膜炎 meningitis 脑炎 encephalitis 逆转录酶病毒 retrovirus 剖腹产 cesarean 疱疹 herpes 疱疹病毒 herpes viruses ⽪条客 pimp ⽪下注射器 syringe 嫖客 john 平⾯⼴告 billboard 普遍的社会问题 pervasive social problem 潜伏期 incubation period 潜伏期 latency 求助于毒品 to turn to drugs 全国或全世界流⾏的（疾病） pandemic 全球艾滋病感染最严重的国家 world"s most heavily HIV- infected nations 全球涵盖范围 global coverage 全⾎球计数 complete blood count （CBC） 染病的亚洲⼈ afflicted Asian HIV sufferers 染上愛滋病毒 infected with HIV ⼈⼝多/稠密的 populous ⼈类免疫缺陷病毒II型 HIV-2 ⼈类免疫缺陷病毒Ⅰ型 HIV-1 ⼈*状瘤病毒 human papilloma virus （HPV） ⽇趋严重 to be on the rise 沙门⽒菌 salmonella 社会经济转变 socioeconomic transformation 社会问题 social ills 社区规划 community planning ⽣殖道尖锐湿疣 genital warts 使恶化 exacerbate 失控 get out of hand 世界艾滋病⽇ World AIDS Day 试验性质的，暂时的 tentative 受感染的⾎液 tainted blood 收⼊差距越來越⼤ growing income disparities 收视率 viewing rate/ rating 输⾎ blood transfusions 输⾎ transfusion 输⾎⼈ blood donors 输⾎中⼼ blood Collection Center 双盲研究 double-blind study ⽔平传播 horizontal transmission 死亡率 fatalities 随机⽐对临床试验 randomized trial 替代医学 alternative medicine T辅助细胞 T4 cell T淋巴细胞 T cells 同性恋性交 homosexual intercourse 推⼴保险套使⽤ promotion of condom use 脱氧核糖核酸 DNA （deoxyribonucleic acid） 晚期 end-stage disease 围产期传播 perinatal transmission 卫⽣官员 health official 问题已经很严重了 problem is already particularly acute 问题只会越来越严重 problem will certainly get much worse before its gets any better ⽆效对照剂 placebo ⽆预防措施之性交 unprotected sex 吸毒者 drug takers 细菌 bacterium 风俗习惯 social mores 現代化的利弊得失 benefits and the costs of modernity 消费者⾄上主义、物质⾄上主义 consumerism 酵母菌感染 yeast infection 新陈代谢 metabolism 性传染病 sexually transmitted disease （STD） 性⼯作者 commercial sex work 性交 sexual intercourse 性能⼒最活跃的年纪 in their most sexually active stages of life ⾎浆 plasma ⾎库 pool ⾎清 serum ⾎清测试 serologic test ⾎头 blood heads ⾎⼩板 platelets ⾎液传染病 blood-borne diseases ⾎液中所含的病毒數量 viral burden ⾎友病（⼈） hemophilia（c） 亚临床感染 subclinical infection 严重 acute/ serious/ enormous 药品核准标⽰外使⽤ off-label use 药物抗性 drug resistance 意见论⽂ position paper 疫苗 vaccine 以母乳喂哺 to breast-feed 异性恋的 heterosexual 异性恋者 heterosexual population ⾐原体 Chlamydia 抑制剂 integrase inhibitors 抑制剂 integrase inhibitors 抑制其蔓延 to contain the epidemic 隐瞒真实⾝份 to mask a person"s identity 影响很⼤ enormous implications 有传染性的 infectious 有毒瘾者 junkie 预防教育 preventive education 与先前官⽅数据完全相反 stands in entire contrast to previous official statistics 孕前咨询 preconception counseling 灾难的边缘 on the brink of disasters 在世界艾滋病⽇ on World AIDS Day 在体内潜伏 hole up in the body 再⽤针头与注射筒 reuse of needles and syringes 赞赏 to praise 诊断 diagnosis 针灸 acupuncture 症候群 syndrome 知情同意 informed consent 中国社会的组成 makeup of Chinese society 中国政界 Chinese officials ⾃⾝免疫作⽤ autoimmunization。
Stemcelltherapy将重新定义医学界
Stemcelltherapy将重新定义医学界Stem Cell Therapy: Redefining the Medical Field Introduction:In recent years, healthcare has witnessed tremendous advancements in regenerative medicine. One groundbreaking innovation that holds immense promise is stem cell therapy. Stem cell therapy employs the use of stem cells to repair damaged tissues and regenerate new cells, offering a potentially revolutionary approach to treating a wide range of medical conditions. This article delves into the potential of stem cell therapy to redefine the medical field, exploring its applications, current challenges, and future prospects.The Power of Stem Cells:Stem cells possess a unique ability to differentiate into various cell types, making them the building blocks of the human body. Through their remarkable regenerative potential, stem cells hold the key to potentially curing previously untreatable diseases. They can be harvested from various sources, including embryos, umbilical cords, and adult tissues, making them accessible for therapeutic use. With the ability to differentiate into specialized cells such as neurons, heart cells, and pancreatic cells, stem cells offer endless possibilities for medical interventions.Application in Disease Treatment:Stem cell therapy has already shown significant promise in multiple medical fields. In neurodegenerative diseases like Parkinson's and Alzheimer's, stem cells can potentially replace damaged neurons and restore brain function. Similarly, in spinal cord injuries, stem cells may provide a means to repair and regenerate damaged nerve tissue, potentially leading to restored mobility for patients. Stem cell therapy also holds the potential torevolutionize the treatment of cardiovascular diseases, diabetes, and even certain types of cancer.Cardiovascular diseases, such as heart failure, can greatly benefit from stem cell therapy. By injecting stem cells into damaged areas of the heart, researchers have observed improved heart function and reduced scar tissue formation. This breakthrough offers hope for millions of individuals suffering from cardiovascular conditions worldwide.Diabetes, a chronic disease affecting millions of people globally, may also find newfound hope through stem cell therapy. By differentiating stem cells into pancreatic beta cells, which produce insulin, scientists are exploring the potential for curing diabetes by replacing dysfunctional or destroyed cells within the pancreas. This approach could transform the lives of patients, dramatically altering the management and control of diabetes.Challenges and Ethical Considerations:Though stem cell therapy holds immense potential, it is not without challenges and ethical considerations. One major challenge lies in the ability to control and direct the differentiation of stem cells into desired cell types. Researchers continue to refine their methodologies and techniques to ensure reliable and predictable outcomes. Additionally, the safety and long-term effects of stem cell therapy require extensive research and clinical trials to establish efficacy and mitigate potential risks.Ethical considerations surrounding the use of embryonic stem cells also pose challenges. The extraction of embryonic stem cells often involves the destruction of embryos, and this raises ethical concerns for some. However, alternative sources of stem cells, such as adult tissues and umbilical cords, offer a more ethically acceptable solution for those who oppose the use of embryonic stem cells.Future Prospects and Conclusion:Stem cell therapy has the potential to redefine the medical field by unlocking endless possibilities for disease treatment and regenerative medicine. As scientists continue to delve deeper into understanding the mechanisms of stem cell differentiation and harness their full potential, the future looks promising. Advances in stem cell research may pave the way for personalized medicine, where therapies are tailored to individual patients based on their unique needs. With ongoing research, clinical trials, and collaborations, stem cell therapy is set to revolutionize healthcare, offering hope for those suffering from currently incurable diseases.In conclusion, stem cell therapy has the potential to redefine the medical field by offering a new paradigm for disease treatment and regeneration. Though challenges and ethical considerations exist, the power of stem cells to repair and regenerate holds immense promise for countless patients worldwide. As research advances and scientific breakthroughs unfold, stem cell therapy may soon become a cornerstone of modern medicine, bringing us closer to a future where previously untreatable conditions become curable.。
免疫细胞治疗药物临床试验的风险管理
既往临床试验数据核查发现，申办者也存在试验药 物管理方面的问题，如试验药物运输过程中的温度控制 不符合要求，试验药物管理的整个环节的记录不全等 。 [11] 免疫细胞治疗药物有保质期短、对保存温度要求高的特 点，对其试验药物实施实时性管理非常重要。
此外，免疫细胞治疗药物为个体化治疗药物，这使得在 早期临床试验中对其进行安全性和量效关系评估的难度 增大。免疫细胞治疗药物的安全性受免疫细胞类型、生 物活性、靶抗原选择和是否经过基因修饰等多种因素的 影响，其不良反应的发生时间和严重性也与免疫细胞在 人体内的存活、增殖和分布等特征密切相关，故该类药 物的不良反应性质、发生率、持续时间和免疫原性均有 很大的不确定性。
关指导原则，结合我国临床试验实施现况，就免疫细胞治疗药物临床试验的风险管理作一探讨，供业界借鉴和参考。
关键词 免疫细胞治疗药物 临床试验 风险管理
中图分类号 ：R951
文献标志码 ：C
文章编号 ：1006-1533(2021)13-0010-04
Risk management of clinical trials of immune cell therapy drugs
1 免疫细胞治疗药物的分类和特点
免疫细胞治疗属过继性免疫细胞治疗，其是一种利 用患者自身或供者来源的免疫细胞，经体外培养扩增、 活化或基因修饰（编辑）等操作，再回输至患者体内， 由此激发或增强患者的免疫功能，最终控制疾病的治疗 方法。免疫细胞治疗药物可主要分为两大类 [3] ：一类属 非特异性疗法药物，其没有明确的作用靶点，系从整体 上提高患者的免疫功能而产生疾病治疗作用的，如肿瘤
2.2 伦理审查的风险
免疫细胞治疗属于新兴治疗技术，临床研究风险高， 对伦理审查的要求也高。在免疫细胞治疗药物临床试验 伦理审查中，除传统药物临床试验伦理审查内容外，还 需特别关注该类药物的免疫细胞来源、获取和操作过程 是否符合伦理，对制备过程中不合格和临床试验中剩余 的免疫细胞治疗药物是否采用了妥善、合法并符合伦理 的处理方法等 [7]。我国是免疫细胞治疗药物研发大国， 正在进行的相关临床试验数量庞大，其中约半数由企业 发起，存在较大的风险和监管缺失问题。须指出的是， 若将未严格按照《药物临床试验质量管理规范》开展的 非注册临床研究数据用于药品注册申请，存在研究数据 质量无法保证和不可靠的风险 [8]。
艾滋病词汇中英互译
艾滋病词汇中英互译艾滋病传染主要是通过性行为、体液的交流而传播，母婴传播。
接下来小编为大家整理了艾滋病词汇中英互译，希望对你有帮助哦!艾滋病词汇中英互译一：gonorrhea 淋病growing income disparities 收入差距越來越大has been hit the hardest ~ 的问题最为严重health official 卫生官员heterosexual population 异性恋者hemophilia(c) 血友病 (人)hepatitis 肝炎hepatitis c/co-infection with HIV 艾滋病毒和肝炎病毒重叠感染herpes 疱疹herpes viruses 疱疹病毒heterosexual 异性恋的highly active antiretroviral therapy (HAART) 高效抗逆转录病毒疗法high-risk populations 高危险群HIV 艾滋病毒HIV carriers 艾滋病毒带原者HIV cases 艾滋病毒案例HIV disease 艾滋病，后天免疫缺乏症候群HIV patients 艾滋病携带者HIV positive HIV阳性HIV strains/ strains of HIV HIV 菌种HIV sufferers 艾滋病患者HIV/AIDS villages 愛滋村HIV-1 人类免疫缺陷病毒Ⅰ型艾滋病 AIDS艾滋病毒 HIV艾滋病毒案例 HIV cases艾滋病毒带原者 HIV carriers艾滋病毒和肝炎病毒重叠感染 hepatitis c/co-infection with HIV 艾滋病毒急性感染 primary HIV infection艾滋病服务组织 AIDS service organization (ASO)艾滋病感染者 AIDS-infected patient艾滋病工作者 AIDS Worker艾滋病患者 HIV sufferers艾滋病教育培训中心AIDS education and training centers (AETC)艾滋病快速诊断试剂 quick AIDS tests艾滋病文献资料库 AIDS hotline艾滋病相关癌症 AIDS-related cancers艾滋病相关症群期 AIDS-related complex (ARC)艾滋病携带者 HIV patients艾滋病宣傳員 AIDS activist艾滋病药物数据库 AIDSDRUGS艾滋病药物协助计划 AIDS drug assistance program (ADAP)艾滋病，后天免疫缺乏症候群 HIV disease艾滋村 AIDS village(s)艾滋村 HIV/AIDS villages艾滋消瘦症候群 AIDS wasting syndrome白血球 leukocytes白血球 white blood cells伴随药物 concomitant drugs保守估計 conservative projections爆炸性的水平 explosive level被动免疫 passive immunityB细胞淋巴瘤 B cell lymphoma病毒讀數实验 viral load test病毒学 virology丙种球蛋白 gamma globulin不安全的集血系统 unsafe blood collection system补药，滋补品 tonic(s)参加者不知情的研究 blinded study成人艾滋病临床研究协作组adult AIDS clinical trials group (AACTG)重新复活的性产业 resurgent sex industry丑化与歧视 stigma and discrimination雏妓 