108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES LE CHI VIEN APPLICATION RESEARCH ON AUTOLOGOUS BONE MARROW STEM CELLS IN THE TREATMENT OF MIDDLE CEREBRAL ARTERY INFARCTION Specialism Neu[.]
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES LE CHI VIEN APPLICATION RESEARCH ON AUTOLOGOUS BONE MARROW STEM CELLS IN THE TREATMENT OF MIDDLE CEREBRAL ARTERY INFARCTION Specialism: Neuroscience Code: 9720158 ABSTRACT OF MEDICAL DOCTORAL THESIS Ha Noi – 2023 The thesis has been completed at 108 Institute of Clinical Medical and Pharmaceutical Sciences Supervisors: Assoc Prof Lê Huu Song Assoc Prof Nguyen Hoang Ngoc Reviewers: The thesis will be presented in front of university examiner and reviewer later at: 108 Institute of Clinical Medical and Pharmaceutical Sciences on .th 2023 National Library: National Informatics Library Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences BACKGROUND About 50 to 70% of patients with middle cerebral artery (MCA) infarction suffer from severe sequelae Most of the current treatments being applied in the subacute period of cerebral infarction have limited effectiveness, therefore, it is necessary to research and apply new treatment therapies Bone marrow stem cells (BMSCs), also known as bone marrow-derived mononuclear cells, had shown clear and consistent experimental evidence in terms of safety and effecacy in treating cerebral infarction when administered via the vascular route (intravenous or intra-arterial infusion) However, there is limited evidence about its efficacy in humans, with several pilot studies reporting a tendency to improve in neurological function, such as Taguchi A (2015) or Bhatia V (2018), but only on limited samples Currently, there are no clinical trials on BMSCs for the treatment of stroke in Vietnam This study was conducted with objectives: Objectives 1: to evaluate the safety of intravenous autologous bone marrow stem cell therapy and intra-arterial autologous bone marrow stem cell therapy in the treatment of MCA infarction Objectives 2: to evaluate the efficacy of intravenous autologous bone marrow stem cell therapy and intraarterial autologous bone marrow stem cell therapy in the treatment of MCA infarction Chapter OVERVIEW 1.1 MIDDLE CEREBRAL ARTERY INFARCTION 1.1.1 Diagnosis of MCA infarction 1.1.1.1 Symptoms and signs According to Mohr J (2012), symptoms of MCA infarction include hemiplagia and/or numbness; ataxia of contralateral extremities; aphasia as a result of a dominant hemisphere lesion; perceptual deficits as a result of a non-dominant hemisphere lesion 1.1.1.2 Diagnostic imaging a Parenchymal imaging: Head CT shows hypodense lesions in territory of MCA, identified and evaluated using the ASPECT scale During the first week, the infarcted parenchyma demonstrates high DWI signal and low ADC signal on head MRI b CT angiography (CTA) or MR angiography (MRA) shows the occlusion of MCA consistent with cerebral infarct territory 1.1.2 Treatment 1.1.2.1 Reperfusion therapies in hyperacute phase 1.1.2.2 Underlying treatment 1.1.2.3 Treatment of complications 1.1.2.4 Secondary prevention 1.1.2.5 Rehabilitation 1.1.3 Prognosis 1.1.3.1 Short-term and long-term prognosis MCA infarction has poor prognosis in the short term with 40-80% mortality and severe sequelae in the long term 1.1.3.2 Prognosis of upper limb and aphasia recovery The ability to recover upper limb motor function, especially the hands and fingers, is low According to SH Jang (2013), the rate of complete recovery of hand and finger motor function is at 0% The ability to recover language function in patients with aphasia is similar 1.2 BONE MARROW STEM CELLS BMSCs are adult stem cells including hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and endothelial progenitor cells 1.2.1 Hematopoietic stem cells 1.2.1.1 Surface markers used in the identification of HSCs CD34 is the most important marker used to identify HSCs 1.2.1.2 Characteristics of HSCs The main characteristics of HSCs are ability of seft renewal, potential for