Stem cell transplantation for ischemic stroke (Review)
Boncoraglio GB, Bersano A, Candelise L, Reynolds BA, Parati EA
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 9 http://www.thecochranelibrary.com Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. T A B L E O F C O N T E N T S 1 HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 13 NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Stem cell transplantation for ischemic stroke Giorgio Battista Boncoraglio 1 , Anna Bersano 2 , Livia Candelise 2 , Brent A Reynolds 3 , Eugenio A Parati 1 1 Department of Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. 2 Dipartimento di Scienze Neuro- logiche, Universita degli Studi di Milano, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy. 3 Queensland Brain Institute, University of Queensland, Brisbane, Australia Contact address: Giorgio Battista Boncoraglio, Department of Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, Milano, 20133, Italy. giorgio_boncoraglio@yahoo.it. Editorial group: Cochrane Stroke Group. Publication status and date: New, published in Issue 9, 2010. Review content assessed as up-to-date: 9 March 2010. Citation: Boncoraglio GB, Bersano A, Candelise L, Reynolds BA, Parati EA. Stem cell transplantation for ischemic stroke. Cochrane Database of Systematic Reviews 2010, Issue 9. Art. No.: CD007231. DOI: 10.1002/14651858.CD007231.pub2. Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. A B S T R A C T Background Studies in animal models of ischemic stroke have shown that stemcells transplanted into the brain can lead to functional improvement. However, to date, evidence for the benets of stem cell transplantation in ischemic stroke patients is lacking. Objectives To assess the efcacy and safety of stem cell transplantation compared with conventional treatments in patients with ischemic stroke. Search methods We searched the Cochrane Stroke Group Trials Register (last searched February 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE (1966 to August 2008), EMBASE (1980 to August 2008), Science Citation Index (1900 to August 2008), and BIOSIS (1926 to August 2008). We handsearched potentially relevant conference proceedings, screened reference lists, and searched ongoing trials and research registers (last searched November 2008). We also contacted individuals active in the eld and stem cell manufacturers (last contacted December 2008). Selection criteria We included randomized controlled trials (RCTs) recruiting patients with ischemic stroke, in any phase of the disease, and an ischemic lesion conrmed by computerized tomography or magnetic resonance imaging scan. We included all types of stem cell transplantation regardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell admin- istration (systemic or local), and dosage. The primary outcome was efcacy (assessed as combined functional outcome or disability and dependency) at longer follow-up (minimum six months). Secondary outcomes included post-procedure safety outcomes (death, worsening of neurological decit, infections and neoplastic transformation). Data collection and analysis Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information. 1 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Main results We identied three very small RCTs. Two are still awaiting classication because only subgroups of patients could be included in this meta-analysis and additional unpublished data are needed. The third trial randomized 30 patients to intravenous transplantation of autologous mesenchymal stem cell (10 participants) or reference group (20 participants) (ve participants, initially randomized to the intervention group, refused the treatment and were allocated to the reference group) and found a statistically non-signicant functional improvement in treated patients at longer follow-up. No adverse cell-related events were reported. Authors conclusions No large trials of stem cell transplantation have been performed in ischemic stroke patients and it is too early to know whether this intervention can improve functional outcome. Large, well-designed trials are needed. P L A I N L A N G U A G E S U M M A R Y Stem cell transplantation for ischemic stroke Once stroke-induced cell damage has occurred, little can be done to improve functional outcome. Stem cell transplantation has been shown to be safe and effective in ischemic stroke animal models but evidence in patients is still lacking. This review found three very small randomized controlled trials. Two of them could not be included in this meta-analysis because additional data are needed. The third one, which included 30 participants, found a statistically non-signicant functional improvement in patients treated