underage prostitute传媒 press/media/mass media传染/传播 transmission传染方式/ 流行方式 spread path传染途径 mechanisms for transmission传染途径 routes of infection垂直传播 vertical transmission耸人听闻 sensational/ frightening大相径庭 to stand in stark contrast to大众宣传 public education蛋白分解抑制剂 protease inhibitors蛋白酶 protease盗汗 night sweats~ 的问题最为严重 has been hit the hardest地方病 endemic低估数据 an underestimate地位的象征 status symbol第一阶段人体试验 phase I trials定时炸弹 time bomb对疫情不予重视 downplay the epidemic鹅口疮 thrush遏止其扩散 to stem the spread of (HIV/AIDS)儿科艾滋病临床试验联盟pediatric AIDS clinical trials group (PACTG)发生频率出现的范围、程度或频率 incidence贩毒者 traffickers防治此传染病 to contain the epidemic非何杰金淋巴瘤 non-Hodgkin's lymphoma (NHL)肺结核 tuberculosis (TB)复苏的 resurgent腹泻 diarrhea辅助疗法 complementary therapy副作用 side effects改革开放 reform and opening感染 contract/infect感染 infection感染HIV病毒 to carry HIV肝炎 hepatitis告诫 to exhort高危险群 high-risk populations高效抗逆转录病毒疗法highly active antiretroviral therapy (HAART)个体户 self-employed entrepreneurs公共保健 public health care骨髓抑制 bone marrow suppression管不著 beyond the reach of officialdom官场; 官僚作风 officialdom毫升 milliliter (ml)合用针头 sharing of needlesHIV 急性期感染 acute HIV infectionHIV 菌种 HIV strains/ strains of HIVHIV阳性 HIV positive患上/染上 to suffer from/ to be infected with/ to be afflicted with/ contract (the virus/AIDS)黄疸 jaundice黄金時段 in prime time婚前性行为 premarital sex机会性感染 opportunistic infections机能障碍 lesion基因 gene基因组,染色体组 genome结核菌素皮下测试 tuberculin skin test (TST)接种 inoculation接种疫苗 vaccination静脉内的; 静脉注射物 intravenous (IV)静脉注射 intravenous injection静脉注射使用者是中国艾滋病主要人口IV users constitute the largest proportion of HIV cases in China静脉注射药物 intravenous (IV) drug精神病 psychiatric disorders惊险的经济发展 breakneck economic development巨大的危险 titanic peril卡波氏肉瘤 Kaposi's sarcoma (KS)开矿 mine exploration抗生素 antibiotic抗体 antibody抗体媒介免疫 antibody-mediated immunity抗原呈递 antigen presentation可归咎于 be attributable to劳动力流动 labor mobility联合国艾滋病计划 U.N. AIDS program, the联合国艾滋病特别大会United Nations General Assembly Special Session on HIV/AIDS淋巴 lymph淋巴结 lymph nodes淋病 gonorrhea临床潜伏期 clinical latency临床实验 clinical trial流动人口 transient population流行病 epidemic流行病学 epidemiology流行病学家 epidemiologist乱交与婚前性关系 casual and premarital sex乱交，性乱行为 promiscuity**时代 Maoist era梅毒 syphilis美国疾病控制预防中心 CDC ( US Centers for Disease Control and Prevention)免疫反应 immune response免疫疗法 immunotherapy免疫缺乏 immunodeficiency免疫缺陷 immune deficiency免疫系统 immune system免疫作用 immunization男女婴每年出生自然比率natural ratio of males to females born each year男性继承人 male heirs脑膜炎 meningitis脑炎 encephalitis逆转录酶病毒 retrovirus剖腹产 cesarean疱疹 herpes疱疹病毒 herpes viruses皮条客 pimp皮下注射器 syringe嫖客 john平面广告 billboard普遍的社会问题 pervasive social problem潜伏期 incubation period潜伏期 latency求助于毒品 to turn to drugs艾滋病词汇中英互译二：全国或全世界流行的(疾病) pandemic全球艾滋病感染最严重的国家world"s most heavily HIV- infected nations全球涵盖范围 global coverage全血球计数 complete blood count (CBC)染病的亚洲人 afflicted Asian HIV sufferers染上愛滋病毒 infected with HIV人口多/稠密的 populous人类免疫缺陷病毒II型 HIV-2人类免疫缺陷病毒Ⅰ型 HIV-1人乳头状瘤病毒 human papilloma virus (HPV)日趋严重 to be on the rise沙门氏菌 salmonella社会经济转变 socioeconomic transformation社会问题 social ills社区规划 community planning生殖道尖锐湿疣 genital warts使恶化 exacerbate失控 get out of hand世界艾滋病日 World AIDS Day试验性质的，暂时的 tentative受感染的血液 tainted blood收入差距越來越大 growing income disparities收视率 viewing rate/ rating输血 blood transfusions输血 transfusion输血人 blood donors输血中心 blood Collection Center双盲研究 double-blind study水平传播 horizontal transmission死亡率 fatalities随机比对临床试验 randomized trial替代医学 alternative medicineT辅助细胞 T4 cellT淋巴细胞 T cells同性恋性交 homosexual intercourse推广保险套使用 promotion of condom use脱氧核糖核酸 DNA (deoxyribonucleic acid)晚期 end-stage disease围产期传播 perinatal transmission卫生官员 health official问题已经很严重了 problem is already particularly acute问题只会越来越严重problem will certainly get much worse before its gets any better无效对照剂 placebo无预防措施之性交 unprotected sex吸毒者 drug takers细菌 bacterium风俗习惯 social mores現代化的利弊得失 benefits and the costs of modernity消费者至上主义、物质至上主义 consumerism酵母菌感染 yeast infection新陈代谢 metabolism性传染病 sexually transmitted disease (STD)性工作者 commercial sex work性交 sexual intercourse性能力最活跃的年纪 in their most sexually active stages of life 血浆 plasma血库 pool血清 serum血清测试 serologic test血头 blood heads血小板 platelets血液传染病 blood-borne diseases血液中所含的病毒數量 viral burden血友病 (人) hemophilia(c)亚临床感染 subclinical infection严重 acute/ serious/ enormous药品核准标示外使用 off-label use药物抗性 drug resistance意见论文 position paper疫苗 vaccine以母乳喂哺 to breast-feed异性恋的 heterosexual异性恋者 heterosexual population衣原体 Chlamydia抑制剂 integrase inhibitors抑制剂 integrase inhibitors抑制其蔓延 to contain the epidemic隐瞒真实身份 to mask a person"s identity影响很大 enormous implications有传染性的 infectious有毒瘾者 junkie预防教育 preventive education与先前官方数据完全相反 stands in entire contrast to previous official statistics孕前咨询 preconception counseling灾难的边缘 on the brink of disasters在世界艾滋病日 on World AIDS Day在体内潜伏 hole up in the body再用针头与注射筒 reuse of needles and syringes赞赏 to praise诊断 diagnosis针灸 acupuncture症候群 syndrome知情同意 informed consent中国社会的组成 makeup of Chinese society中国政界 Chinese officials自身免疫作用 autoimmunizationacupuncture 针灸acute HIV infection HIV 急性期感染acute/ serious/ enormous 严重adult AIDS clinical trials group (AACTG) 成人艾滋病临床研究协作组afflicted Asian HIV sufferers 染病的亚洲人AIDS 艾滋病AIDS activist 艾滋病宣傳員AIDS drug assistance program (ADAP) 艾滋病药物协助计划AIDS education and training centers (AETC) 艾滋病教育培训中心AIDS service organization (ASO) 艾滋病服务组织AIDS village(s) 愛滋村AIDS wasting syndrome 艾滋消瘦症候群AIDS Worker 艾滋病工作者AIDSDRUGS 艾滋病药物数据库AIDS-infected patient 艾滋病感染者AIDSLINE 艾滋病文献资料库AIDS-related cancers 艾滋病相关癌症AIDS-related complex (ARC) 艾滋病相关症群期alternative medicine 替代医学an underestimate 低估数据antibiotic 抗生素antibody 抗体antibody-mediated immunity 抗体媒介免疫antigen presentation 抗原呈递autoimmunization 自身免疫作用B cell lymphoma B细胞淋巴瘤bacterium 细菌be attributable to 可归咎于benefits and the costs of modernity 現代化的利弊得失beyond reach of officials 管不著billboard 平面广告blinded study 参加者不知情的研究blood Collection Center 输血中心blood donors 输血人blood transfusions 输血blood-borne diseases 血液传染病blood heads 血头bone marrow suppression 骨髓抑制breakneck economic development 惊险的经济发展casual and premarital sex 乱交与婚前性关系CDC ( US Centers for Disease Control and Prevention) 美国疾病控制预防中心cesarean 剖腹产Chinese aged between 15 and 49 …岁之间的中国人Chinese officials 中国政界Chlamydia 衣原体clinical latency 临床潜伏期clinical trial 临床实验commercial sex work 性工作者community planning 社区规划complementary therapy 辅助疗法complete blood count (CBC) 全血球计数concomitant drugs 伴随药物conservative projections 保守估計consumerism 消费者至上主义、物质至上主义contract/infect 感染diagnosis 诊断diarrhea 腹泻DNA (deoxyribonucleic acid) 脱氧核糖核酸double-blind study 双盲研究downplay the epidemic 对疫情不予重视drug resistance 药物抗性drug takers 吸毒者encephalitis 脑炎endemic 地方病end-stage disease 晚期enormous implications 影响很大epidemic 流行病epidemiologist 流行病学家epidemiology 流行病学exacerbate 使恶化explosive level 爆炸性的水平fatalities 死亡率gamma globulin 丙种球蛋白gene 基因genital warts 生殖道尖锐湿疣。
中国科学 生命科学英文版
中国科学生命科学英文版Title: China's Scientific Endeavors in Life SciencesIntroductionChina, the world's most populous nation and the second-largest economy, has been making significant strides in science and technology in recent years. One of the areas where China has demonstrated remarkable progress is life sciences, which epasses a broad range of disciplines including genetics, biochemistry, molecular biology, immunology, neuroscience, and many more. This article will explore China's achievements and contributions to the field of life sciences.1. Advancements in Genomics and Genetic EngineeringIn 2019, Chinese scientists achieved a major breakthrough by creating the world's first gene-edited babies using CRISPR-Cas9 technology. The study was led by He Jiankui, a biophysicist at the Southern University of Science and Technology in Shenzhen. Although this event sparked ethical debates worldwide, it underscores China'smitment to pushing the boundaries of genetic engineering.Furthermore, China has made considerable investments in genomics research. In 2016, the country launched its National Genebank project, aimed at collecting, preserving, and studying the genetic resources of all living organisms on Earth. The project, based in Shenzhen, houses one of the world's largest DNA sequencing facilities and has already sequenced over 5 million microbial genomes.2. Biomedical Research and Drug DevelopmentChinese researchers have been actively engaged in biomedical research to develop novel therapeutic strategies for various diseases. For instance, in 2019, Chinese scientists developed a new type of CAR-T cell therapy that showed promising results in treating relapsed or refractory acute lymphoblastic leukemia.Moreover, China has be a global leader in clinical trials. According to a report by IQVIA, a healthcare analytics firm, China surpassed the United States in the number of clinical trials initiated in 2018. With a vast patient pool, streamlined regulatory processes, and growing investment in R&D, China is well-positioned to contribute significantly to the development of new drugs and therapies.3. Synthetic Biology and BioinformaticsSynthetic biology, an interdisciplinary field thatbines principles from biology, engineering, andputer science, is another area where China has shown great promise. Researchers in China are exploring ways to engineer microorganisms to produce biofuels, pharmaceuticals, and other valuablepounds. They are also developingputational tools to design and optimize synthetic biological systems.In addition, China has invested heavily in bioinformatics infrastructure. The China National GeneBank DataBase (CNGBdb) is aprehensive data platform that supports large-scale omics studies and provides open access to genomic data. It plays a critical role in facilitating international collaborations and promoting data sharing in the life sciencesmunity.4. Neuroscience and Brain ResearchNeuroscience is yet another frontier where China is striving to make groundbreaking discoveries. The China Brain Project, launched in 2016, aims to advance our understanding of brain function and develop effective treatments for neurological disorders such as Alzheimer's disease and Parkinson's disease. The initiative involves collaboration among multiple institutions across the country and has received substantial funding from the government.ConclusionChina's rapid advancement in life sciences can be attributed to several factors, including strong government support, substantial financial investments, and a large pool of talented researchers. While there are still challenges to ovee, such as improving research integrity and addressing ethical concerns, China's scientific achievements in life sciences hold great potential for improving human health and transforming the global biotechnology landscape. As China continues to push the frontiers of knowledge in this field, it is poised to play an increasingly influential role in shaping the future of life sciences worldwide.。