differentiation, "homing" and apoptosis 1.2.1.3 Plasticity of HSCs 1.2.2 Mesenchymal stem cells 1.2.2.1 Surface markers used in the identification of MSCs Confirming MSC identity requires the use of several surface markers The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy defines mesenchymal stem cells as positive for CD105, CD73, CD90, and negative for CD45, CD34, CD14 or CD11b, CD79ᵅ or CD19, MHC-class II 1.2.2.2 Characteristics of MSCs The main characteristics of MSCs are (1) supporting hematopoiesis, (2) immunoregulatory properties, (3) migration and homing, (4) potential for differentiation 1.3 BMMCS IN THE TREATMENT OF CEREBRAL INFARCTION 1.3.1 Mechanism of intravenous or intra-arterial BMSCs therapy in cerebral infarction 1.3.1.1 The ability of BMMCs to cross the blood-brain barrier By labeling BMSCs before infusion and monitoring its presence in brain tissues after infusion, several experimental studies have demonstrated that BMSCs cross the blood-brain barrier to cerebral parenchyma when infused through the vascular system: Bing Yang (2013); Vasconcelos-dos-Santos A (2012) or Zhang H L (2018) 1.3.1.1 BMSC-derived paracrine factors After being infused into the circulatory system, BMSCs release several crucial paracrine factors, including chemokines, cytokines, growth factors and extracellular vesicles These factors promote the endogenous repair process to regenerate new neurovascular units (NVU) through endogenous angiogenesis, endogenous neurogenesis, anti-inflammation and immune regulation 1.3.1.2 Angiogenesis There is clear experimental evidence on the angiogenic effect of BMSCs in cerebral infarction (Youshi Fujita, 2010) 1.3.1.3 Neurogenesis The neurogenic effect of intravascularly injected BMSCs has been evidenced in experimental studies, including research by Zhang HL (2018) Direct mechanism: Stem cells pass through the blood-brain barrier to the cerebral infarction area and differentiate directly into brain cells Indirect mechanism: stimulating endogenous neurogenesis through paracrine substances released from BMSCs 1.3.1.4 Anti-inflammatory and immunomodulatory effects 1.3.1.5 Differences in mechanism of action between intravenous BMSCs and intra-arterial BMSCs in cerebral infarction A larger number of stem cells can pass through the blood-brain barrier to the area of cerebral infarction when BMSCs are infused via the arterial route compared to using the venous route, according to Bing Yang (2013); Zhang H L (2018) In terms of neurogenic effect, Bing Yang (2013) reported no difference between the two routes, while according to Zhang HL (2018), the arterial route was more effective In terms of the angiogenic effect, there was no difference between two routes according to Bing Yang (2013) 1.3.2 Experimental evidence on the safety and efficacy of BMSCs in the treatment of cerebral infarction 1.3.2.1 The safety and efficacy The experimental evidence on the safety and effectiveness of both intravenous BMSCs infusion and intra-arterial BMSCs infusion is quite strong and consistent, the difference between the groups is only in terms of TBG TX dose level and infusion time, shown by the results of some meta-analyses, such as Vahidy FS (2016) (IV route); Guzman R (2018) (IA route) Also according to some meta-analyses, BMSCs infusion via IA route has the advantage of being more effective 1.3.2.2 BMSCs doses in experimental studies The dose of 1x106 cells/kg is not effective in terms of clinical improvement, the minimum effective dose is 10x106 cells/kg in IV BMSCs infusion and 5x10 cells/kg in IA BMSCs infusion The doses in several studies are listed in Table 1.3 of the full text of the thesis 1.3.3 Clinical evidence on the safety and efficacy of BMSCs in the treatment of cerebral infarction 1.3.3.1 Safety a IV route: Several meta-analyses have shown that IV BMSCs infusion was safe A few adverse events were recorded such as fever, mild infection, seizures, recurrent stroke however there was no difference compared to the control group Savitz S (2011) used high