Assessment of the Role of NOGO Gene Block in Enhancing the Neuro-regenerative Effect of Mesenchymal Stem Cells.

Abstract Background: Amyotrophic Lateral Sclerosis (ALS) is a fatal disease. Mesenchymal stem cells (MSCs) have a therapeutic potential in neuronal diseases, factors as NOGO-A limit axonal regeneration. In this study, gene silencing was used to suppress Nogo-A expression in MSCs to enhance its neuro-regenerative role. Methods: mouse models of motor neuron degeneration were created, effect of non-modified and plasmid transfected MSCs were studied clinically and histologically. Group 1 received no treatment. Group 2 received IV injection of non modified MSCs and sacrificed after 8 days (subgroup 2a) and 15 days (subgroup 2b) following treatment, Group 3 received IV injection of transfected MSCs and were sacrificed after 8 days (subgroup 3a) and 15 days (subgroup 3b) following treatment. Results: A significant increase in weight and motor scores of subgroups 2a & 2b occurred in comparison to subgroups1a & 1b respectively (p values <0.001, <0.001, 0.001 & 0.026 respectively), GAP43 expression in group 2 mice was significantly higher compared to group 1 mice (p value <0.001). Deformed neurons and glial cells in group 2 were significantly lower compared to group 1 mice (p value <0.001). Deformed neurons and glial cells in subgroup 2b were significantly less in comparison to subgroup 2a (p values = 0.002 and 0.03) indicating an improvement with time. GAP43 in subgroup 2b was significantly higher compared to subgroup 2a (p value = 0.030).Weight and motor power in group 3 mice was significantly higher when compared to group 1 on days; 14 and 21 (p values <0.001, <0.001, <0.001 and 0.008) respectively. Deformed neurons and glial cells in group 3 mice were significantly lower when compared to group 1 mice (p values <0.001). GAP43 expression in group 3 mice was significantly higher when compared to group1 (p value <0.001). Deformed neurons in subgroup 3b was significantly less than subgroup 3a (p value <0.001). GAP43 expression in group 3 mice was significantly increased when compared to group 2 mice (p value <0.001).Conclusion: NOGO-A gene SiRNA is a potential enhancer of the neuro-regenerative action of MSCs.

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Umbilical Cord Blood Mesenchymal Stem Cells as an Infertility Treatment for Chemotherapy Induced Premature Ovarian Insufficiency

Biomedicines ◽

10.3390/biomedicines7010007 ◽

2019 ◽

Vol 7 (1) ◽

pp. 7 ◽

Cited By ~ 10

Author(s):

Sara Mohamed ◽

Shahinaz Shalaby ◽

Soumia Brakta ◽

Lelyand Elam ◽

Amro Elsharoud ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Treatment Group ◽

Cord Blood ◽

Umbilical Cord Blood ◽

Serum Levels ◽

Ovarian Insufficiency ◽

Group 3 ◽

Group 2 ◽

Group 1

Background: Premature ovarian insufficiency (POI) is a challenging disease, with limited treatment options at the moment. Umbilical cord blood mesenchymal stem cells (UCMSCs) have demonstrated promising regenerative abilities in several diseases including POI. Materials and Method: A pre-clinical murine case versus vehicle control randomized study. Two experiments ran in parallel in each of the three groups. The first was to prove the ability of UCMSCs in restoring ovarian functions. The second was to prove improved fertility. A total of 36 mice were randomly assigned; 6 mice into each of 3 groups for two experiments. Group 1 (control), group 2 (sham chemotherapy), group 3 (stem cells). Results: In the first experiment, post-UCMSCs treatment (group 3) showed signs of restored ovarian function in the form of increased ovarian weight and estrogen-dependent organs (liver, uterus), increased follicular number, and a significant decrease in FSH serum levels (p < 0.05) compared to group 2, and anti-Mullerian hormone (AMH) serum levels increased (p < 0.05) in group 3 versus group 2. Immuno-histochemistry analysis demonstrated a higher expression of AMH, follicle stimulating hormone receptor (FSHR) and Inhibin A in the growing follicles of group 3 versus group 2. In the second experiment, post-UCMSCs treatment (group 3) pregnancy rates were higher than group 2, however, they were still lower than group 1. Conclusion: We demonstrated the ability of UCMSCs to restore fertility in female cancer survivors with POI and as another source of stem cells with therapeutic potentials.