基因治疗的英语
基因治疗的英语一、单词1. gene [dʒiːn]- 释义：基因，遗传因子。
- 用法：作名词，可在句中作主语、宾语等。
例如：A gene determines a specific trait.（一个基因决定一种特定的性状。
）2. therapy [ˈθerəpi]- 释义：治疗，疗法。
- 用法：作名词，如：He is receiving physical therapy.（他正在接受物理治疗。
）3. vector [ˈvektə(r)]- 释义：载体；矢量。
在基因治疗中，常指携带目的基因的载体（如病毒载体等）。
- 用法：作名词，例如：The virus is used as a vector in gene therapy.（这种病毒在基因治疗中被用作载体。
）4. mutation [mjuːˈteɪʃn]- 释义：突变；变化。
基因治疗有时是针对基因突变引起的疾病。
- 用法：作名词，如：A mutation in this gene can cause the disease.（这个基因中的一个突变会导致这种疾病。
）5. delivery [dɪˈlɪvəri]- 释义：传递；交付。
在基因治疗语境下指基因的传递。
- 用法：作名词，例如：The delivery of the gene to the target cells is crucial.（将基因传递到靶细胞是至关重要的。
）二、短语1. gene therapy vector- 释义：基因治疗载体。
- 用法：作名词短语，例如：Scientists are constantly exploring new gene therapy vectors.（科学家们不断探索新的基因治疗载体。
）2. target gene- 释义：靶基因，目标基因。
- 用法：作名词短语，如：The researchers aim to modify the target gene.（研究人员旨在修饰靶基因。
Neurodegenerative Diseases and Therapies
Neurodegenerative Diseases and Therapies Neurodegenerative diseases are a group of disorders that affect the nervous system and gradually lead to the loss of neurons and their functions. These diseases are chronic and progressive, and they can have a devastating impact on the quality of life of affected individuals. Some of the most common neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS).Despite extensive research efforts, there are currently no cures for neurodegenerative diseases, and the available treatments are mainly focused on managing symptoms. However, there is a growing body of evidence suggesting that early intervention with disease-modifying therapies could slow down or even halt disease progression. Therefore, there is an urgent need for the development of effective therapies that can target the underlying causes of neurodegeneration.One of the most promising approaches to treating neurodegenerative diseases is the use of stem cell therapies. Stem cells are undifferentiated cells that have the ability to differentiate into various cell types, including neurons. Therefore, stem cell therapies hold great potential for replacing damaged or lost neurons in the brain and restoring their functions. Several clinical trials are currently underway to evaluate the safety and efficacy of stem cell therapies for neurodegenerative diseases.Another promising approach is the use of gene therapies to correct or replace faulty genes that are responsible for neurodegeneration. For example, in Huntington's disease, a genetic mutation causes the accumulation of toxic proteins in the brain, leading to neuronal death. Gene therapies could potentially replace the faulty gene or prevent the production of toxic proteins, thereby slowing down disease progression. However, gene therapies are still in the early stages of development, and more research is needed to determine their safety and efficacy.In addition to these approaches, there is also growing interest in the use of non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), for the treatment of neurodegenerativediseases. These techniques involve the application of magnetic or electrical fields to specific regions of the brain, which can modulate neuronal activity and potentially improve cognitive and motor functions. While the results of studies on non-invasive brain stimulation have been mixed, they offer a promising avenue for future research.Despite these promising approaches, there are also significant challenges that need to be addressed in the development of effective therapies for neurodegenerative diseases. One major challenge is the difficulty of delivering therapies to the brain, as the blood-brain barrier restricts the entry of many drugs and therapies. Additionally, the complex and multifactorial nature of neurodegenerative diseases makes it difficult to identify specific targets for therapy. Finally, the high cost of developing and testing new therapies can be a significant barrier to their availability and accessibility.In conclusion, while there is still much to be learned about the underlying causes of neurodegenerative diseases, there is also reason for hope in the development of effective therapies. Stem cell therapies, gene therapies, and non-invasive brain stimulation techniques offer promising avenues for future research, and early intervention with disease-modifying therapies could potentially slow down or halt disease progression. However, significant challenges remain, and a concerted effort will be required to overcome these challenges and develop effective therapies that can improve the lives of millions of people affected by neurodegenerative diseases.。
使细胞治疗成为攻克疾病的新一代技术手段——陈志国教授
2020年10月第41卷第5期Oco2020Vol.41No.5首都医科大学学报JournaO of CapitaO Medical University[doi:10.3969/j.issn.1006-7795.2020.05.011]-国家优秀青年科学基金获得者•使细胞治疗成为攻克疾病的新一代技术手段----陈志国教授李默韩德强赵宇陈志国*(首都医科大学宣武医院细胞治疗中心，北京100053%%摘要】作为一种全新的治疗手段，细胞治疗已经成为继手术、化学药物治疗、放射治疗之后的第四种临床治疗手段，并被广泛 应用于包括再生医学修复、抗肿瘤治疗等多种重大疾病的临床治疗中。
作为首都医科大学宣武医院细胞治疗中心的学术带头人,陈志国教授在细胞治疗领域深耕多年，并取得了多项研究突破,为推动细胞治疗技术从基础研发到临床转化应用做出了贡献。
%关键词】细胞治疗;干细胞;免疫细胞%中图分类号】R392.12Harnessing cell therapy an;therapeutic strategy to fight diseasn------Professor Chen ZhiguoLt Mo,Han Deqiang,Zhao Yu,Chen Zhiguo*(Cell Therapy Centee,Xuanwu Hospital,Capital Medical University,Beijing100053,China%/Abstract]Ae one of the de nove therapeutic strateaies,cel.therapy hae become an alternative clinicaO treatmeni in addition to suroeo, chemotherapy,and radiotherapy.Celt therapy has been applied to treat verious life-threatening diseases,including degenerative diseases and cancea.As the directoa of Cell Therapy Centea of Xuanwu Hospital,Capital Medical University,Professor Chen Zhifuo has devoted himseli in the field of cell therapy foe many years and has made significant contributions te advoncing the research and promoting the translation from basic research to clinicat applications./Key words]celt therapy；stem cells；immune celts1个人简介陈志国教授（图1%,1977年11月出生于江苏省邳州市，首都医科大学宣武医院细胞治疗中心主任,万人计划科技创新领军人才。
关于医学创新的英语作文
关于医学创新的英语作文Medical innovation has been a driving force in the advancement of healthcare and the improvement of human wellbeing. From the development of life-saving vaccines to the creation of groundbreaking surgical techniques, the field of medicine has witnessed remarkable progress that has transformed the way we approach and manage various health conditions. In this essay, we will explore the significance of medical innovation, the factors that drive it, and the challenges that innovators face in bringing their ideas to fruition.At the heart of medical innovation lies the relentless pursuit of knowledge and the desire to alleviate human suffering. Researchers, clinicians, and entrepreneurs alike are constantly seeking new ways to diagnose, treat, and prevent diseases more effectively. This pursuit is fueled by a deep understanding of the complexities of the human body and the intricate mechanisms that govern its functioning. Through rigorous scientific research, innovative thinkers are able to identify unmet needs and develop novel solutions that can have a profound impact on the lives of patients.One of the key drivers of medical innovation is the rapid advancement of technology. The integration of cutting-edge technologies, such as artificial intelligence, robotics, and nanotechnology, has opened up new frontiers in healthcare. For instance, the use of AI-powered algorithms in medical imaging has revolutionized the way we detect and diagnose various conditions, enabling earlier and more accurate diagnoses. Similarly, the development of minimally invasive surgical techniques, facilitated by robotic systems, has led to faster recovery times and reduced patient discomfort.Another crucial factor that propels medical innovation is the collaborative nature of the field. Researchers, clinicians, and industry partners often work together, pooling their expertise and resources to tackle complex healthcare challenges. This interdisciplinary approach allows for the cross-pollination of ideas and the integration of diverse perspectives, ultimately leading to more comprehensive and effective solutions. Collaborative efforts also foster the sharing of knowledge, enabling the rapid dissemination of new discoveries and innovations, which can have a far-reaching impact on global health.Despite the immense potential of medical innovation, the path to bringing new ideas to market is often fraught with challenges. Oneof the primary obstacles is the stringent regulatory framework that governs the development and approval of new medical products and treatments. Innovators must navigate a complex maze of safety and efficacy requirements, ensuring that their innovations meet the highest standards of quality and safety. This process can be time-consuming and resource-intensive, often delaying the introduction of potentially life-saving technologies.Another significant challenge is the need for substantial financial investment. Developing new medical solutions, from research and development to clinical trials and commercialization, requires significant capital. Securing funding from sources such as government grants, venture capital, or pharmaceutical companies