dose (10x106 cells/kg) and concluded that the therapy was safe Lee J S (2010) used dose of 5x107 cells and did not record any cancer-related adverse events after year follow-up b IA route: Bhatia V (2018) used dose of 1,02 x 108 BMSCs and recorded safety According to Guzman R (2018), no embolic complications were recorded when infusing BMSCs at high doses 1.3.3.2 Efficacy on neurological function a IV route: Taguchi A (2015) used dose of 3,4×108 cells and concluded a tendency of improved neurological function b IA route: Several preliminary studies reported that there was a tendency of improved neurological function in patients having IA BMSCs infusion, while Bhatia, V (2018) reported that the outcome in IA BMSCs group (10 patients) was better than that in control group (10 patients), shown by the proportion of patients achieving mRS≤2 (80% in IA BMSC group vs 40% in control group) Similarly, Friedrich et al (2021) reported that the pecentage of patients achieving mRS≤2 after months using IA BMSCs infusion was 40% Some studies that published negative results all used doses of 0.05) Including: - Table 3.1: Median (interquartile range - IR) age of the IV, IA and control groups are 60.5 (55 - 66); 59 (52 – 65) and 60 (54 – 67), 14 respectively The male proportion in the IV group was 68.8%, in the IA group 74.2%, and control group 87.1% Table 3.4: NIHSS (IR) scores of the IV, IA and control groups were 14.5 (11.2 – 18); 13 (10 – 17) and 12 (10 – 16), respectively Table 3.5: Median (IR) BI scores of the IV, IA and control groups were 22.5 (20 – 25); 25 (20 – 30) 25 (20 – 30), respectively The median BI score of - 35 accounts for the majority in all groups (IV: 96.9%; IA: 83.8%; control group: 90.3%) Table 3.6: Motor Arm-NIHSS scores of the IV, IA and control groups are (3 – 4); (3 – 4) and (3 – 4), respectively Table 3.7: BRS-H stage I accounted for the majority in all groups (IV: 90.6%; IA: 80.6%; and control group: 87.1%) Table 3.8: LanguageNIHSS scores of the IV, IA and control groups were (3 – 3); (1 – 3) and (2 – 3), respectively 3.1.2 Laboratory characteristics and cranial MRI - Table 3.12: Median (IR) volume of cerebral infarction on MRI of the IV, IA and control groups were 93.5 (54.3–149.8); 58 (28.3– 113.9) and 114.8 (73.8–165.3) mL, respectively; (p>0.05) 3.1.3 Characteristics of BMSC dose and timing infusion - Table 3.13: Median (IR) number of mononuclear cells in the transfused BMSC block in the IV and IA groups were 460.2 (370.0 – 665.9) and 691.2 (354.9 – 843.6) (x 106 cells), respectively; in which the proportion of subgroups receiving a dose of ≥ 310 x 106 cells in the IV group was 81.2%; in the IA group was 77.4% Adult stem cell components include: + Median (IR) number of CD34+ stem cells in the IV group was 9.8 (7.1 – 20.7) x 106 cells; and in the IA group was 11.3 (7.2 – 14.9) x 106 cells + The number of mesenchymal stem cells in the IV group was 33.9 (18.5 – 53.1) x 104 cells; and in the IV group was 32.7 (21.8 – 46.9) x 104 cells The difference in the number of bone marrow mononuclear cells, 15 CD 34+ stem cells, and mesenchymal stem cells in the IV and IA infusion doses was not statistically significant with p>0.05 - Table 3.14: All BMSC blocks using IV and IA infusions had negative bacterial, fungal, and mycoplasma culture results and Endotoxin concentration tests within normal limits - Table 3.15: Time (days) from cerebral infarction to stem cell infusion for the IV and IA groups were 16 (13.2 – 19) and 17 (12 – 20), respectively In each group, the transfusion rates at ≤ 13 days were 75% and 64.5%, respectively There was no statistically significant difference with p>0.05 - Table 3.16 and 3.17: At time T0, the subgroup with BMSC infusion ≤ 13 days and the subgroup ≥ 14 days in the IA group at T0 were similar in terms of some anthropometric, gender, comorbidities, and hemispheric ratio of cerebral infarction, NIHSS score, BI score, volume of cerebral infarction on MRI, BMSCs dose infused For the IV group: except for the rate of atrial fibrillation, other