with autologous mesenchymal stem cells at longer follow-up. No adverse cell-related events were reported. Larger and better-designed trials are needed. B A C K G R O U N D Acute stroke is one of the leading causes of morbidity and mortality worldwide. Inindustrializedcountries, stroke is the secondor third most common cause of death and the primary cause of morbidity and long-term disability (EUSI 2003). Some thrombolytic interventions given in the acute phase of is- chemic stroke, such as intravenous recombinant tissue plasmino- gen activator (rtPA), improve outcomes, including survival and residual disability (Kwiatkowski 1999; Hacke 2008; Wardlaw 2009). However, despite signicant clinical benet, only a minor- ity of eligible patients receive thrombolysis within the required four-and-a-half hours. When aspirin is administered within 48 hours of stroke onset, the resulting small but signicant decline in morbidity and mortality seems to be due to a reduction of early re- current stroke rather than limitation of neurological consequences (Adams 2007; Sandercock 2008). Therefore, once stroke-induced cell damage has occurred, little can be done to improve functional outcome, except for rehabilitation therapy and pharmacological management of co-morbidities. A growing number of studies highlight the potential of stem cell transplantation as a novel therapeutic approach for stroke. Studies in animal models of ischemic stroke have shown that stem cells transplanted into the brain not only survive, but also lead to func- tional improvement (Chopp 2002). Although many experimental studies have shown that cell transplantation improves stroke re- covery, the mechanisms responsible for this are largely unknown. It is hypothesized that the cell grafts provide trophic factors that enhance cell survival and function, establish local connections that enhance synaptic activity, or provide a bridge for host axonal re- generation (Chopp 2002; Wechsler 2003). Following these results, clinical trials of stem cell transplantation in patients with ischemic stroke have commenced (Savitz 2004; Pluchino 2005; Bliss 2007). However, effective therapies will de- pend onstrategies that increase the survival of the newneurons and enhance their incorporation into the reorganizing neural circuitry (Lindvall 2006). Many factors may be critical for transplantation success: the localization and extension of the infarct area; the time window (acute or chronic phase); the source of stem cells (human or animal; embryonic, fetal or adult; from brain or other tissues); the need for immunosuppression; and the route of administration (local or systemic) (STEPS 2009). To date, evidence for the benets of stemcell transplantation in is- chemic stroke patients is lacking. The safety of these interventions also requires careful evaluation (Bliss 2007). A systematic review 2 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. of the available clinical trials is needed to assess the benet-to-risk prole of this type of intervention. O B J E C T I V E S The review aimed to assess the efcacy and safety of stem cell transplantation compared with conventional treatments in pa- tients with ischemic stroke. M E T H O D S Criteria for considering studies for this review Types of studies We only included randomized controlled trials (RCTs). Types of participants We included patients with ischemic stroke, with an ischemic le- sion conrmed by computerized tomography (CT) or magnetic resonance imaging (MRI) scan, in any phase of the disease, from acute to chronic. This long time period allows for the inclusion of studies investigating both the acute neuroprotective and non- acute neurorestorative effects of transplanted stem cells. Types of interventions We compared stem cell transplantation with conventional treat- ments. We included all types of stemcell transplantationregardless of cell source (autograft, allograft, or xenograft; embryonic, fetal, or adult; from brain or other tissues), route of cell administration (systemic or local), and dosage. Types of outcome measures Primary outcomes Efcacy (functional outcome or disability/dependency, or both) at longer follow-up assessed using clinical outcome measures or validated international scales (e.g. National Institutes of Health Stroke Scale (NIHSS), modied Rankin Scale (mRS), Barthel In- dex (BI)), or both. The minimum follow-up period accepted was six months. Secondary outcomes We evaluated the following post-procedure safety outcomes. Any cause of death within 30 days of the procedure and thereafter. Severe worsening of neurological decit (increase of four points on the NIHSS scale or equivalent) within 30 days of procedure and thereafter. Infections within 30 