can be a daunting task, particularly for small startups and individual researchers. The high costs associated with medical innovation can deter some individuals and organizations from pursuing their ideas, limiting the overall pace of progress in the field.Furthermore, the inherent complexity of the human body and the diverse range of health conditions present unique challenges for medical innovators. Developing solutions that are both effective and safe requires a deep understanding of the underlying biological mechanisms and the ability to anticipate potential unintended consequences. This complexity can make the innovation process more challenging, requiring extensive testing and refinement beforenew technologies or treatments can be safely introduced.Despite these obstacles, the drive for medical innovation remains strong, fueled by the potential to save lives and improve the quality of life for individuals around the world. Innovative thinkers continue to push the boundaries of what is possible, leveraging the power of science, technology, and collaboration to address pressing healthcare needs.One promising area of medical innovation is the field of personalized medicine, where treatments are tailored to the unique genetic and physiological characteristics of individual patients. By leveraging advances in genomics, proteomics, and bioinformatics, healthcare providers can develop more targeted and effective therapies, reducing the risk of adverse reactions and improving patient outcomes. This personalized approach has the potential to transform the way we manage a wide range of diseases, from cancer to neurological disorders.Another exciting area of medical innovation is the development of regenerative therapies, which aim to harness the body's natural ability to heal and restore damaged tissues and organs. Stem cell research, tissue engineering, and gene therapy are at the forefront of this field, offering the promise of new treatments for conditions such as spinal cord injuries, organ failure, and degenerative diseases.These innovative approaches hold the potential to revolutionize the way we address some of the most challenging and debilitating health conditions.In conclusion, medical innovation is a vital component of the ongoing quest to improve human health and wellbeing. By harnessing the power of technology, fostering collaborative efforts, and overcoming the challenges that innovators face, we can unlock new frontiers in healthcare and transform the lives of patients around the world. As we continue to push the boundaries of what is possible in the field of medicine, we can look forward to a future where innovative solutions become the norm, rather than the exception, and where the pursuit of better health becomes a shared global endeavor.。
治疗一种病的方法英语
治疗一种病的方法英语IntroductionIn today's fast-paced world, diseases and illnesses are becoming more prevalent. Researchers and medical professionals are constantly striving to find effective treatments for various conditions. In this article, we will discuss the treatment for a specific disease, exploring its causes, symptoms, and the latest advancements in medical science. This information aims to provide insights into the scientific community's efforts to combat diseases and improve overall healthcare.Disease BackgroundThe disease we will focus on is Acute Lymphoblastic Leukemia (ALL). ALL is a type of cancer that affects the blood and bone marrow. It originates in the bone marrow, where the body produces new blood cells. In ALL, abnormal white blood cells, known as lymphoblasts, grow rapidly and crowd out healthy cells in the bone marrow. This condition can inhibit the production of red blood cells, platelets, and normal white blood cells, leading to anemia, infections, and bleeding issues.Causes and Risk FactorsThe exact cause of ALL is unknown. However, certain risk factors have been associated with this disease. These risk factors include genetic abnormalities, exposure to high levels of radiation or chemicals, specific inherited genetic disorders, and a weakened immune system. Althoughthese factors increase the likelihood of developing ALL, it is crucial to understand that the disease can affect individuals without any identifiable risk factors.SymptomsThe symptoms of ALL can vary from person to person. Common symptoms include fatigue, frequent infections, unexplained weight loss, joint or bone pain, easy bruising or bleeding, fever, and enlarged lymph nodes. Individuals experiencing these symptoms should consult a healthcare professional for proper diagnosis and treatment. Traditional Treatment MethodsTraditionally, the treatment for ALL involved a combination of chemotherapy, radiation therapy, and stem cell transplantation. Chemotherapy, the primary treatment modality, involves the use of drugs to kill cancer cells. Radiation therapy utilizes high-energy X-rays or other particles to destroy remaining cancer cells after chemotherapy. Stem cell transplantation, often used in cases of high-risk ALL or relapse, replaces damaged or destroyed bone marrow with healthy stem cells. Advancements in TreatmentMedical science has made remarkable advancements in the treatment of ALL, leading to improved outcomes and quality of life for patients. Targeted therapies, such as monoclonal antibodies, have become a crucial component of ALL treatment. These drugs are designed toidentify and attack specific cancer cells, leaving healthy cells unharmed. Targeted therapy not only enhances the effectiveness of treatment but also reduces side effects commonly associated with chemotherapy. Immunotherapy is another groundbreaking approach to treating ALL. It involves using the body's immune system to fight cancer. Immunotherapy drugs stimulate the immune system, enabling it to recognize and destroy cancer cells. This treatment modality has shown promising results in multiple clinical trials and has the potential to revolutionize ALL treatment in the future.Furthermore, advancements in genetic testing and sequencing have helped identify specific mutations or genetic changes that drive the growth of ALL. This information allows healthcare professionals to tailor treatments for individual patients based on their genetic profile. This personalized medicine approach enhances treatment efficacy and reduces unnecessary side effects.ConclusionThe treatment landscape for diseases like Acute Lymphoblastic Leukemia has evolved significantly over the years. By combining traditional therapies with targeted therapies, immunotherapy, and personalized medicine, medical professionals can provide better care and improve the prognosis for individuals with ALL. As scientific research progresses, newtreatment options continue to emerge, offering hope for patients and their families worldwide. It is crucial for healthcare professionals, researchers, and policymakers to continue working together to advance medical science and ultimately find a cure for all diseases.。
基于决策曲线法分析血清D-D二聚体及纤维蛋白原-白蛋白比值对上皮性卵巢癌的预测价值
基于决策曲线法分析血清D-D二聚体及纤维蛋白原-白蛋白比值对上皮性卵巢癌的预测价值摘要：目的：本研究旨在探讨基于决策曲线法分析血清D-D二聚体及纤维蛋白原/白蛋白比值在上皮性卵巢癌（EOC）的预测价值。
方法：在本次研究中，我们收集了200例EOC患者和200例健康对照组，分别测定了血清D-D二聚体和纤维蛋白原/白蛋白比值，并使用决策曲线法分析其在EOC的预测价值。
同时，我们还评估了两个指标在EOC诊断中的临床应用价值。
结果：血清D-D二聚体和纤维蛋白原/白蛋白比值在EOC的预测价值均较高，且双指标联合应用可以显著提高其预测能力。
在本研究中，最佳截断值为D-D二聚体为4.08mg/L，纤维蛋白原/白蛋白比值为5.81。
结论：血清D-D二聚体和纤维蛋白原/白蛋白比值联合应用可有效提高EOC的预测能力，对于EOC的临床诊断具有良好的参考价值。
关键词：决策曲线法；血清D-D二聚体；纤维蛋白原/白蛋白比值；上皮性卵巢癌；预测价值Abstract:Objective: This study aims to explore the predictive value of serum D-Dimer and Fibrinogen/Albumin Ratio based on decision curve analysis in Epithelial Ovarian Cancer (EOC).Methods: In the present study, we collected 200 EOC patients and 200 healthy controls, determined the levels of serum D-Dimer and Fibrinogen/Albumin Ratio respectively, and analyzed their predictive value on EOC using decision curve analysis. Meanwhile, we also evaluated the clinical application value of the two indicators in EOC diagnosis.Results: Serum D-Dimer and Fibrinogen/Albumin Ratio have relatively high predictive value in EOC, and the joint application of the two indicators can significantly improve their predictive ability. In the present study, the optimal cut-off value for D-Dimer was 4.08mg/L, and for Fibrinogen/Albumin Ratio was5.81.Conclusion: The joint application of serum D-Dimer and Fibrinogen/Albumin Ratio can effectively improve the predictive ability of EOC, and has good reference value for the clinical diagnosis of EOC.Keywords: Decision curve analysis; serum D-Dimer; Fibrinogen/Albumin Ratio; Epithelial Ovarian Cancer; predictive valuEpithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies, with a poor prognosis and high mortality rate. Early diagnosis and identification of high-risk patients are crucial for improving prognosis and survival rates. In this study, we investigated the predictive value of serum D-Dimer and Fibrinogen/Albumin Ratio in EOC.Our results showed that both serum D-Dimer and Fibrinogen/Albumin Ratio were significantly associated with the risk of EOC. When combined, their predictive ability was further enhanced, indicating that these two biomarkers can complement each other in predicting EOC. The decision curve analysis confirmed theclinical utility of the joint application of these two biomarkers, as it showed a higher net benefit compared to other strategies.Interestingly, we found that the optimal cut-off value for D-Dimer was 4.08mg/L, and for Fibrinogen/Albumin Ratio was 5.81. These cut-off values can be used as reference values in the clinical diagnosis of EOC.In conclusion, our study suggests that the joint application of serum D-Dimer and Fibrinogen/Albumin Ratio can significantly improve the predictive ability of EOC. These two biomarkers can be easily measured in clinical practice and can provide important information for the early detection and risk stratification of EOC patients. Further studies are needed to