indicators did not show statistically significant differences 3.2 EVALUATE THE SAFETY OF INTRAVENOUS AND INTRAARTERIAL AUTOLOGOUS BMSC THERAPIES IN THE TREATMENT OF MCA INFARCTION - Table 3.18: No adverse events (accidents, complications) related to bone marrow aspiration, intravenous BMSC infusion technique, or intra-arterial BMSC infusion technique were recorded The IV group had patients with fever (37.5-38 degrees Celsius), on days and after stem cell infusion, lasting ≤ days These were patients with retained bladder catheters - Table 3.19: There was no statistically significant difference (p>0.05) in the rate of adverse events between the groups at months after MCA infarction (T6) In the IV group, patient died (in the 2nd month, due to severe infection originating from the lower back); The control group had deaths (the first case died at month 3, due to 16 progressive heart failure; the second case at month due to severe recurrence of cerebral infarction) In the IA group, no patient died during the first months after MCA infarction Cranial MRI at T6 did not show a new type of lesion that could suggest an intracranial tumor - Table 3.20: There was no statistically significant difference (p>0.05) in the rate of adverse events between groups at 12 months after MCA infarction (T12) Recurrent cerebral infarction and seizures were recorded in all groups Compared to T6, one more patient died in the IV group (at month 7, due to progressive heart failure); One more patient died in the control group (at 11 months, debilitated due to joint stiffness due to being bedridden for a long time) No intracranial tumors or other organ cancers were noted 3.3 EVALUATE THE EFFICACY OF INTRAVENOUS AND INTRA-ARTERIAL AUTOLOGOUS BMSC THERAPIES IN THE TREATMENT OF MCA INFARCTION 3.3.1 months after cerebral infarction (T6) Figure 3.3 Percentage of patients achieving mRS score ≤2 in the IV group, IA group and control groups at T6 and T0 timepoint 3.3.1.1 Primary outcomes - Table 3.23 and Figure 3.3: The rate of mRS ≤ in the IA group was higher than the control group (25.8% vs 6.9%; p>0.05) and the 17 IV group (25.8 vs 3.2%; p0.05) 3.3.1.2 Secondary outcomes - Table 3.24: The NIHSS score in the IV group and IA group was lower than that of the control group [IA group: (4 – 9.25); IV group: (3 – 9) compared with control group: (5 – 9)]; with p>0.05 The rate of NIHSS scores 0-4 in the IA group was higher than in the control group (45.2% compared with 22.2%; p>0.05) - Figure 3.4 and Table 3.25: The IA group has the total BI score, improved BI score, and the proportion of patients achieving BI score ≥ 90 higher than those in the control group, the difference is statistically significant The IV group had a higher improvement in BI scores than the control group BI IV group (1) (n=30) IA group (2) (n=31) Control (3) (n=27) p p (1-3) (2-3) p (1-2) Total BI score 90 (78.75 – 90) 90 (80 – 95) 75 (55 – 90) 0.05 0.01* 0.43 30 – 100 25 – 100 30 – 95 0,06 0,02 0,79 45 (30 – 60) 0.007 0.03 0.91 Max – Min Classification N % n % n % BI < 90 13 43.3 12 38.7 19 70.4 BI ≥ 90 17 56.7 19 61.3 29.6 Improved score BI 62.5 (53.7 – 70) 65 (35 – 70) - Table 3.26: The rate of patients achieving Motor Arm - NIHSS point in the IA group (35.5%) was higher than the control group (7.4%) and the IV group (10%), the difference was statistically significant with p 0.05 - Table 3.27: The proportion of patients achieving BRS-H ≥ IV in the IA group (35.5%) was higher than the IV group (13.3%) and the control group (14.8%), with p>0.05 - Table 3.28: Median Language – NIHSS scores of the IA, IV and 18 control groups were (3 – 3); 2.5 (1 – 3) and (3 – 3), respectively; p>0.05 - Table 3.29: The volume of cerebral infarction (mL) improved (compared to time T0) on MRI of the IV, IA and control groups were: 20.3 (-3.3–73.9); 6.4 (-9.1–38.8) and 71.9 (27.3–86.7), respectively, the difference was not statistically significant 3.3.2 12 months after cerebral infarction (T12) Figure 3.7 Percentage of mRS score ≤ in the IV, IA and control groups