days of the procedure and thereafter. Neoplastic transformation of ischemic lesion at longer follow-up. We also considered the following subgroups. Type of participant: phase of disease: acute and subacute (within three months of ischemic stroke) versus chronic (more than three months after ischemic stroke). Type of treatment: source of stem cells: human versus non-human, embryonic and fetal versus adult, neural versus non-neural; route of administration: neurosurgery versus intra- arterial versus intravenous. Search methods for identication of studies See the Specializedregister sectioninthe Cochrane Stroke Group module. We searched the Cochrane Stroke Group Trials Register, which was last searched by the Managing Editor on 15 February 2010, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3), MEDLINE(1966 to August 2008) (Appendix 1), EMBASE (1980 to August 2008) (Appendix 2), Science Citation Index (1900 to August 2008), and BIOSIS (1926 to August 2008) (Appendix 3). In an effort to identify further published, unpublished, and ongo- ing trials we: handsearched the following conference proceedings (2009 International Stroke Conference, San Diego, California, USA; 2009 European Stroke Conference, Stockholm, Sweden); screened reference lists of relevant papers; searched the following ongoing trials and research registers: Current Controlled Trials (www.controlled-trials.com), the Internet Stroke Center Stroke Trials Registry ( www.strokecenter.org), and the International Stem Cell Forum ( www.stemcellforum.org/) (last searched November 2008); contacted individuals active in the eld and the following stem cell manufacturers (identied from www.stem-cell- companies.com/): ReNeuron and Athersys (last contacted December 2008). We searched for relevant trials in all languages and arranged trans- lation of relevant research reports published in languages other than English. 3 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Data collection and analysis Selection of studies Two review authors (GBB and AB) read titles and abstracts (if available) of the identied references and eliminated obviously ir- relevant studies. Two reviewauthors (GBBand AB) independently examined potentially relevant studies using the predetermined cri- teria of whether: the study is a RCT; the participants have had an ischemic stroke with an ischemic lesion conrmed at neuroimaging and the intervention is stem cell transplantation; functional impairment or disability/dependency, or both, are measured at entry and at the minimum follow-up period of six months using validated international scales. We ranked studies as excluded, included, or uncertain using a checklist. We resolved any disagreements through discussion with a third review author (LC). Assessment of methodological quality of included studies Two review authors (GBB and AB) independently assessed the methodological quality of the trials using standard Cochrane crite- ria: method of randomization (true or quasi-randomization), con- cealment of allocation(adequate, inadequate, or unclear), blinding of outcome evaluators, analysis by intention-to-treat, and losses to follow up. We ranked methodological quality as high, low, or ambiguous. We resolved disagreements through discussion with a third review author (LC). Data extraction and analysis Two review authors (GBB and AB) independently extracted data from publications on quality parameters (as above); source, route, and timing of stem cell transplantation; the number of events; and status within 30 days after the treatment, at six months, and at the end of the follow-up period. We contacted trialists directly to obtain missing data, as well as data collected but not reported. Where intention-to-treat analyses were not possible fromthe pub- lished and unpublished data, we did on-treatment (per protocol) analyses. We intended to combine the results using a meta-analytic ap- proach, calculating the weighted treatment effect and 95% con- dence intervals across trials using a random-effects model. For proportions (dichotomous outcomes) we intended to calculate the relative risk (RR). We intended to convert continuous data to the mean difference (MD) and calculate an overall MD. To quantify between-study heterogeneity, we intended to use the I 2 statistic. If we had found substantial heterogeneity (I 2 > 75%) we would have explored the reasons. To test the robustness of the results, we intended to undertake a sensitivity analysis by incorporating or removing studies that are assessed to be of lower or ambiguous methodological quality. If there were sufcient RCTs, we intended to conduct a subgroup analysis using meta-regression techniques (Chi 2 test) in order to compare: acute and