validate our findings and explore the underlying mechanismsAdditionally, our study highlights the importance of exploring new biomarkers for the diagnosis and treatment of EOC. Despite advances in treatment options, the prognosis for EOC is still poor due to the lack of effective early detection methods. Therefore, identifying reliable biomarkers for EOC is crucial to improve patient outcomes.Future studies could focus on evaluating the diagnostic and prognostic value of other potential biomarkers such as CA125, HE4, and miRNAs. Moreover, combining multiple biomarkers could potentially enhance the accuracy of EOC diagnosis and prognosis. Furthermore, investigating the underlying mechanisms of these biomarkers in the development and progression of EOC could lead to the discovery of new therapeutictargets for this deadly disease.In summary, the use of serum D-Dimer andFibrinogen/Albumin Ratio as biomarkers cansignificantly improve the diagnostic accuracy and risk stratification of EOC. These findings can aid in the early detection and timely treatment of EOC, thereby improving patient outcomes. Future studies are needed to validate these findings and explore the potential of other biomarkers for EOC diagnosis and prognosisIn addition to the use of biomarkers, there are other promising approaches to improve the diagnosis and treatment of EOC. One of these is genetic testing, which can identify mutations that increase the risk of ovarian cancer. This can help guide decisions about screening and prophylactic surgery in women who carry these mutations. For example, women with mutations in the BRCA1 or BRCA2 genes have a significantly increased risk of developing EOC, and may benefit from prophylactic surgery to remove their ovaries and fallopian tubes.Another promising approach is immunotherapy, which has shown success in treating other types of cancer. Immunotherapy works by targeting the body’s own immune system to attack cancer cells. There areseveral types of immunotherapy being tested inclinical trials for EOC, including checkpoint inhibitors and CAR-T cell therapy.Checkpoint inhibitors work by blocking proteins that prevent the immune system from recognizing and attacking cancer cells. Clinical trials have shown promising results with checkpoint inhibitors in patients with recurrent or metastatic EOC. CAR-T cell therapy involves taking immune cells from a patient, modifying them to target cancer cells, and then infusing them back into the patient. This approach is still in early-stage clinical trials for EOC, but has shown promising results in other types of cancer.In conclusion, ovarian cancer remains a challenging disease to diagnose and treat, but there are promising approaches on the horizon. The use of biomarkers such as serum D-Dimer and Fibrinogen/Albumin Ratio can improve the diagnosis and risk stratification of EOC, while genetic testing can identify women at high risk who may benefit from early screening or prophylactic surgery. In addition, immunotherapy shows promise as a new treatment approach for EOC. Future research is needed to continue to improve our understanding ofthis complex disease and develop more effective treatmentsIn conclusion, ovarian cancer remains a challenging disease to diagnose and treat, with a high mortality rate. However, promising approaches are on the horizon that can improve diagnosis, risk stratification, and treatment for this disease. The use of biomarkers such as serum D-Dimer and Fibrinogen/Albumin Ratio, genetic testing, and immunotherapy are all potential avenues for improving patient outcomes. Further research is needed to fully explore and develop these approaches in the fight against ovarian cancer。
具核梭杆菌与结直肠癌关系的研究进展
１６３９．［２６］ ＭＡＲＴＩＮＣ，ＬＵＰＩＮＡＣＣＩＬ，ＰＥＲＡＺＺＯＦ，ｅｔａｌ．Ｅｆｆｉｃａｃｙａｎｄｓａｆｅｔｙｏｆｎｉｖｏｌｕｍａｂｉｎｐｒｅｖｉｏｕｓｌｙｔｒｅａｔｅｄｐａｔｉｅｎｔｓｗｉｔｈｎｏｎ－ｓｍａｌｌ－ｃｅｌｌｌｕｎｇｃａｎｃｅｒ：ＲｅａｌｗｏｒｌｄｅｘｐｅｒｉｅｎｃｅｉｎＡｒｇｅｎｔｉｎａ［Ｊ］．ＣｌｉｎｉｃａｌＬｕｎｇＣａｎｃｅｒ，２０２０：Ｓ１５２５－７３０４（２０）３００３９－５．［２７］ ＳＨＡＶＥＲＤＩＡＮＮ，ＬＩＳＢＥＲＧＡＥ，ＢＯＲＮＡＺＹＡＮＫ，ｅｔａｌ．Ｐｒｅｖｉｏｕｓｒａｄｉｏｔｈｅｒａｐｙａｎｄｔｈｅｃｌｉｎｉｃａｌａｃｔｉｖｉｔｙａｎｄｔｏｘｉｃｉｔｙｏｆｐｅｍｂｒｏｌｉｚｕｍ ａｂｉｎｔｈｅｔｒｅａｔｍｅｎｔｏｆｎｏｎ－ｓｍａｌｌ－ｃｅｌｌｌｕｎｇｃａｎｃｅｒ：ＡｓｅｃｏｎｄａｒｙａｎａｌｙｓｉｓｏｆｔｈｅＫＥＹＮＯＴＥ－００１ｐｈａｓｅ１ｔｒｉａｌ［Ｊ］．ＬａｎｃｅｔＯｎｃｏｌｏ ｇｙ，２０１７，１８（７）：８９５－９０３．［２８］ ＭＥＴＲＯＧ，ＡＤＤＥＯＡ，ＳＩＧＮＯＲＥＬＬＩＤ，ｅｔａｌ．Ｏｕｔｃｏｍｅｓｆｒｏｍｓａｌｖａｇｅｃｈｅｍｏｔｈｅｒａｐｙｏｒｐｅｍｂｒｏｌｉｚｕｍａｂｂｅｙｏｎｄｐｒｏｇｒｅｓｓｉｏｎｗｉｔｈｏｒｗｉｔｈｏｕｔｌｏｃａｌａｂｌａｔｉｖｅｔｈｅｒａｐｉｅｓｆｏｒａｄｖａｎｃｅｄｎｏｎ－ｓｍａｌｌｃｅｌｌｌｕｎｇｃａｎｃｅｒｓｗｉｔｈＰＤ－Ｌ１≥５０％ｗｈｏｐｒｏｇｒｅｓｓｏｎｆｉｒｓｔ－ｌｉｎｅｉｍｍｕ ｎｏｔｈｅｒａｐｙ：Ｒｅａｌ－ｗｏｒｌｄｄａｔａｆｒｏｍａＥｕｒｏｐｅａｎｃｏｈｏｒｔ［Ｊ］．ＪｏｕｒｎａｌｏｆＴｈｏｒａｃｉｃＤｉｓｅａｓｅ，２０１９，１１（１２）：４９７２－４９８１．［２９］ ＣＨＥＮＤ，ＭＥＮＯＮＨ，ＶＥＲＭＡＶ，ｅｔａｌ．Ｒｅｓｐｏｎｓｅａｎｄｏｕｔｃｏｍｅｓａｆｔｅｒａｎｔｉ－ＣＴＬＡ４ｖｅｒｓｕｓａｎｔｉ－ＰＤ１ｃｏｍｂｉｎｅｄｗｉｔｈｓｔｅｒｅｏｔａｃｔｉｃｂｏｄｙｒａｄｉａｔｉｏｎｔｈｅｒａｐｙｆｏｒｍｅｔａｓｔａｔｉｃｎｏｎ－ｓｍａｌｌｃｅｌｌｌｕｎｇｃａｎｃｅｒ：Ｒｅｔｒｏｓｐｅｃｔｉｖｅａｎａｌｙｓｉｓｏｆｔｗｏｓｉｎｇｌｅ－ｉｎｓｔｉｔｕｔｉｏｎｐｒｏｓｐｅｃｔｉｖｅｔｒｉａｌｓ［Ｊ］．ＪＩｍｍｕｎｏｔｈｅｒＣａｎｃｅｒ，２０２０，８（１）：ｅ０００４９２．［３０］ ＱＩＮＡ，ＲＥＮＧＡＮＲ，ＬＥＥＳ，ｅｔａｌ．Ａｐｉｌｏｔｓｔｕｄｙｏｆａｔｅｚｏｌｉｚｕｍａｂｐｌｕｓｈｙｐｏｆｒａｃｔｉｏｎａｔｅｄｉｍａｇｅ－ｇｕｉｄｅｄｒａｄｉｏｔｈｅｒａｐｙｆｏｒｔｈｅｔｒｅａｔ ｍｅｎｔｏｆａｄｖａｎｃｅｄｎｏｎ－ｓｍａｌｌｃｅｌｌｌｕｎｇｃａｎｃｅｒ［Ｊ／ＯＬ］．Ｉｎｔｅｒｎａ ｔｉｏｎａｌＪｏｕｒｎａｌｏｆＲａｄｉａｔｉｏｎＯｎｃｏｌｏｇｙＢｌｏｌｏｇｙＰｈｙｓｉｃｓ．［２０１９－１０－２５］．ｈｔｔｐｓ：／／ｄｏｉ．ｏｒｇ／１０．１０１６／ｊ．ｉｊｒｏｂｐ．２０１９．１０．０４７．［３１］ ＴＨＥＥＬＥＮＷ，ＰＥＵＬＥＮＨＭＵ，ＬＡＬＥＺＡＲＩＦ，ｅｔａｌ．Ｅｆｆｅｃｔｏｆｐｅｍｂｒｏｌｉｚｕｍａｂａｆｔｅｒｓｔｅｒｅｏｔａｃｔｉｃｂｏｄｙｒａｄｉｏｔｈｅｒａｐｙｖｓｐｅｍｂｒｏｌｉｚｕｍａｂａｌｏｎｅｏｎｔｕｍｏｒｒｅｓｐｏｎｓｅｉｎｐａｔｉｅｎｔｓｗｉｔｈａｄｖａｎｃｅｄｎｏｎ－ｓｍａｌｌｃｅｌｌｌｕｎｇｃａｎｃｅｒ：ＲｅｓｕｌｔｓｏｆｔｈｅＰＥＭＢＲＯ－ＲＴＰｈａｓｅ２ｒａｎｄｏｍｉｚｅｄｃｌｉｎｉｃａｌｔｒｉａｌ［Ｊ］．ＪＡＭＡＯｎｃｏｌｏｇｙ，２０１９，５（９）：１２７６－１２８２．［３２］ ＲＡＴＮＡＹＡＫＥＧ，ＳＨＡＮＫＥＲＭ，ＲＯＢＥＲＴＳＫ，ｅｔａｌ．Ｐｒｉｏｒｏｒｃｏｎｃｕｒｒｅｎｔｒａｄｉｏｔｈｅｒａｐｙａｎｄｎｉｖｏｌｕｍａｂｉｍｍｕｎｏｔｈｅｒａｐｙｉｎｎｏｎ－ｓｍａｌｌｃｅｌｌｌｕｎｇｃａｎｃｅｒ［Ｊ］．Ａｓｉａ－ＰａｃｉｆｉｃＪｏｕｒｎａｌｏｆＣｌｉｎｉｃａｌＯｎｃｏｌｏｇｙ，２０２０，１６（１）：５６－６２．（编校：闫沛）具核梭杆菌与结直肠癌关系的研究进展丁 滨，曾慧明，罗利琼ＲｅｓｅａｒｃｈｐｒｏｇｒｅｓｓｏｎｔｈｅｒｅｌａｔｉｏｎｓｈｉｐｂｅｔｗｅｅｎＦｕｓｏｂａｃｔｅｒｉｕｍｎｕｃｌｅａｔｕｍａｎｄｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒＤＩＮＧＢｉｎ，ＺＥＮＧＨｕｉｍｉｎｇ，ＬＵＯＬｉｑｉｏｎｇＤｅｐａｒｔｍｅｎｔｏｆＯｎｃｏｌｏｇｙ，ＴｉａｎｙｏｕＨｏｓｐｉｔａｌＡｆｆｉｌｉａｔｅｄｔｏＷｕｈａｎＵｎｉｖｅｒｓｉｔｙｏｆＳｃｉｅｎｃｅａｎｄＴｅｃｈｎｏｌｏｇｙ，ＨｕｂｅｉＷｕｈａｎ４３４０００，Ｃｈｉｎａ．【Ａｂｓｔｒａｃｔ】Ｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒｉｓｏｎｅｏｆｔｈｅｍｏｓｔｃｏｍｍｏｎｍａｌｉｇｎａｎｔｔｕｍｏｒｓｉｎｔｈｅｗｏｒｌｄａｎｄｉｎｃｈｉｎａ．Ｉｎｔｈｅｐａｓｔｔｅｎｙｅａｒｓ，ｔｈｅｉｎｃｉｄｅｎｃｅａｎｄｆａｔａｌｉｔｙｒａｔｅｏｆｔｈｅｄｉｓｅａｓｅｈａｖｅｓｈｏｗｎａｎｏｂｖｉｏｕｓｕｐｗａｒｄｔｒｅｎｄ．Ｉｔｓｏｃｃｕｒｒｅｎｃｅｉｓａｍｕｌｔｉ－ｆａｃｔｏｒａｎｄｍｕｌｔｉ－ｓｔｅｐｐｒｏｃｅｓｓ，ｓｕｃｈａｓｈｅｒｅｄｉｔｙ，ｅｎｖｉｒｏｎｍｅｎｔ，ｍｉｃｒｏｏｒｇａｎｉｓｍａｎｄｓｏｏｎ．ＭｏｒｅａｎｄｍｏｒｅｓｔｕｄｉｅｓｈａｖｅｓｈｏｗｎｔｈａｔＣｌｏｓｔｒｉｄｉｕｍｎｕｃｌｅｏｓｕｓ（Ｆｕｓｏｂａｃｔｅｒｉｕｍｎｕｃｌｅａｔｕｍ，Ｆｎ）ｐｌａｙｓａｎｉｍｐｏｒｔａｎｔｒｏｌｅｉｎｔｈｅｏｃｃｕｒｒｅｎｃｅａｎｄｄｅ ｖｅｌｏｐｍｅｎｔｏｆｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒ．ＴｏｓｔｕｄｙｈｏｗＣｌｏｓｔｒｉｄｉｕｍｎｕｃｌｅｏｓｕｓｐｒｏｍｏｔｅｓｔｈｅｏｃｃｕｒｒｅｎｃｅａｎｄｄｅｖｅｌｏｐｍｅｎｔｏｆｃｏｌｏｒ ｅｃｔａｌｃａｎｃｅｒａｎｄｈｏｗｉｔａｆｆｅｃｔｓｔｈｅｐｒｏｇｎｏｓｉｓｏｆｐａｔｉｅｎｔｓｗｉｔｈｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒｉｓｏｆｇｒｅａｔｓｉｇｎｉｆｉｃａｎｃｅｆｏｒｏｕｒｄｉａｇｎｏｓｉｓａｎｄｐｒｅｖｅｎｔｉｏｎａｎｄｔｒｅａｔｍｅｎｔｏｆｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒ．Ｉｎｔｈｉｓｐａｐｅｒ，ｔｈｅｌａｔｅｓｔｐｒｏｇｒｅｓｓｉｓｒｅｖｉｅｗｅｄ．【Ｋｅｙｗｏｒｄｓ】ｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒ，Ｆｕｓｏｂａｃｔｅｒｉｕｍｎｕｃｌｅａｔｕｍ，ｇｅｎｅｓｉｓａｎｄｄｅｖｅｌｏｐｍｅｎｔ，ｐｒｏｇｎｏｓｉｓＭｏｄｅｒｎＯｎｃｏｌｏｇｙ２０２１，２９（０４）：０７１２－０７１５【指示性摘要】结直肠癌（ｃｏｌｏｒｅｃｔａｌｃａｎｃｅｒ，ＣＲＣ）是目前世界范围内及国内最常见的恶性肿瘤之一。
Stem Cell Therapy for Neurological Disorders
Stem Cell Therapy for NeurologicalDisordersStem cell therapy for neurological disorders is a promising and rapidly evolving field in the medical world. Neurological disorders, such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis, have long been considered incurable, with treatment options limited to managing symptoms. However, the potential of stem cell therapy to repair damaged tissues and restore lost function has sparked hope for patients and their families. This innovative approach involves the use of stem cells, which have the unique ability to develop into different types of cells in the body, including brain cells. While the potential benefits of stem cell therapy for neurological disorders are substantial, there are also ethical, scientific, and practical considerations that need to be carefully evaluated. From a scientific perspective, the use of stem cells for treating neurological disorders holds great promise. Stem cells can be derived from various sources, including embryos, adult tissues, and induced pluripotent stem cells (iPSCs). These cells can be manipulated in the laboratory to develop into specific types of neurons or glial cells that are damaged or lost in neurological disorders. By replacing these damaged cells with healthy, functional ones, stem cell therapy has the potential to restore lost function and improve the quality of life for patients. Additionally, stem cells have been shown to haveanti-inflammatory and neuroprotective effects, which could further benefitpatients with neurological disorders. However, despite the potential benefits, there are ethical considerations surrounding the use of embryonic stem cells for therapy. The use of embryonic stem cells raises ethical concerns due to the destruction of human embryos during the cell extraction process. This has led to ongoing debates and controversies regarding the use of embryonic stem cells in research and therapy. On the other hand, the use of adult stem cells and iPSCs does not raise the same ethical concerns, as these cells can be obtained without harm to human embryos. As research in stem cell therapy continues to advance, it is essential to consider the ethical implications and seek alternative sources of stem cells that do not raise ethical concerns. In addition to ethicalconsiderations, there are practical challenges that need to be addressed in the development and implementation of stem cell therapy for neurological disorders. One of the main challenges is the need for rigorous clinical trials to demonstrate the safety and efficacy of stem cell therapies. While there have been some promising preclinical and early-stage clinical studies, more extensive research is needed to establish the long-term safety and effectiveness of these therapies. Furthermore, the cost of stem cell therapy and the accessibility to treatment are also significant barriers for many patients. The development of stem cell therapies for neurological disorders requires substantial investment in research, development, and manufacturing, which can make these treatments expensive and inaccessible to those who need them the most. From a patient's perspective, the potential of stem cell therapy for neurological disorders brings a mixture of hope and uncertainty. For many patients living with neurological disorders, current treatment options are limited and often only provide symptomatic relief. The possibility of a treatment that could potentially reverse the progression of their condition and restore lost function is incredibly appealing. However, patients and their families also face the uncertainty of the long-term safety and effectiveness of stem cell therapies, as well as the practical challenges of accessing these treatments. It is essential for patients to be well-informed about the current state of research and the potential risks and benefits of stem cell therapy, so they can make informed decisions about their treatment options. In conclusion, stem cell therapy for neurological disorders holds great promise for the future of medicine. The potential to repair damaged tissues, restore lost function, and provide new hope for patients with conditions that were once considered incurable is truly remarkable. However, it is crucial to carefully consider the ethical, scientific, and practical considerations surrounding the use of stem cells for therapy. By addressing these challenges, we can work towards realizing the full potential of stem cell therapy for neurological disorders and improving the lives of patients and their families.。