at T12 compared to T6 and T0 - Figures 3.6 - 3.7 and Table 3.30: The rate of mRS ≤ in the IA group was higher than the control group (23.3% vs 9.7%; p>0.05) The IV group had this rate lower than the control group (6.9% vs 9.7%; p>0.05) - Figures 3.8 – 3.9 and Table 3.1: BI scores, improved BI scores and the proportion of patients achieving BI scores ≥ 90 of the IV and IA groups were all higher than the control group, but not statistically significant with p> 0.05 - Table 3.32-33: Proportion of patients achieving Motor ArmNIHSS points in the IA group (34.5%) and the IV group (7.4%) compared to the control group (21.4%), p>0.05 The rate of BRS-H ≥ IV in the IA group (34.5%) was higher than the control group (17.9%), p>0.05 Table 3.34: The rate of Language - NIHSS points in the IA 19 group was higher than that in the control group (16.7% compared to 0%; with p>0.05) 3.3.3 The relationship between effectiveness outcomes and the timing of BMSC infusion and the dose of BMSCs 3.3.3.1 The IA group a Relationship with the timing of BMSC infusion - Table 3.35: At T6: the rate of mRS ≤ in the subgroup ≤ 13 days was higher than the subgroup ≥ 14 days (36.4% vs 20%; p>0.05) The ≤ 13 days subgroup had a higher median value of total BI score and the proportion of patients achieving BI scores ≥ 90 than those in the ≥ 14 days subgroup, p0.05 Figure 3.10 Correlation between BI score at T6 and the time of BMSCs infusion in the IA group - Table 3.36: At T12, the proportion of patients with mRS≤2 in the subgroup ≤13 days was higher than that in the subgroup ≥14 days (p>0.05) The ≤13 days subgroup had a higher percentage of patients achieving a BI score ≥90 than that in the ≥14 days subgroup, p0,05) NIHSS ≥ was selected as an inclusion criterion as patients with NIHSS ≤ tend to recover spontaneously early in the first months of stroke (Adams H P 1999) 4.1.1.2 Infusion timing and intravenous BMSC dose a IV Infusion timing (time from the stroke onset to stem cell infusion): BMSC infusion was performed at subacute stage for the following reasons: (1) endogenous neurogenic activity is strongest during the first 1-2 weeks of cerebral infarct; and some preliminary clinical studies reported a tendency to improve neurological function after IV 21 BMSC infusion at subacute stage of stroke such as Bhatia V (2018), Taguchi A (2015); (2) To avoid confounding factors due to the spontaneous recovery or severe complications caused by cerebral edema often occuring in the first days after stroke; (3) The effectiveness of current pharmacotherapy is limited in the subacute stage of cereberal infarction b Intravenous BMSC dose: The dose of BMSCs used in IV group was high (compared to Prasad K (2014), but still lower than the dose being used in Savitz S.I ’s research (2011) (10 x 106 cells/kg) and no serious adverse event was recorded in these two studies According to Moniche F (2016), the rate of mRS ≤ at months after infusion in high dose group (> 3.1 x 108 mononuclear cells) was higher than in the low dose group (0.05) a IA Infusion timing: The median time from onset to stem cell infusion in IA group was 17 days, the earliest was days and the latest was 37 days Most other clinical trials also chose the timepoint of stem cell infusion after the 7th day from stroke onset, including V Bhatia (2018): - 15 days; Savitz, S.I (2019): 13 – 19 days b IA BMSC dose: BMSC dose was used in IA group at >3.1x108 cells, and collected bone marrow volume was 240 mL Bhatia V (2018) used BMSC dose of 6.1x108 cells; IBIS trial (2023) used dose of 5x106 cells per kg 4.1.3 Baseline characteristics of IV group compared to IA group 22 There were no statistical differences between the IV group and control group on baseline characteristics at T0 timepoint, including age, sex and clinical scores and infarct volume on MRI 4.2 SAFETY OUTCOMES 4.2.1 Safety outcomes of IV group 4.2.1.1 Short-term AEs - Peri-bone marrow aspiration procedure AEs: safe, risk of bleeding complication was low IA BMSC infusion related - AEs: safe, Taguchi A (2015) and Vahidy F S (2019) reported similar results - AEs after BMSC infusion until discharge: patients in the IV group had fever lasting and days, respectively, with mild fever (0.05 Cases of death had the following characteristics: far from the timepoint of stem cell infusion (after discharge), causes were determined to be recurrent ischemic stroke or underlying diseases No cancer-related events were recorded Jaillard A (2020) and Lee J S (2011) reported similar results 4.2.2 Safety outcomes of IA group 4.2.2.1 Short–term AEs - No AEs relating to the bone marrow aspiration procedure were observed - No AEs relating to the IA BMSC infusion procedure were observed Moniche F (2023) reported similar result Guzman R (2018): Microvascular embolism events rarely occur in BMSCs, but higher risks in MSCs due to the large size of these cells (25 μm) 4.2.1.2 Long-term AEs 23 - At T6 and T12 timepoint: seizures, recurrent stroke, death (due to any cause) occured in several cases There was no difference in the rate of adverse events between the IA group and the control group with p>0.05 Cases of death had the following characteristics: far from the timepoint of stem cell infusion (after discharge), causes were determined to be recurrent ischemic stroke or underlying diseases Guzman R (2018) and Chumnanvej S (2020) reported similar results 4.2.3 Comparison of safety between IV group and IA group In comparison with the IV group, the IA group had a lower rate of AEs at both months (9.7% vs 19.4%) and at 12 months (16.6% vs 37.9%) (p>0.05) This result was consistent with Fauzi AA’s research 4.3 EFFICACY OUTCOMES 4.3.1 IV group IV group had improved BI score at T6 better than that in the control group The primary outcome and other secondary outcomes were not satistically different compared to the control group Bhasin A (2013) reported similar result 4.3.2 IA group 4.3.2.1 At months after ischemic stroke (T6) a Primary outcome: The proportion of patients achieving mRS ≤2 in the IA group was higher than in control group, the difference was not statistical (25.8% vs 6.9%, p=0.08) Moniche F (2012) reported similar result (mRS score ≤ 2: 20% in IA group vs 0% in the control group; and Bhatia V (2018): 80% vs 40%, p=0.068) b Secondary outcomes: Both NIHSS and BI scores tended to improve better in the IA group, however only the BI score had a statistically significant difference compared to the control group Chumnanvej S (2020): IA stem cell infusion improved NIHSS score at months after stroke Other authors did not evaluate upper limb motor improvement, but mainly relied on scales like mRS, NIHSS, BI The infarct volume at 24 T6: there was no difference between IA group and the control group (p>0.05) IBIS trial (2023) reported similar result 4.3.2.2 At 12 months after ischemic stroke (T12) Efficacy tended to be better in IA group, but the difference is not statistically significant compared to control group 4.3.3 IV group vs IA group The efficacy outcomes tended to improve better in the IA group According to Zhang HL (2018) (experimental study): Intra-arterial BMSC infusion is more effective (shown by microscopic neurological function and microscopic evidence of neurogenesis) 4.3.4 Association between efficacy outcomes and the timepoint of BMSCs infusion and BMSC dose 4.3.4.1 The timing of BMSCs infusion - IA group: The BI score at T6 had a moderate negative correlation with the timing of infusion The rate of patient achieving BI ≥ 90 in the "≤ 14 days subgroup” was better than that in the "≥ 14 days subgroup" There was no association or correlation in IV group According to Kasahara Y (2017): the endogenous neurogenesis process is the strongest within the first 14 days after ischemic stroke Several paracrine factors that play a crucial role in the endogenous angiogenesis and endogenous neurogenesis mechanisms of BMSCs tend to decrease after the first 1-2 weeks of stroke Experimental research on the timing of infusion: with the IV route, according to AV Dos Santos (2010), the therapy was ineffective