subacute with chronic transplantations; human with non-human transplantations; embryonic and fetal with adult transplantations; neural with non-neural transplantations; and local with systemic transplantations. We used RevMan 5 for all data entry and analysis (RevMan 2008). R E S U L T S Description of studies See: Characteristics of includedstudies; Characteristics of excluded studies; Characteristics of studies awaiting classication. See: Characteristics of includedstudies; Characteristics of excluded studies; Characteristics of studies awaiting classication Two review authors (GBB and AB) scrutinized 2274 titles and abstracts (if available) resulting fromthe CENTRAL, MEDLINE, EMBASE, Science Citation Index, and BIOSIS searches and 29 titles resulting from the Cochrane Stroke Group Trials Register search. Two reviewauthors (GBB and AB) scrutinized a further 94 titles identied from conference proceedings, citation searching, and trials registers. Three review authors (GBB, BAR, and EAP) took part in a meeting with individuals active in the eld and stem cell manufacturers (STEPS 2009). Between them, the authors identied 13 studies of stemcell trans- plantation in ischemic stroke patients, of which three RCTs met our inclusion criteria (Kondziolka 2000; Bang 2005; Kondziolka 2005); we excluded the remaining 10 studies (eight case series, one feasibility study and one case-control study). In their rst study Kondziolka et al studied safety and feasibil- ity of stem cell transplantation in four non-randomized and eight randomized-dose ischemic stroke patients (no reference group). However, we need unpublished data on the randomized-dose sub- group to include patients in a meta-analysis. We requested further data and the study is awaiting classication (Kondziolka 2000). In their second study Kondziolka et al randomized 18 stroke pa- tients - nine ischemic stroke patients and nine hemorrhagic stroke patients - tostemcell transplantationplus rehabilitation(14partic- ipants) or rehabilitation alone (four participants). The trial did not report results separately for ischemic stroke patients. We requested further data and the study is awaiting classication (Kondziolka 2005). 4 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Bang et al assessed feasibility, efcacy, and safety of culture-ex- panded autologous mesenchymal stem cells in patients with acute cerebral infarction within the middle cerebral arterial territory and persisting severe neurological decits, dened as a NIHSS score 7 after seven days of symptom onset (Bang 2005). Thirty par- ticipants were randomly assigned to intravenous infusion of 1 x 10 8 stem cells plus standard therapy and rehabilitation (10 par- ticipants) or standard therapy and rehabilitation alone (20 partic- ipants). In patients assigned to stem cell infusion, bone marrow was aspirated under local anaesthesia from the posterior iliac crest seven days after admission, then mesenchymal stem cells were ex- panded until four to ve and seven to nine weeks after symptom onset when, respectively, the rst and the second boosting of 5 x 10 7 cells were infused into a peripheral catheter. Five patients, initially randomized to the intervention group, refused the treat- ment and were allocated to the reference group (nal allocation was: ve patients to stem cells plus rehabilitation and 25 patients to rehabilitation alone). The primary endpoints were the NIHSS score as an index of neurological decit and the BI and mRS as indices of functional recovery. Data were collected at baseline and three, six, and 12 months. Risk of bias in included studies Allocation In Bang 2005, on the seventh day of admission, a blinded, inde- pendent co-ordinator randomly allocated patients to one of two groups, the stem cells or control group, by use of a randomization table. Blinding In Bang 2005, after the initial random allocation of patients to treatment groups, experimental procedures were not blinded. However, the primary outcomes (NIHSS score, BI, and mRS) were checked at follow-up by a neurologist who was blind to the group allocation. Intention-to-treat analysis InBang 2005, ve patients initially randomizedtothe intervention group refused the treatment and were allocated to the reference group. Losses to follow-up In Bang 2005, three patients from the reference group were lost to follow-up at six months and eight patients from the reference group were lost to follow-up at 12 months (unpublished data). Effects of interventions We could not performmeta-analysis because we included only one RCT. At longer follow-up (12 months) Bang 2005 showed a statistically non-signicant improvement of BI in the stem cell-treated group compared with the reference group (MD 