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COMPREHENSIVE REVIEWThe Rise of Cell Therapy Trials for Stroke:Review of Published and Registered StudiesPaulo Henrique Rosado-de-Castro,1Pedro Moreno Pimentel-Coelho,2Lea Mirian Barbosa da Fonseca,1Gabriel Rodriguez de Freitas,2,3and Rosalia Mendez-Otero 2Stroke is the second leading cause of death and the third leading cause of disability worldwide.Approximately 16million first-ever strokes occur each year,leading to nearly 6million deaths.Nevertheless,currently,very few therapeutic options are available.Cell therapies have been applied successfully in different hematological dis-eases,and are currently being investigated for treating ischemic heart disease,with promising results.Recent preclinical studies have indicated that cell therapies may provide structural and functional benefits after stroke.However,the effects of these treatments are not yet fully understood and are the subject of continuing inves-tigation.Meanwhile,different clinical trials for stroke,the majority of them small,nonrandomized,and un-controlled,have been reported,and their results indicate that cell therapy seems safe and feasible in these conditions.In the last 2years,the number of published and registered trials has dramatically increased.Here,we review the main findings available in the field,with emphasis on the clinical results.Moreover,we address some of the questions that have been raised to date,to improve future studies.IntroductionStroke is responsible for *11.1%of all deaths,and is the second leading cause of death worldwide after ischemic heart disease [1].After a stroke,roughly a quarter of patients die within a month,and half within 1year [2].There were an estimated 16million first-ever strokes and 5.7million deaths in 2005[3].These numbers are expected to increase to 23million first-ever strokes and 7.8million deaths in 2030[3].Stroke was responsible for 102million disability-adjusted life years (DALYs)in 2010,an increase to the third leading cause of DALYS from the fifth leading cause in 1990[4].Approxi-mately 80%of all strokes are ischemic,and currently,tissue plasminogen activator (tPA)is the only pharmacological agent approved for treatment of acute ischemic stroke.However,tPA therapy has important limitations,notably the narrow therapeutic window of 4.5h,which limits its use to a small minority (2%to 4%)of patients [5].Moreover,tPA prevents disability in only six patients per 1000ischemic strokes,and does not reduce the mortality rate [6].The ad-ministration of aspirin within 48h of onset of ischemic stroke decreases the mortality rate or the incidence of disability in about nine patients per 1000treated,probably due to early secondary prevention [2].The injury produced by stroke is largely complete after 24–48h,and neuroprotective therapies that must be administered within a time window such as 3–6h are difficult to apply in clinical practice [7].On the otherhand,neurorestorative therapies,including cell therapies,seek to enhance regenerative mechanisms such as angiogen-esis,neurogenesis,and synaptogenesis,and have been in-vestigated extensively in the preclinical models of ischemia [7,8].Neurorestorative cell therapies can be grossly divided into endogenous or exogenous.Endogenous therapies are those that aim to stimulate,for example,bone marrow-cell migration to the blood stream,with pharmacological agents such as granulocyte-colony stimulating factor (G-CSF).The exogenous approach involves the injection of a variety of cells to produce structural or functional benefits,and will be the focus of this article.Although excellent reviews have been recently made on different aspects of cell therapies for stroke [9–13],there has been a dramatic increase in the number of published and registered trials in the past years that has not been comprehensively assessed.In the following sections,we will review the main preclinical and clinical results to date and comment on some of the questions that have been raised.Main Cell Types Used in Neurorestorative Cell Therapies for Stroke Neural stem/progenitor cellsNeural stem/progenitor cells (NSPC)are cells with a self-renewing capacity and the potential to generate neurons and glial cells.NSPC can be isolated from the fetal brain or from one of the two neurogenic niches that persist in the adult1Hospital Universita´rio Clementino Fraga Filho,Universidade Federal do Rio de Janeiro,Rio de Janeiro,Brazil.2Instituto de Biofı´sica Carlos Chagas Filho,Universidade Federal do Rio de Janeiro,Rio de Janeiro,Brazil.3D’Or Institute for Research and Education,Rio de Janeiro,Brazil.STEM CELLS AND DEVELOPMENT Volume 22,Number 15,2013ÓMary Ann Liebert,Inc.DOI:10.1089/scd.2013.00892095brain:the subventricular zone of the lateral ventricles and the hippocampal subgranular zone[14–16].Despite the evidence that transplanted fetal NSPC can functionally integrate into the brain of patients with Parkinson’s disease[17],there are several obstacles to the use of NSPC from these two sources in clinical trials in stroke.For instance,the need for multiple fetal donors to treat a single patient could raise ethics con-cerns and may not be feasible in large-scale trials.Moreover, the isolation of adult NSPC for autologous transplantation would require brain biopsies and many days in culture for expansion,and may have some limitations,given that adult NSPC are regionally specified to generate a limited number of neuronal subtypes,even after cerebral ischemia[18]. NSPC can also be generated from pluripotent stem cells, including embryonic stem cells(ES,derived from the inner cell mass of blastocysts)and induced pluripotent stem cells (iPS,obtained after epigenetic reprogramming of adult cells by a combination of transcription factors).In each case, NSPC can be expanded in vitro,formingfloating cell clusters called neurospheres,composed of a heterogeneous popula-tion of proliferating cells,which can be induced to differen-tiate into diverse phenotypes of the neuronal or glial lineage. However,the clinical use of ES-derived NSPC is still asso-ciated with the risks of neural overgrowth or teratoma for-mation,if undifferentiated ES persist in the transplant pool [19].In addition,transplantation of allogeneic NSPC grafts requires immunosuppression,which is also associated with several side effects.iPS-derived NSPC can be obtained after reprogramming of somatic cells from the patient himself,allowing an autol-ogous transplantation.Although a recent study has cau-tioned that mouse iPS-derived teratomas can trigger immunogenicity in matched mice through a T-cell immune response[20],immunogenicity may not occur when ES-or iPS-derived terminally differentitated cells are transplanted [21].Nevertheless,the creation of public banks of human leukocyte antigen-typed ES-or iPS-derived cell lines(and their differentiated cells)could be a more practical form of generating these cells using good manufacturing practices,at the appropriate time for transplantation,while reducing the immunogenicity of NSPC[22].Other potential sources of neural cells for transplantation include induced neuronal cells and induced NSPC generated directly fromfibroblasts or other somatic cells by a combination of transcription fac-tors[23–25].Human teratocarcinoma-derived neurons have also been used in clinical trials in stroke,as discussed below [26–30].Non-NSPCMesenchymal stem cells(MSC)and hematopoietic stem/ progenitor cells(HSPC)are the two non-neural cell types that are most frequently used in preclinical and clinical neurorestorative studies in stroke.HSPC can be isolated from bone marrow or from umbil-ical-cord blood(UCB),or can be mobilized into the blood by the administration of pharmacological agents such as G-CSF and plerixafor.Most of the studies in animal models of stroke have transplanted the whole mononuclear cell(MNC) fraction from one of these sources,which also contains other cell types,including monocytes and lymphocytes,in addi-tion to HSPC,MSC,and endothelial progenitor cells[31].Alternatively,a smaller group of studies have transplanted human CD34+MNCs,a subpopulation enriched in HSPC and endothelial progenitor cells.MSC are multipotent cells with the capacity to give rise to cells of the osteogenic,chondrogenic,and adipogenic line-ages.MSC can be isolated,and the culture expanded from several tissues,including bone marrow,adipose tissue,and UCB.Although a set of minimal criteria defined by the In-ternational Society for Cellular Therapy can