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Differentiation of bone marrow derived mesenchymal stem cells into male germ-like cells in co-culture with testicular cells

Endocrine Regulations ◽

10.2478/enr-2019-0011 ◽

2019 ◽

Vol 53 (2) ◽

pp. 93-99

Author(s):

Nasim Malekmohamadi ◽

Alireza Abdanipour ◽

Mehrdad Ghorbanlou ◽

Saeed Shokri ◽

Reza Shirazi ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Treatment Group ◽

Mouse Bone Marrow ◽

Testicular Cells ◽

Morphogenetic Protein ◽

Group 2 ◽

Group 1

AbstractObjective. Stem cell therapy, specifically, pre-induction of mesenchymal stem cells toward male germ-like cells may be useful in patients with azoospermia. The aim of this study was to evaluate in vitro differentiation of mouse bone marrow-derived mesenchymal stem cells (BMSCs) into male germ-like cells by indirect co-culture with testicular cells in the presence of bone morphogenetic protein 4 (BMP4).Methods. Experimental groups included: control (mouse BMSCs), treatment group-1 (BMSCs treated with BMP4), treatment group-2 (indirect co-culture of BMSCs with mouse testicular cells in the presence of BMP4) and treatment group-3 (indirect co-culture of BMSCs with testicular cells). BMSCs-derived male germ-like cells were evaluated by the expression of Dazl, and Stra8 using RT-qPCR.Results. Stra8 gene expression was significantly increased in the treatment group-2 and Dazl gene was significantly increased in the treatment group-1 compared to other groups. In conclusion, indirect co-culturing of BMSCs with testicular cells and BMP4 leads to the differentiation of BMSCs into male germ-like cells which express specific male germ-like genes. Testicular cells released factors that contributed to the differentiation of BMSCs into male germ progenitor cells.Conclusion. This study suggests that mesenchymal stem cells may be differentiated into male germ-like cells and therefore, may be a novel treatment option for men with azoospermia.

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Management of toxic optic neuropathy via a combination of Wharton’s jelly-derived mesenchymal stem cells with electromagnetic stimulation

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02577-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Emin Özmert ◽