19.36, 95% CI -2.05 to 40.77) (unpublished data). However, at three and six months, the improvement of BI was signicant (MD 28.80, 95% CI 11.59 to 46.01; MD 27.23, 95% CI 13.03 to 41.43) (unpublished data). By contrast, changes in the NIHSS scores were less prominent than changes in the BI (unpublished data). Within the one-year follow-up period, there were no adverse cell-related events. No deaths or stroke recurrence were reported in either group. D I S C U S S I O N Summary of main results We identied only three very small published RCTs and no on- going RCTs. Of the three published RCTs, two are still awaiting classication because only subgroups of patients could be included in this systematic review(Kondziolka 2000 and Kondziolka 2005, eight and nine patients respectively). The only included study, Bang 2005, showed a non-signicant improvement in stem cell- treated patients (ve participants) compared with the reference group (25 participants) at longer follow-up; however, the study is potentially biased due to losses to follow-up and lack of intention- to-treat analysis. Overall completeness and applicability of evidence Our review was deliberately broad and we sought to include trials in which stem cells were transplanted in ischemic stroke patients so that the review would inform future research. The trials we identied, although very small, are relevant to our reviewquestion. Quality of evidence We cannot draw robust conclusions as we identied only one completed study providing data on a total of 30 patients, with some methodological limitations (Bang 2005). Potential biases in the review process We attempted to limit bias in the review process. This review in- corporated extensive literature searches guided by the Cochrane 5 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Stroke Group and we sought unpublished and ongoing work through contact with authors of included studies and other experts in the eld. Two review authors independently decided whether studies should be included, and two review authors independently extracted data. Agreements and disagreements with other studies and reviews As far as we know, there are no other systematic reviews of stem cell transplantationfor ischemic stroke. Another systematic review, which also included hemorrhagic strokes and non-randomized controlled studies, had similar results (Yuan 2007). Our ndings are consistent with previously published papers calling for more research to determine the effectiveness of stemcell transplantation for ischemic stroke. A U T H O R S C O N C L U S I O N S Implications for practice Currently there is insufcient evidence to support stem cell trans- plantation in treating ischemic stroke. Implications for research Given the high prevalence of long-termdisability following stroke, more research is urgently needed to identify new treatments. Stem cells seempromising in animal models. Large, well-designed trials are urgently needed (STEPS 2009). A C K N O W L E D G E M E N T S We are very grateful to Brenda Thomas and Hazel Fraser of the Cochrane Stroke Group who helped develop the search strate- gies, searched the Cochrane Stroke Group Trials Register and the Cochrane Central Register of Controlled Trials. We are grateful to the editors and peer reviewers for their helpful comments on the review (Professor Graeme Hankey, Dr Ale Algra, Dr Steff Lewis, Mrs Brenda Thomas, Dr Tim England). Dr Oh Young Bang, Samsung Medical Center, Seoul, provided unpublished numerical data from the Bang 2005 trial. Dr Dou- glas Kondziolka, University of Pittsburgh, provided inclusion and exclusion criteria from the Kondziolka 2000 trial. R E F E R E N C E S References to studies included in this review Bang 2005 {published and unpublished data} Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Annals of Neurology 2005;57(6):87482. References to studies excluded from this review Li 2007 {published data only} Li JB, Man Y, Shan H, Duan YL. Sterile preparation of umbilical cord derived mesenchymal stem cells with multiple bags: method and effect. Journal of Clinical Rehabilitative Tissue Engineering Research 2007;11(24): 47814. Lin 2008 {published data only} Lin SZ, Shyu WC, Li H. CD34+ stem cell therapy in chronic stroke patients - Phase I trial. Cell Transplantation 2008;17(4):472. Man 2006 {published data only} Man Y, Li J, Yang B, Ma J. Vein transplantation using human umbilical cord blood stem cells in the treatment of stroke sequela. Neural Regeneration Research 2006;1(7): 61821. Mendona 2006 {published data only} Mendez-Otero R, de Freitas GR, Andr C, de Mendona ML, Friedrich M, Oliveira-Filho J. Potential roles of bone marrow stem cells in stroke therapy. Regenerative Medicine 2007;2(4):41723.