be used to identify MSC,there are some functional and phenotypic differences among MSC derived from different sources [32,33].Potential Mechanisms of Action of Cell-Based Therapies in StrokeNeural stem/progenitor cellsIntracerebrally administered human NSPC migrate to-ward the sites of injury in the ischemic brain[34],where they survive for up to2months and differentiate into functional neurons,astrocytes,and oligodendrocytes[35]. However,the need to generate several neuronal subtypes that must extend long axons and form the appropriate synaptic connections is still one of the main challenges in regenerative medicine,and has been extensively reviewed elsewhere[13,36].In addition to the potential of NSPC to replace the lost neurons,recent preclinical studies have observed that part of the therapeutic effects of NSPC in the ischemic brain could be attributed to a paracrine mechanism,since NSPC consti-tutively express mRNA and secrete several neurotrophic and growth factors in vitro[37–39].For example,it has been shown that human NSPC transplantation increases neo-vascularization and enhances the integrity of the blood–brain barrier after stroke,through a human vascular endothelial growth factor(VEGF)-dependent mechanism[40].VEGF is also one of the main factors involved in the modulatory role of an NSPC-derived conditioned medium in microglia function[41].Accordingly,NSPC remain in close contact with microglial cells,even when injected into the brain of control animals[34],suggesting that a similar mechanism may occur in vivo[41].Interestingly,NSPC transplantation contributes to the functional recovery in animal models of stroke,independent of the route of injection[42–44].NSPC migrate to the sites of injury,even when intra-arterially delivered,and this re-cruitment is dependent on the chemokine receptor CCR2 [43,45].In contrast,intravenous(IV)transplantation of NSPC results only in marginal migration of cells to the damaged brain,and in an animal model of intracerebral hemorrhage, the injected NSPC migrated mainly to the spleen.Never-theless,the treatment resulted in the reduction of inflam-mation,edema formation,and apoptosis in the brain.Since these effects were not observed in splenectomized animals, the authors suggested that NSPC could provide neuropro-tection by modulating the inflammatory response in the spleen[46].Similarly,despite the low levels of engraftment and neu-ronal differentiation in the ischemic brain,intravenously transplanted adult NSPC showed neuroprotective and anti-inflammatory effects in a rodent model of stroke[42].2096ROSADO-DE-CASTRO ET AL.Taken together,these studies provide evidence that besides neuronal replacement,NSPC could contribute to functional recovery after a stroke by a combination of mechanisms, including neuroprotection and immunomodulation.NSPC could also stimulate endogenous mechanisms of brain plas-ticity and regeneration,enhancing hippocampal neurogenesis [47],stimulating the repair of the neurovascular unit[40], rescuing axonal transport,and inducing dendritic plasticity and axonal sprouting[38].Non-NSPCAlthough it has been proposed that HSPC and MSC could differentiate into neural cells in vitro,HSPC-or MSC-derived neuronal-like cells do notfire action potentials[48,49],and this phenomenon has not been reproduced in vivo[50,51]. An interesting study has estimated that only a small fraction (around0.02%)of intravenously injected bone marrow-derived HSPC migrate to the ischemic brain,where most of the transplanted cells adopt a macrophage/microglial phe-notype.In spite of this,HSPC transplantation decreases the infarct size and reduces inflammation in the brain and the spleen of the treated animals[51].Moreover,it has been observed that MSC only transiently engraft the ischemic brain after an intra-arterial infusion[52],and that systemi-cally delivered UCB-MNCs promote the behavioral recovery in an animal model of stroke,despite the low engraftment level in the host brain[53].In summary,MSCs,bone marrow MNCs(BM-MNCs),and UCB-MNCs can improve neuro-logical function in several models of stroke,through a combination of effects,such as neuroprotection,immuno-modulation,and stimulation of neural plasticity[54–64],but these effects are not necessarily due to the presence of the cells at the injury site.In addition,MSC and HSPC trans-plantation can also induce angiogenesis and neurogenesis in the ischemic brain[65,66],two processes that are tightly linked by several regulatory mechanisms[67].These mech-anisms of action seem to rely on the secretion of neurotrophic factors and immunomodulatory molecules by the trans-planted cells[68,69],an effect that can be further modulated by the host microenvironment.A recent study has raised the possibility that MSC could also exert their therapeutic ac-tions by a mechanism of exosome-mediated transfer of mi-croRNAs to neurons and astrocytes.Interestingly,the microRNA133b levels in MSC exosomes increased when these cells were exposed to the ischemic brain extracts[70]. Thus,the transient engraftment of the transplanted cells and the dynamic changes that occur in the ischemic brain during the repair process may suggest that multiple injections may be required to optimize the release of the appropriate factors by the injected cells[71].In addition,stroke-induced sys-temic inflammation can also modulate the phenotype of the BM-MNC populations,improving their potential to induce recovery after cerebral ischemia,if the cells are harvested and transplanted on thefirst day after the insult[72].Hence, it is still necessary to evaluate the best timing for bone marrow harvest after stroke,in the case of autologous transplantation.Finally,endothelial progenitor cells can be isolated and the culture expanded from the peripheral blood or from the UCB.These cells home to the ischemic brain through a stromal-derived factor1-dependent mechanism,reducing the infarct size and improving the neurological outcome in mice[73].The coadministration of culture-expanded UCB-derived endothelial and smooth-muscle progenitor cells has also been shown to increase angiogenesis and neurogenesis in an animal model of stroke[74].Therefore,preclinical studies comparing the efficacy of endothelial progenitor cells,MSC,and HSPC from different sources are needed.In this regard,it has been shown that an intravenous admin-istration of bone marrow-derived MSC promotes a similar degree of functional recovery to bone marrow-derived mononuclear cell transplantation in a rodent model of stroke, as long as the dose is optimized for each cell type[59].An-other study showed that there was no difference in the therapeutic effects of bone marrow-derived and umbilical cord tissue-derived MSCs(UC-MSCs)in a model of focal ischemia[75].Published Clinical TrialsWe found31articles in the English language involving20 different trials of cell therapies for stroke,with a total of243 treated patients.Sixteen of these articles and12of the trials were published in the last2years.Twelve trials were for ischemic,two for hemorrhagic,and six for ischemic or hemorrhagic strokes(Table1and Fig.1).Six trials performed intravenous transplants;five injected the cells in the paren-chyma;five used the intra-arterial route;three carried out intrathecal administrations;and one trial compared intra-arterial and intravenous routes(Table1and Fig.1).Trials with Intracerebral AdministrationHuman teratocarcinoma-derived neuronsKondziolka et al.[26]conducted thefirst clinical trial of cell therapy for stroke.It involved the transplantation of LBS-Neurons(Layton BioScience,Inc.,Sunnyvale,CA),derived from a human teratocarcinoma cell line(NT2N)that was induced to differentiate into neurons by the addition of re-tinoic acid.This phase I,nonrandomized,observer-blind study included12patients with basal ganglia stroke and fixed motor deficits that occurred6months to6years before the transplantation.Eight of these patients received a total of 2million cells,divided into three injections,into the area of the infarction,and the other four patients received6million cells divided into nine implants.Immunosuppression was accomplished with cyclosporine A started1week before surgery and continued for8weeks.One patient had a single generalized seizure6months after surgery,and another patient had a new brainstem stroke distant from the area of neuronal cell transplantation.However,these complications were thought not to be connected to the procedure,and no cell-related adverse effects were observed in the5-year follow-up.Seven of11positron-emission tomography(PET) scans carried out at6months indicated an increase in fluorodeoxyglucose uptake at the implant site,while at12 months,this number decreased to three[30].The authors suggested that this could be related to cell viability in the area of the stroke,or alternatively to increased metabolic activity due to an inflammatory process,although no mod-ifications indicative of inflammation were seen on magnetic resonance imaging(MRI).The procedure was evaluated as safe and feasible,and autopsy on one patient who died ofCELL THERAPY TRIALS FOR STROKE2097T a b l e 1.T r i a l s w i t h P u b l i s h e d C l i n i c a l R e s u l t sS t u d y r e f e r e n c e /C o u n t r yS t u d y d e s i g nR o u t eC e l l t y p e T y p e o f s t r o k e A g e r a n g e (m e a n )T i m e r a n g e f r o m s t r o k e o n s e t t o t r a n s p l a n t a t i o n N o .o f t r e a t e d p a t i e n t s (N o .o f c o n t r o l s )N o .o f c e l l s i n j e c t e dI n f u s i o n v o l u m e ,r a t e a n d d u r a t i o nF o l l o w -u pK o n d z i o l k a e t a l .,2000/U n i t e d S t a t e sP h a s e I ,n o n r a n d o m i z e d ,s i n g l e -b l i n dI C N T 2N c e l l s I s c h e m i c s t r o k e i n b a s a l g a n g l i a (8c a s e s )o r c o r t e x a n d b a s a l g a n g l i a (4c a s e s )44–757t o 55m o n t h s (m e a n 27m o n t h s )12(n o c o n t r o l s )2·106(8p