Umut Arslan

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Optic Neuropathy ◽

Electromagnetic Stimulation ◽

Toxic Optic Neuropathy ◽

Delta Change ◽

Group 3 ◽

The Mean ◽

Group 2 ◽

Group 1

Abstract Purpose To investigate the effect of the combination of Wharton's jelly derived mesenchymal stem cells (WJ-MSC) and high frequency repetitive electromagnetic stimulation (rEMS) in the therapy of toxic optic neuropathies with severe symptoms after the available current therapy modalities which were unsucessful. Material and methods This prospective, open-label clinical phase-3 study was conducted at Ankara University Faculty of Medicine, Department of Ophthalmology between April 2019 and April 2021. Thirty-six eyes of 18 patients with toxic optic neuropathy (TON) were included in the study. Within 1–3 months after the emergency interventions, patients with various degrees of sequela visual disturbances were studied in this clinical trial. The cases were divided into three groups according to similar demographic characteristics. Group 1: Consists of 12 eyes of 12 patients treated with the WJ-MSC and rEMS combination in one eye. Group 2: Consists of 12 eyes of 12 patients treated with only rEMS in one eye. Group 3: Consists of 12 eyes of six patients treated with only WJ-MSC in both eyes. The course was evaluated by comparing the quantitive functional and structural assessment parameters measured before and at the fourth month of applications in each group. Results The mean best corrected visual acuity (BCVA) delta change percentages of the groups can be ranked as: Group 1 (47%) > Group 3 (32%) > Group 2 (21%). The mean fundus perimetry deviation index (FPDI) delta change percentages of the groups can be ranked as: Group 1 (95%) > Group 2 (33%) > Group 3 (27%). The mean ganglion cell complex (GCC) thickness delta change (decrease in thickness) percentages can be ranked as: Group 1 (− 21%) > Group 3 (− 15%) > Group 2 (− 13%). The visual evoked potential (VEP) P100 latency delta change percentages of the groups can be ranked as: Group 1 (− 18%) > Group 3 (− 10%) > Group 2 (− 8%). The P100 amplitude delta change percentages of the groups can be ranked as: Group 1 (105%) > Group 3 (83%) > Group 2 (24%). Conclusion Toxic optic neuropathies are emergent pathologies that can result in acute and permanent blindness. After poisoning with toxic substances, progressive apoptosis continues in optic nerve axons and ganglion cells. After the proper first systemic intervention in intensive care clinic, the WJ-MSC and rEMS combination seems very effective in the short-term period in cases with TON. To prevent permanent blindness, a combination of WJ-MSC and rEMS application as soon as possible may increase the chance of success in currently untreatable cases. Trial Registration ClinicalTrials.gov ID: NCT04877067.

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Adipose-derived Mesenchymal Stem Cells Improve the Healing of Tracheoesophageal Fistula in a Beagle Model

10.21203/rs.3.rs-146858/v1 ◽

2021 ◽

Author(s):

Yuchao Wang ◽

Shifang Yang ◽

Pingping Chen ◽

Hanyi Xu ◽

Jinghua Cui ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tracheoesophageal Fistula ◽

Saline Water ◽

Clinical Problem ◽

Endoscopic Observation ◽

Volume Group ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Background Tracheoesophageal fistula (TEF) is still a devastating clinical problem with high mortality. New clinical strategies were developed to sustain survival time. Mesenchymal stem cells were applied in many clinical wound healing fields. This study aims to investigate the main effect of stem cell to TEF.Material and Method We established a beagle model with TEF by punching the trachea and esophagus membrane and suturing. The beagles were divided into three groups (group 1 = 1, group 2 = 6, group 3 = 6). Group 2 and 3 received a TEF building operation. Group 3 were injected 2 ml stem cells (106 per animal), and group 2 injected saline water with same volume. Group 1 did not receive any intervention. All animals receipted total parental nutrition. The closure degree of fistula tissue was observed by bronchoscope and post-mortem after 35 d.Result Morphologic and histopathologic changes of fistulas were assessed by gross and endoscopic observation. The fistulas diameter was measured. In 35 d postoperatively, group 2 showed that 3 animals died for acute smother, 2 animal died for severe chronic pneumonia and 1 animal with consistent fistula. Group 3 showed that 2 animals fully closed, 3 animals fistula diameter significantly decreased, and 1 animal died for acute smother. In autopsy result, group 2 animals showed severer pneumonia degree than group 3 animals in 35 d.Conclusion The transplantation of stem cells can promote healing degree of TEF without any complications and relieve pneumonia at the same time.

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Young people's lifestyle and frequency of physical activity – an original study

Pomeranian Journal of Life Sciences ◽

10.21164/pomjlifesci.681 ◽

2020 ◽

Vol 66 (4) ◽

pp. 54-60

Author(s):

Barbara Janota ◽

Elżbieta Szczepańska ◽

Karolina Janion

Keyword(s):