Mendona ML, Freitas GR, Silva SA, Manfrim A, Falco
CH, Gonzles C, et al.Intra-arterial autologous bone marrow mononuclear cell transplantation for acute ischemic stroke. Arquivos Brasileiros de Cardiologia 2006;86(1):525. Rabinovich 2005 {published data only} Rabinovich SS, Seledtsov VI, Banul NV, Poveshchenko OV, Senyukov VV, Astrakov SV, et al.Cell therapy of brain stroke. Bulletin of Experimental Biology and Medicine 2005; 139(1):1268. Savitz 2005 {published data only} Savitz SI, Dinsmore J, Wu J, Henderson GV, Stieg P, Caplan LR. Neurotransplantation of fetal porcine cells in patients with basal ganglia infarcts: a preliminary safety and feasibility study. Cerebrovascular Diseases 2005;20(2): 1017. Wang 2007 {published data only} Wang YC, Zhang CQ, Wang LZ, Wen H, Yin ZM, Wang L, et al.Autologous bone marrow-derived mononuclear cell transplant for treatment of nervous system damage and degenerative disease: a report of 42 cases. Journal of Clinical Rehabilitative Tissue Engineering Research 2007;11 (20):39947. 6 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Yang 2005 {published data only} Yang QC, Zhang XD, Liang CC, Du Y, Li HW. Functional evaluation of stroke patients 6 months after intrathecal injection of neural stem cells. Chinese Journal of Clinical Rehabilitation 2005;9(9):20810. Yang 2007 {published data only} Yang QC, Liang CC, Li MX, Zhang XD, Ma DF. Neural stem cell transplantation for treating stroke sequela in 59 cases. Journal of Clinical Rehabilitative Tissue Engineering Research 2007;11(20):40335. Zhang 2006 {published data only} Zhang RY, Zheng YR, Hu SS, Cheng HB, An YH. Clinical analysis of neural stem cells for treatment of sequela in 50 stroke patients. Chinese Journal of Clinical Rehabilitation 2006;10(9):1389. References to studies awaiting assessment Kondziolka 2000 {published data only (unpublished sought but not used)}
Kondziolka D, Wechsler L, Goldstein S, Meltzer C,
Thulborn KR, Gebel J, et al.Transplantation of cultured human neuronal cells for patients with stroke. Neurology 2000;55(4):5659. Meltzer CC, Kondziolka D, Villemagne VL, Wechsler L, Goldstein S, Thulborn KR, et al.Serial [18F] uorodeoxyglucose positron emission tomography after human neuronal implantation for stroke. Neurosurgery 2001;49(3):58691. Nelson PT, Kondziolka D, Wechsler L, Goldstein S, Gebel J, DeCesare S, et al.Clonal human (hNT) neuron grafts for stroke therapy: neuropathology in a patient 27 months after implantation. American Journal of Pathology 2002;160(4): 12016. Kondziolka 2005 {published data only}
Elder E, Gebel J, et al.Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. Journal of Neurosurgery 2005;103(1):3845. Stilley CS, Ryan CM, Kondziolka D, Bender A, DeCesare S, Wechsler L. Changes in cognitive function after neuronal cell transplantation for basal ganglia stroke. Neurology 2004; 63(7):13202. Additional references Adams 2007 Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al.Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology afrms the value of this guideline as an educational tool for neurologists. Stroke 2007;38(5): 1655711. Bliss 2007 Bliss T, Guzman R, Daadi M, Steinberg GK. Cell transplantation therapy for stroke. Stroke 2007;38(2): 81726. Chopp 2002 Chopp M, Li Y. Treatment of neural injury with marrow stromal cells. Lancet Neurology 2002;1(2):92100. EUSI 2003 European Stroke Initiative Executive Committee, EUSI Writing Committee, Olsen TS, Langhorne P, Diener HC, Hennerici M, Ferro J, Sivenius J, et al.European Stroke Initiative Recommendations for Stroke Management - update 2003. Cerebrovascular Diseases 2003;16(4):31137. Hacke 2008 Hacke W, Kaste M, Bluhmki E, Brozman M, Dvalos A, Guidetti D, ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. New England Journal of Medicine 2008;359(13):131729. Kwiatkowski 1999 Kwiatkowski TG, Libman RB, Frankel M, Tilley BC, Morgenstern LB, Lu M, et al.Effects of tissue plasminogen activator for acute ischemic stroke at one year. National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group. New England Journal of Medicine 1999;340(23):17817. Lindvall 2006 Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. Nature 2006;441(7097):10946. Pluchino 2005 Pluchino S, Zanotti L, Deleidi M, Martino G. Neural stem cells and their use as therapeutic tool in neurological disorders. Brain Research Reviews 2005;48(2):2119. RevMan 2008 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008. Sandercock 2008 Sandercock PAG, Counsell C, Gubitz GJ, Tseng MC. Antiplatelet therapy for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2008, Issue 3. [Art. No.: CD000029. DOI: 10.1002/14651858.CD000029.pub2] Savitz 2004 Savitz SI, Dinsmore JH, Wechsler LR, Rosenbaum DM, Caplan LR. Cell therapy for stroke. NeuroRx 2004;1(4): 40614. STEPS 2009 The STEPS Participants. Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke 2009;40(2):5105. Wardlaw 2009 Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2009, Issue 4. [Art. No.: CD000213. DOI: 10.1002/14651858.CD000213.pub2] 7 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Wechsler 2003 Wechsler LR, Kondziolka D. Cell therapy: replacement. Stroke 2003;34(8):20812. Yuan 2007 Yuan Y, Zeng X, Wu T. Stem cell transplantation for stroke: a systematic review. Chinese Journal of Evidence-Based Medicine 2007;7(10):7439.
