Celulasmadres ECV

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)
[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.
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)
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
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.
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).
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
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.
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}
Kondziolka D, Steinberg GK, Wechsler L, Meltzer CC,

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
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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.
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The Nordic Cochrane Centre, The Cochrane Collaboration.
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Sandercock PAG, Counsell C, Gubitz GJ, Tseng MC.
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Savitz SI, Dinsmore JH, Wechsler LR, Rosenbaum DM,
Caplan LR. Cell therapy for stroke. NeuroRx 2004;1(4):
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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.
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Wardlaw JM, Murray V, Berge E, del Zoppo GJ.
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Indicates the major publication for the study

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]
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
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
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
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.
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]; Mesenchymal Stem Cell Transplantation [adverse effects;
methods]; Randomized Controlled Trials as Topic; Stem Cell Transplantation [adverse effects;

methods]; Stroke [
surgery]
MeSH check words
Humans

Celulasmadres ECV

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Stem cell transplantation for ischemic stroke (Review)

Boncoraglio GB, Bersano A, Candelise L, Reynolds BA, Parati EA

Mendona ML, Freitas GR, Silva SA, Manfrim A, Falco

Kondziolka D, Wechsler L, Goldstein S, Meltzer C,

Kondziolka D, Steinberg GK, Wechsler L, Meltzer CC,

Indicates the major publication for the study

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