Physical Activity ◽

Positive Impact ◽

High Rate ◽

P Value ◽

Daily Consumption ◽

Unhealthy Lifestyle ◽

School Students ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Introduction A healthy lifestyle, including healthy eating, frequent physical activity, abstention from recreational substances, appropriate amounts of sleep and restricted amounts of television and computer time have a positive impact on the development and health of adolescents. The aim of the study was to assess selected aspects of adolescent lifestyle with a focus on rates of physical activity. Materials and methods The study material included a questionnaire completed by 304 secondary school students. The answers were analysed with respect to the physical activity of the respondents and then grouped accordingly: group 1 consisted of respondents with a low rate of physical activity, group 2 with a moderate rate of physical activity and group 3 with a high rate of physical activity. Differences in the the percentages of healthy behaviour the groups engaged in was assessed using the Kruskal–Wallis ANOVA on ranks test. Post hoc, a 2-way test with Bonferroni correction was performed. A p value of <0.05 was considered statistically significant for all analyses. Results The recommended number of 4–5 meals a day is consumed mostly by individuals from group 2 (52.94%) and to the least extent by those in group 1 (47.17%). The recommended daily consumption of fruit is mostly reported by respondents from group 3 (39.34%) and the least, by those from group 1 (26.42%). Subjects from group 2 are least likely to drink alcohol, which is harmful for one's health (26.47%); this group also includes the largest number of individuals who do not smoke cigarettes (69.12%). The most favorable behaviour with regards to sleep is displayed by subjects from group 3, in which 10.38% of participants slept for the recommended 8–10 h a day. Conclusions The majority of adolescents, regardless of the frequency of physical activity they undertook, had an unhealthy lifestyle. The most favourable lifestyle was led by subjects who performed physical activity between once a week and a few times a month.

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Abstract 14551: Biomarkers Predicting the Treatment-Resistant Kawasaki Disease

Circulation ◽

10.1161/circ.142.suppl_3.14551 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Yukako Yoshikane ◽

Ryuji Fukazawa ◽

Kyoko Imanaka-yoshida ◽

Naho Kobayashi ◽

Yasuhiro Katsube

Keyword(s):

Treatment Group ◽

Kawasaki Disease ◽

Predictive Value ◽

Scoring Systems ◽

Line Treatment ◽

Treatment Resistant ◽

Cutoff Value ◽

Group 3 ◽

Group 2 ◽

Group 1

Introduction: Kawasaki disease (KD), which is the most common multisystem vasculitis with unknown causes in childhood, causes coronary artery lesions (CALs). Treatment with a high dose of intravenous immunoglobulin (IVIG), plus steroids if needed, is the most effective therapy for the acute phase of KD. However, there are some very severe cases who need several times additional treatments and are at risk for CALs. In Japan, there are some scoring systems that initially predict IVIG-resistant patients. However, the problem is that these scoring systems fail in multiethnic populations. The aim of this study is to find universal biomarkers that predict treatment-resistant cases of KD. Methods: The subject was 276 KD patients, including Group 1 (n=214) who needed only 1 st line treatment, Group 2 (n=48) who needed 2 nd line treatment, Group 3 (n=14) who needed 3 rd line treatment or more. Tenascin C (TN-C), Pentraxin 3 (PTX3) and Procalcitonin (PCT) values, which were selected by systematic review, were measured before initial treatment in each group. Results: TN-C; 99.8±41.05 ng/ml in Group 1, 118.0±71.4 ng/ml in Group 2 and 183.0±25.0 ng/ml in Group 3. The TN-C level of Group 3 was significantly higher than that of all the others (p<0.01). The cutoff value for distinguishing Group 3 was 142.0 ng/ml (Area under the Curve (AUC)=0.81). PTX3; 16.2±9.0 ng/ml in Group 1, 31.4±19.7 ng/ml in Group 2 and 58.0±33.0 ng/ml in Group 3. The PTX3 level of Group 3 was significantly higher than that of all the others (p<0.01). The cutoff value for distinguishing Group 3 was 35.1 ng/ml (AUC=0.86). PCT; 0.79±0.77 ng/ml in Group 1, 2.55±3.01 ng/ml in Group 2 and 4.15±4.49 ng/ml in Group 3. The PCT level of Group 3 was significantly higher than that of all the others (p<0.01). The cutoff value for distinguishing Group 3 was 2.55 ng/ml (AUC=0.88). When those three biomarkers combined, Group 3 can be predicted with the sensitivity 79%, the specificity 96%, the positive predictive value 50% and the negative predictive value 99%. Conclusions: It may be possible to predict treatment-resistant KD cases with high sensitivity and specificity by combining the measurement from the universal biomarkers, TN-C, PTX3 and PCT, before initial treatment.