Indicates the major publication for the study
8 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] Bang 2005 Methods Randomized controlled trial Participants 30 patients with cerebral infarcts within the middle cerebral arterial territory and severe neurological decits Interventions Intravenous infusion of culture-expanded autologous mesenchymal stem cell Outcomes NIHSS score as an index of neurological decit and the BI and mRS as indices of functional recovery Notes - Risk of bias Item Authors judgement Description Allocation concealment? Yes Patients were randomly allocated by a blinded, indepen- dent co-ordinator using a randomization table Blinding? All outcomes Yes Experimental procedures were not blinded Primary outcomes were checked by blinded neurologist Incomplete outcome data addressed? All outcomes No 8 patients from the reference group were lost to follow- up at 6 months Free of other bias? No 5 patients initially randomized to stem cells refused the treatment and were allocated to the control group BI: Barthel Index mRS: modied Rankin Scale NIHSS: National Institutes of Health Stroke Scale Characteristics of excluded studies [ordered by study ID] 9 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Study Reason for exclusion Li 2007 Not a RCT (case series) Lin 2008 Not a RCT (case series) Man 2006 Not a RCT (case series) Mendona 2006 Not a RCT (case series) Rabinovich 2005 Not a RCT (case-control design) Savitz 2005 Not a RCT (feasibility study with 5 participants) Wang 2007 Not a RCT (case series) Yang 2005 Not a RCT (case series) Yang 2007 Not a RCT (case series) Zhang 2006 Not a RCT (case series) RCT: randomized controlled trial Characteristics of studies awaiting assessment [ordered by study ID] Kondziolka 2000 Methods Randomized dose controlled trial Participants 8 randomized patients with xed motor decits following (6 months to 6 years) a basal ganglia ischemic stroke Interventions Stereotactic implantation of cultured neuronal cells produced from the NT2/D1 cell line derived from a human teratocarcinoma Outcomes Neurological decit, functional disability and quality of life at baseline and follow-up Notes The study includes 4 non-randomized and 8 randomized-dose ischemic stroke patients. Complete and separated results for randomized patients were not available from either the publications or the corresponding author 10 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Kondziolka 2005 Methods Randomized controlled trial Participants 18 patients with xed motor decits following (1 to 6 years) a basal ganglia ischemic or hemorrhagic stroke Interventions Stereotactic implantation of cultured neuronal cells produced from the NT2/D1 cell line derived from a human teratocarcinoma Outcomes Primary outcome: European Stroke Scale motor score at 6 months Secondary outcomes: Fugl-Meyer, Action Research Arm Test, Stroke Impact Scale scores and the results of other motor, neuropsychological and functional tests Notes Separated results for ischemic and hemorrhagic stroke patients were not available from either the publications or the corresponding author 11 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. D A T A A N D A N A L Y S E S This review has no analyses. A P P E N D I C E S Appendix 1. MEDLINE search strategy We used the following search strategy for MEDLINE (Ovid) and modied it to search the other databases: 1. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or exp brain ischemia/ or carotid artery diseases/ or carotid artery thrombosis/ or intracranial arterial diseases/ or cerebral arterial diseases/ or exp intracranial embolism and thrombosis/ or exp stroke/ 2. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw. 3. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw. 4. 