a t i e n t s );6·106(4p a t i e n t s )N o t s p e c i fie d 52–60m o n t h sR a b i n o v i c h e t a l .,2005/R u s s i aC a s e s e r i e s ,n o n r a n d o m i z e d ,o p e n l a b e lI T H u m a n F e t a l C e l l s H e m o r r h a g i c (3c a s e s )i n M C A a n d i s c h e m i c (7c a s e s )i n M C A o r M C A +A C A 35–564t o 24m o n t h s (m e a n 12.1m o n t h s )10(10h i s t o r i c a l c o n t r o l s )1(5p a t i e n t s )o r 2(5p a t i e n t s )i n f u s i o n s o f 2·108N o t s p e c i fie d 6m o n t h sK o n d z i o l k a e t a l .,2005/U n i t e d S t a t e sP h a s e I I ,r a n d o m i z e d ,s i n g l e -b l i n dI C N T 2N c e l l s I s c h e m i c (9c a s e s )o r h e m o r r h a g i c (9c a s e s )i n v o l v i n g b a s a l g a n g l i a 40–701t o 5y e a r s (m e a n 3.5y e a r s )14(4c o n t r o l s w i t h o u t i n j e c t i o n )5·106(7p a t i e n t s );1·107(7p a t i e n t s )N o t s p e c i fie d18t o 29m o n t h sS a v i t z e t a l .,2005/U n i t e d S t a t e s P h a s e I ,n o n r a n d o m i z e d ,o p e n l a b e l I CF e t a l P o r c i n e c e l l s I s c h e m i c i n v o l v i n g t h e s t r i a t u m 25–52(m e a n 39.8)4t o 10y e a r s (m e a n 4.9y e a r s )5(n o c o n t r o l s )U p t o 5i n j e c t i o n s o f 10710m L /m i n ,106c e l l s /m L 4y e a r sM a n e t a l .,2006/C h i n a C a s e s e r i e s ,n o n r a n d o m i z e d ,o p e n l a b e l I VA l l o g e n e i c U C -M N C s I s c h e m i c (6c a s e s )o r h e m o r r h a g i c (4c a s e s )35–75(m e a n 56)3m o n t h s t o 7y e a r s (m e a n 23.5m o n t h s )10(n o c o n t r o l s )6i n f u s i o n s o f ‡1·108,1t o 7d a y s a p a r tN o t s p e c i fie d 3m o n t h s M e n d o n c a e t a l .,2006;C o r r e a e t a l .,2007/B r a z i l C a s e r e p o r t s o n p h a s e I ,n o n r a n d o m i z e d ,o p e n l a b e l I AA u t o l o g o u sB M -M NC s M C A i s c h e m i c s t r o k e54a n d 375(1p a t i e n t )a n d 9d a y s (1p a t i e n t )2(n o c o n t r o l s )1·108(1p a t i e n t )a n d 3·107(1p a t i e n t )3m L i n 10m i n (fir s t p a t i e n t )2–4m o n t h sS u a r e z -M o n t e a g u d o e ta l .,2009/C ub aC a s e s e r i e s ,n o n r a n d o m i z e d ,o p e n l a b e l I C A u t o l o g o u sB M -M NC s I s c h e m i c o r h e m o r r h a g i c i n t h a l a m u s ,b a s a l g a n g l i a o r c o r t e x 41–64(m e a n 51.4)3t o 8y e a r s (m e a n 5y e a r s )5(n o c o n t r o l s )1.4·107t o 5.5·107(m e a n 3.4·107)8s e e d s o f 2.5m L1(4c a s e s )a n d 5y e a r s (1c a s e )L e e e t a l .,2010(c o n t .o f B a n g e t a l .,2005)/S o u t h K o r e a P h a s e I /I I ,r a n d o m i z e d ,s i n g l e -b l i n d I V A u t o l o g o u s B M -M S C s M C A i s c h e m i c s t r o k e M e a n 64I n j e c t i o n s 19t o 37d a y s (m e d i a n 32.5d a y s )a n d 2w e e k s l a t e r16(36c o n t r o l s w i t h o u t i n j e c t i o n )5·107(2d o s e s 2w e e k s a p a r t )N o t s p e c i fie d 5y e a r sB a t t i s t e l l a e t a l .,2011;R o s a d o -d e -C a s t r o e t a l .,2013/B r a z i l P h a s e I ,n o n r a n d o m i z e d ,o p e n l a b e l I A o r I V A u t o l o g o u s B M -M N C s M C A i s c h e m i c s t r o k e 24–68(m e a n 58.5)19t o 89d a y s (m e a n 64.5)12(n o c o n t r o l s )1·108t o 5·108(m e a n 3.1·108)10m L i n 10m i n (1m L /m i n )6m o n t h sH o n m o u e t a l .,2011/J a p a n P h a s e I ,n o n r a n d o m i z e d ,o p e n l a b e l I V A u t o l o g o u s B M -M S C sI s c h e m i c g r a y m a t t e r ,w h i t e m a t t e r a n d m i x e d l e s i o n s41–73(m e a n 59.2)36t o 133d a y s (m e a n 68d a y s )12(n o c o n t r o l s )0.6·108t o 1.6·108(m e a n 1.1·108)I n 30m i n ;v o l u m e n o t s p e c i fie d12m o n t h s(c o n t i n u e d )2098T a b l e 1.(C o n t i n u e d )S t u d y r e f e r e n c e /C o u n t r yS t u d y d e s i g nR o u t eC e l l t y p e T y p e o f s t r o k e A g e r a n g e (m e a n )T i m e r a n g e f r o m s t r o k e o n s e t t o t r a n s p l a n t a t i o n N o .o f t r e a t e d p a t i e n t s (N o .o f c o n t r o l s )N o .o f c e l l s i n j e c t e d I n f u s i o n v o l u m e ,r a t e a n d d u r a t i o n F o l l o w -u pS a v i t z e t a l .,2011/U n i t e d S t a t e s P h a s e I ,n o n r a n d o m i z e d ,o p e n l a b e l I V A u t o l o g o u s B M -M N C s M C A i s c h e m i c s t r o k eM e a n 5524t o 72h 10(79h i s t o r i c a l c o n t r o l s )7·108/k g t o 1·109/k g (m e a n 9.6·108/k g )I n 30m i n ;v o l u m e n o t s p e c i fie d 6m o n t h sH a n e t a l .,2011/S o u t h K o r e aN o t s p e c i fie d I T A l l o g e n e i c U C -M S C sI s c h e m i c i n p o n s ,m i d b r a i n a n d r i g h t s u p e r i o r c e r e b e l l u m 1735d a y s1(n o c o n t r o l s )3.6·107N o t s p e c i fie d2m o n t h sB h a s i n e t a l .,2011,2012a ,2012b /I n d i aP h a s e I ,n o n r a n d o m i z e d ,s i n g l e -b l i n d (f M R I )I V A u t o l o g o u s B M -M S C s o r B M -M N C sM C A i s c h e m i c o r h e m o r r h a g i c s t r o k eM e a n 45m e a n 9.6m o n t h s 20(14B M -M N C g r o u p ;6B M -M S C g r o u p ;20c o n t r o l s w i t h o u t i n j e c t i o n )5·107t o 6·107250m L i n 3h(1.4m L /m i n )6m o n t h sF r i e d r i c h e t a l .,2012/B r a z i lP h a s e I /I I ,n o n r a n d o m i z e d ,s i n g l e -b l i n d (C T )I AA u t o l o g o u sB M -M NC sM C A i s c h e m i c s t r o k e 30–78(m e a n 63)3t o 10d a y s (m e a n 6d a y s )20(n o c o n t r o l s )5.1·107t o 6·108(m e a n 2.2·108)15m L i n 30m i n (0.5m L /m i n )6m o n t h sE n g l a n d e t a l .,2012,U n i t e d K i n g d o m S u b g r o u p o f p h a s e I I b ,r a n d o m i z e d ,c o n t r o l l e d t r i a l w i t h I VA u t o l o g o u s C D 34+PB -H P SC s I s c h e m i c s t r o k eN o t s p e c i fie d f o r s u b -g r o u p3t o 30d a y s 8(6G -C S F g r o u p ;2p l a c e b o g r o u p ;n o c o n t r o l s )2·107t o 4.3·108N o t s p e c i fie d3m o n t h sS h a r m a e t a l .,2012/I n d i a N o t s p e c i fie dI TA u t o l o g o u sB M -M NC s L e f t t h a l a m i c h e m o r r h a g i c s t r o k e 691y e a r 1(n o c o n t r o l s )5·107N o t s p e c i fie dN o t s p e c i fie dM o n i c h e e t a l .,2012/S p a i nP h a s e I /I I ,n o n r a n d o m i z e d ,s i n g l e -b l i n d I AA u t o l o g o u sB M -M NC sM C A i s c h e m i c s t r o k eM e a n 66.95t o 9d a y s (m e a n 6.4d a y s )10(10c o n t r o l s w i t h o u t i n j e c t i o n )m e a n 1.6·1080.5t o 1m L /m i n ;d u r a t i o n n o t s p e c i fie d 6m o n t h sP r a s a d e t a l .,2012/I n d i a P h a s e I ,n o n r a n d o m i z e d ,o p e n l a b e l I VA u t o l o g o u sB M -M NC s M C A o r M C A +A C A i s c h e m i c s t r o k e 30–70(m e a n 51.5)8t o 29d a y s (m e a n 17d a y s )11(n o c o n t r o l s )1.9·108t o 1.9·109(m e a n 8·107)I n 5m i n ;v o l u m e n o t s p e c i fie d 12m o n t h sL i e t a l .,2012/C h i n a P h a s e I ,n o n r a n d o m i z e d ,s i n g l e -b l i n d I CA u t o l o g o u sB M -M NC s B a s a l g a n g l i a h e m o r r h a g i c s t r o k e 39–74(m e a n 56.3)5t o 7d a y s (m e a n 5.9d a y s )60(40c o n t r o l s w i t h s a l i n e )2.5·108t o 2.3·109(m e d i a n 1.3·109)3.5m L ;d u r a t i o n n o t s p e c i fie d 6m o n t h sJ i a n g e t a l .,2012/C h i n a P h a s e I ,n o n -r a n d o m i z e d ,o p e n l a b e lI AA l l o g e n e i c U C -M S C sM C A i s c h e m i c (3c a s e s )o r h e m o r r h a g i c (1c a s e )s t r o k e40–59(m e a n 49)11t o 50d a y s (m e a n 25.5)4(n o c o n t r o l s )2·10720m L i n 20m i n (1m L /m i n )6m o n t h sI C ,i n t r a c e r e b r a l ;I A ,i n t r a -a r t e r i a l ;I V ,i n t r a v e n o u s ;I T ,i n t r a t h e c a l ;B M -M N C s ,b o n e m a r r o w m o n o n u c l e a r c e l l s ;B M -M S C s ,b o n e m a r r o w -d e r i v e d m e s e n c h y m a l s t e m c e l l s ;U C B -M N C s ,u m b i l i c a l c o r d b l o o d m o n o n u c l e a r c e l l s ;U C -M S C s ,u m b i l i c a l c o r d -d e r i v e d m e s e n c h y m a l s t e m c e l l s ;M C A ,m i d d l e c e r e b r a l a r t e r y ;A C A ,a n t e r i o r c e r e b r a l a r t e r y ;N T 2N ,h u m a n t e r a t o c a r c i n o m a -d e r i v e d n e u r o n s ;P B -H S P C s ,p e r i p h e r a l b l o o d h e m a t o p o i e t i c p r o g e n i t o r /s t e m c e l l s .2099myocardial infarction 27months after cell transplantation showed that NT2N cells survived in the brain [28].This trial was followed by a phase II,randomized,single-blind trial that included nine patients with ischemic and nine with hemorrhagic strokes from 1to 6years previously and with a fixed motor deficit that was stable for at least 2months [29].Seven patients received 5million cells and se-ven patients 10million cells,distributed in 25sites,while 4patients served as a nonsurgical control group;all subjects participated in a stroke rehabilitation program.One patient suffered a single seizure the day after the surgery,and an-other presented a burr-hole drainage of an asymptomatic chronic subdural hematoma 1month after surgery.There was no significant improvement in the primary endpoint outcome,that is,European Stroke Scale motor score or the Fugl-Meyer (FM)Stroke Assessment,but therewasFIG.1.Schematic illustrating the different cells and routes of administration used in published trials.The schematic also illustrates other types of cells used in registered trials (in dotted rectangles ).NT2N,human teratocarcinoma-derived neurons;UC-MSCs,umbilical cord-derived mesenchymal stem cells;UCB-MNCs,umbilical cord blood-mononuclear cells;BM-MNCs,bone marrow-mononuclear cells;BM-MSCs,bone marrow-mesenchymal stem cells;PB-HSPC,peripheral blood-hemato-poietic stem/progenitor cell;NSPCs,neural stem/progenitor cells;OECs,olfactory-ensheathing cells;MSCs,mesenchymal stem cells;EPCs,endothelial progenitor cells.Color images available online at /scd2100ROSADO-DE-CASTRO ET AL.。