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The effect of hGH on hypothalamic-pituitary-thyroid function in patients with pituitary dwarfism

Acta Endocrinologica ◽

10.1530/acta.0.0930013 ◽

1980 ◽

Vol 93 (1) ◽

pp. 13-19 ◽

Cited By ~ 14

Author(s):

Reiko Demura ◽

Hajime Yamaguchi ◽

Ichiji Wakabayashi ◽

Hiroshi Demura ◽

Kazuo Shizume

Keyword(s):

Treatment Group ◽

Thyroid Function ◽

Half Life ◽

Good Growth ◽

Normal Range ◽

Pituitary Dwarfism ◽

Group 3 ◽

Group 2 ◽

Symptoms And Signs ◽

Group 1

Abstract. The effect of growth hormone (hGH) on the hypothalamic-pituitary-thyroid function was studied in patients with pituitary dwarfism. Twenty-six patients were given KABI hGH, 0.5 U/kg/week, for a period of 4—18 months. Three groups of patients were identified according to their T4 levels before and during the treatment. Group 1: T4 levels were initially normal and stayed in the normal range throughout a course of treatment. Group 2: T4 levels were initially normal but dropped to the subnormal range after hGH. Group 3: T4 levels were initially subnormal and decreased further after hGH. Changes in T4 levels after hGH in groups 2 and 3 were accompanied by a decrease in plasma T3RSU without concomitant decrease in plasma T3. Clinically, most of them lacked symptoms and signs of hypothyroidism and exhibited a good growth response to hGH. Plasma TSH response to TRH in these patients revealed a sustained delayed pattern, which was suggestive of hypothalamic hypothyroidism. This pattern of TSH response to TRH became further exaggerated after hGH therapy. In contrast, TSH response to TRH among patients in group 1 was normal and was not influenced by hGH. Administration of 4.0 U of KABI hGH daily for 21 consecutive days to 3 patients resulted in a shortened half-life of T4 and inversely prolonged that of T3. These results suggest that various degrees of TRH deficiency exist among patients with idiopathic pituitary dwarfism. Therapy with hGH discloses a mild TRH deficiency by accelerating the half-life of T4. This also causes a further drop in the T4 levels in those with marked TRH deficiency. The development of clinical hypothyroidism is not so obvious in these patients because of inverse delay in half-life of T3 by hGH.

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Mobilization of Stem Cells from the Bone Marrow Is Required for Neovascularization of Ischemic Limbs in Mice.

Blood ◽

10.1182/blood.v106.11.4233.4233 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4233-4233

Author(s):