if infused at day 14 and 28 after stroke With the IA route, Makkiyah F (2021) reported the therapy was still effective when administered at day 28 4.3.4.2 BMSC dose The BI score at T6 was a secondary outcome that improved with statistical significance in both the IV and IA groups, compared to the control group However there was no correlation between the BI score and the dose of BMSCs used in each group According to Moniche F (2016), the rate of patients achieving mRS ≤ at months after 25 infusion in the high dose group (> 3.1x108 cells) is significantly higher than the low dose group (< 3.1x108 cells) (18.2% vs 4.5%; p=0.009) In our study, the proportion of patients receiving a dose of ≥ 3.1x10 cells was 77.4% in the IA group and 81.2% in the IV group Currently, the optimal doses are still not determined Ghali AA (2016) using dose of 1x106 cells reported negative outcome, while RECOVER-Stroke trial (2019) with the dose of 3.08×106 cells had similar outcome 4.4 STRENGTHS AND LIMITATIONS OF THIS STUDY Strength: this is the fist clinical trial using stemcells in treatment of stroke in Vietnam However, the study has limitations: (1) This is an open-label study; (2) While rehabilitation were recommended to all patients from discharge until the end of the study period, it is difficult to control the homogeneity of rehabilitation in patients of different groups in terms of exercises, quality and duration, that virtually all other trials with outpatient monitoring have encountered CONCLUSION Objective Evaluation of safety Intravenous autologous BMSCs infusion and intra-arterial autologous BMSCs infusion in the treatment of MCA infarction were safe during follow-up period of the study Objective Evaluation the efficacy a Intravenous autologous BMSCs infusion: Except for the BI score improvement at months after stroke, which was higher in the IV group (with statistical significance) than the control group, there was no significant difference between the IV group and the control group in terms of the primary outcome (percentage of patients with mRS ≤ 2) and other secondary outcomes (NIHSS score, Motor Arm-NIHSS, BRS-H and Language-NIHSS, infarct volume on MRI) at both months and 12 months after stroke b Intra-arterial autologous BMSCs infusion: 26 - IA autologous BMSCs infusion have a tendency to improve neurological function (not statistically significant) in the treatment of MCA infarction - The percentage of patients achieving BI score ≥ 90 at T6 and T12 in the patient subgroup which received BMSCs at ≤ 13 days after stroke onset was statistically significantly higher than the patient subgroup which received BMSCs infusions at ≥ 14 days - BI score at months after stroke has a moderate, negative correlation with the timing of BMSC infusion (time from the stroke onset to BMSCs timepoint) SUGGESTIONS - More research is needed with longer-term follow-up and evaluation of safety and efficacy of autologous BMSC infusion in the treatment of ischemic stroke - Further research is needed to optimize key factors that have an impact on the efficacy of BMSCs in the treatment of ischemic stroke LIST OF PUBLISHED ARTICLES Le VC, Nguyen NH, Le SH (2021) Intra-arterial infusion of autologous bone marrow mononuclear cells combined with intravenous injection of cerebrolysin in the treatment of middle cerebral artery ischemic stroke: Case report SAGE Open Medical Case Reports doi:10.1177/2050313X211002313 VienL C., TuyenN V., KhaiL T., ToanL Đinh, TruongH X., SongL H., & NgocN H (2023) Significant improvement of Barthel index scores in patients with subacute middle cerebral artery infarct after intravenous autologous bone marrow-derived stem cells infusion Journal of 108 - Clinical Medicine and Phamarcy, 17(TA) VienL C., TuyenN V., KhaiL T., ToanL D., TruongH X., TuyenN T., SongL H., & NgocN H (2023) Safety and efficacy of internal carotid artery infusion of autologous bone marrowderived stem cells in subacute middle cerebral artery infarct Journal of 108 - Clinical Medicine and Phamarcy, 17(TA)