1 or 2 or 3 5. cell transplantation/ or stemcell transplantation/ or cord blood stemcell transplantation/ or hematopoietic stemcell transplantation/ or mesenchymal stem cell transplantation/ or peripheral blood stem cell transplantation/ 6. stem cells/ or adult stem cells/ or embryonic stem cells/ or fetal stem cells/ or broblasts/ or hematopoietic stem cells/ or myeloid progenitor cells/ or erythroid progenitor cells/ or mesenchymal stem cells/ or multipotent stem cells/ or exp myoblasts/ or pluripotent stem cells/ or totipotent stem cells/ or tumor stem cells/ 7. exp cells/tr 8. ((stem or progenitor or embryo$ or fetal or foetal or umbilical or bone marrow or cord blood) adj5 (cell or cells)).tw. 9. (cell adj5 (transplant$ or graft$)).tw. 10. (broblast$ or myoblast$).tw. 11. cell transplantation.jn. 12. 5 or 6 or 7 or 8 or 9 or 10 or 11 13. 4 and 12 14. limit 13 to humans Appendix 2. EMBASE search strategy We used the following search strategy for EMBASE (Ovid): 1. cerebrovascular disease/ or cerebral artery disease/ or cerebrovascular accident/ or stroke/ or vertebrobasilar insufciency/ or carotid artery disease/ or exp carotid artery obstruction/ or exp brain infarction/ or exp brain ischemia/ or exp occlusive cerebrovascular disease/ 2. stroke patient/ or stroke unit/ 3. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw. 4. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw. 5. 1 or 2 or 3 or 4 6. cell therapy/ or somatic cell therapy/ or cell transplantation/ or exp stem cell transplantation/ 7. exp stem cell/ 8. ((stem or progenitor or embryo$ or fetal or foetal or umbilical or bone marrow or cord blood) adj5 (cell or cells)).tw. 9. (cell adj5 (transplant$ or graft$)).tw. 10. (broblast$ or myoblast$).tw. 11. cell transplantation.jn. 12. 6 or 7 or 8 or 9 or 10 or 11 13. 5 and 12 14. limit 13 to human 12 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Appendix 3. BIOSIS and Science Citation Index search strategy We used the following search strategy to search BIOSIS and Science Citation Index (ISI Web of Knowledge): 1. stroke or cerebr* = TS 2. stem cell* or cell transplant* = TS 3. trial* or random* or placebo* or blind* = TS 4. 1 and 2 and 3 H I S T O R Y Protocol rst published: Issue 3, 2008 Review rst published: Issue 9, 2010 C O N T R I B U T I O N S O F A U T H O R S Giorgio B Boncoraglio drafted the protocol, searched electronic databases and conference proceedings, contacted trialists about unpub- lished data, screened titles and abstracts of references identied by the search, selected and assessed trials, extracted trial and outcome data, and drafted and approved the nal manuscript of the review. Anna Bersano contributed to the conception and design of the protocol, searched electronic databases and conference proceedings, screened titles and abstracts of references identied by the search, selected and assessed trials, extracted trial and outcome data, contributed to and approved the nal manuscript of the review. Livia Candelise contributed to the conception and design of the protocol, guided trial selection and assessment, contributed to and approved the nal manuscript of the review. Brent A Reynolds contributed to the conception and design of the protocol, contributed to the search of unpublished data and interpretation of the data, contributed to and approved the nal manuscript of the review. Eugenio A Parati contributed to the conception and design of the protocol, contributed to the search of unpublished data and interpretation of the data, contributed to and approved the nal manuscript of the review. D E C L A R A T I O N S O F I N T E R E S T None known. D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W None. 13 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. N O T E S None. I N D E X T E R M S Medical Subject Headings (MeSH) Acute Disease; Infarction, Middle Cerebral Artery [rehabilitation;
surgery] MeSH check words Humans 14 Stem cell transplantation for ischemic stroke (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.