Jeong-A Kim ◽

Chang -Hoon Lee ◽

Jin-A. Yoon ◽

Woo-Sung Min ◽

Chun-Choo Kim

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hind Limb ◽

Limb Ischemia ◽

Hind Limb Ischemia ◽

Ischemic Limb ◽

Group 3 ◽

Group 2 ◽

Surgically Induced ◽

Group 1

Abstract We examined whether the injection of bone marrow mononuclear cells (BM-MNCs) or mesenchymal stem cells (MSCs) might augment angiogenesis and collateral vessel formation in a mouse model of hind limb ischemia. C57BL/6 BM-MNCs were isolated by centrifugation through a Histopaque density gradient and MSCs were obtained from C57BL/6 bone marrow and cultured in low-glucose DMEM media. Unilateral hind limb ischemia was surgically induced in C57BL/6 mice (control; n=4), and autologous BM-MNCs (Group 1; n=4, 1.8±0.2 x107/animal) or MSCs (Group 2; n=4, 1.0±0.14 x106/animal) or BM-MNCs and MSCs (Group 3; n=4, 2.3±0.1 x107 and 1.1±0.21 x106/animal) were transplanted into the ischemic tissue. Six weeks after transplantation, the group 1, group 2 and group 3 had a higher capillary/muscle ratio (0.82±0.12 vs 0.85±0.08 vs 0.97 ±0.03) than control (0.46±0.12, p<0.05) (Fig. 1). This result suggested that direct local transplantation of autologous BM-MNCs or MSCs seems to be a useful strategy for therapeutic neovascularization in ischemic tissues. Next, we evaluated whether bone marrow derived stem cells were participated in the process of local injected stem cells forming new vessels. In general, mobilizing stem cells from bone marrow to local site, MMP-9 has been known as an important molecule. So we used the MMP-9 deficient KO mice and wild type, 129SvEv mice were used in the experiments. Autologous BM-MNCs and MSCs were transplanted into the ischemic limb in MMP-9 (−/−) (n=4) after unilateral hind limb ischemia was surgically induced and then the same experiments was done in MMP-9 (+/+) mice (n=4). The number of the injected BM-MNCs and MSCs was 2.2±0.05 x107 and 0.87±0.17 x106/animal in MMP-9 (−/−). And the number of the injected BM-MNCs and MSCs was 2.1±0.17 x107 and 0.98±0.09 x106/animal in MMP-9 (+/+). No difference was seen in the BM-MNCs and MSCs were injected or not (0.52±0.07 vs 0.49±0.03,) in MMP-9 (−/−). But, in the case that BM-MNCs and MSCs were injected, the higher capillary/muscle ratio was seen in MMP-9 (+/+) compared to control (0.86 ±0.09 vs 0.49±0.03, P<0.05) (Fig 2). This data indicated that the mobilization of bone marrow derived stem cells would have an important role in the neovasculrization although the stem cells were injected directly into the muscle of ischemic limb. Figure Figure Figure Figure

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Platelet Function and Activation in Patients with Immune Thrombocytopenia Treated with Eltrombopag: Comparison with Steroid-Treated and Untreated Patients,

Blood ◽

10.1182/blood.v118.21.3280.3280 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3280-3280

Author(s):

Johanna Haselboeck ◽

Alexandra Kaider ◽

Ingrid Pabinger ◽

Simon Panzer

Keyword(s):

Platelet Count ◽

Treatment Group ◽

Prospective Study ◽

Platelet Function ◽

Immune Thrombocytopenia ◽

Steroid Treatment ◽

Group 3 ◽

Group 2 ◽

Group 1 ◽

Normally Distributed

Abstract Abstract 3280 Background: Eltrombopag has recently been approved for treatment in immune thrombocytopenia (ITP). Studies on platelet function in eltrombopag-treated patients in comparison to steroid-treated or untreated ITP patients are not available. Objectives: To assess the function of eltrombopag-induced platelets, we compared platelets from eltrombopag-treated patients to those from ITP patients treated with steroids and a group of patients without treatment in a prospective study (ClinicalTrials.gov number NCT00888901). Patients/Methods: We compared platelet function in patients treated with eltrombopag after treatment-induced platelet rise (group 1) to those under steroid treatment (group 2) and ITP patients without treatment (group 3) in a non-randomized prospective study. Platelet function was assessed by adhesion under high shear conditions (surface coverage, SC), P-selectin expression, and formation of platelet-monocyte aggregates (PMA) after treatment induced platelet rise or, in group 3, in patients with ITP without treatment and platelet count between 50–100×109/L at the time of inclusion. Data are given as median [quartiles]. Correlations of the outcome measures are described by the Spearman correlation coefficient. In case of normally distributed data, analysis of variance (ANOVA) and of covariance (ANCOVA) models and in case of non-normally distributed parameters the nonparametric Kruskal-Wallis test were used to compare the groups Results: Eleven patients (female=9) were included in the treatment group with eltrombopag (group 1), thirteen (female=5) in the steroid treatment (group 2) and 6 patients as untreated controls (group 3). None of these patients developed severe bleeding during the study period, none received rescue medication. Four/30 patients were not included in the final analysis, three because they had no treatment induced platelet rise (1 on eltrombopag and 2 on steroids) and 1 because of aspirin medication. Thus, ten patients on eltrombopag, ten patients on steroid treatment and 6 untreated patients were evaluated in the comparative analyses of platelet function. Platelet counts [x109/L] were 48.25 [45.00–59.00] in group 1 after eltrombopag-induced platelet rise, 82.75 [78.50–112.00] in group 2 and 69.25 [65.00–73.00] in group 3. SC was highest in steroid-treated patients (11.25% [8.10–14.00%]) compared to eltrombopag-treated (5.80% [1.80–9.00%]) and untreated (5.03% [3.80–6.20%]) patients and correlated significantly with the platelet count (r=0.72, p<0.0001). There were no differences in P-selectin expression [GeoMFI] (1.15 [0.47–2.77] in group 1, 0.27 [0.10–0.99] in group 2 and 0.59 [0.47–1.44] in group 3; p=0.34) and PMA levels (6.19% [3.91–21.39%] in group 1, 9.73% [1.88–13.29%] in group 2, and 6.56% [4.82–8.43%] in group 3; p=0.93) between the groups. Two patients developed venous thromboses during eltrombopag treatment. No characteristic alteration of platelet function and activation was identified in those 2 patients when compared to the other eltrombopag-treated patients. Conclusions: We proofed a good functional competence of eltrombopag-induced platelets. No substantial hyper-reactivity of eltrombopag-induced platelets in comparison to those of steroid-treated and untreated patients was determined. Disclosures: Pabinger: GlaxoSmithKline: Research Funding, Speakers Bureau. Panzer:GlaxoSmithKline: Speakers Bureau.

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Predictive Value of Minimal Residual Disease: Analysis By Flow-Cytometry in Children with Relapsed Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v126.23.2494.2494 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2494-2494

Author(s):

Myriam Ruth Guitter ◽

Jorge Gabriel Rossi ◽

Elisa Sajaroff ◽

Carolina Carrara ◽

Pizzi Silvia ◽

...

Keyword(s):

Flow Cytometry ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

P Value ◽

Time Points ◽

Group 3 ◽

Group 2 ◽

To Receive ◽

Group 1

Abstract Introduction: Despite the advances observed in the outcome of pediatric acute lymphoblastic leukemia (ALL) treatment during the last 20 years, relapse remains the most common cause of treatment failure in childhood ALL. Several factors have been associated to the prognosis of these patients; however, minimal residual disease (MRD) emerges as a relevant predictor of outcome. Objectives: The aims of this study were to assess MRD by flow-cytometry in relapsed ALL and to evaluate its prognostic impact as a predictor factor of outcome at the end of the induction therapy and prior to hematopoietic stem cell transplantation (HSCT). Patients and Methods: From Aug'10 to Jun'15, 123 ALL patients were treated at our center. MRD determination at least at two time-points during relapse treatment was a requirement for considering a patient eligible for the present study. Sixty-six cases were excluded due to the following causes: 10 patients died during induction, 2 died early in complete remission (CR), 29 did not respond to chemotherapy, in 13 patients MRD determination was not performed: 4 did not have clinical data available, 4 patients were Down Syndrome and 4 children received treatment for relapse in other centers. Thus, fifty-seven patients achieved CR and were evaluated for MRD at two time points. Of them, 56 patients belonged to S4 and S3 and 1 patient to S1 group as defined by the Berlin-Frankfurt-Münster stratification for relapsed ALL. MRD was analyzed by multiparametric flow-cytometry following ALL-IC 2009 guidelines. Negative MRD was defined as disclosing less than 0.1% of blasts. For this analysis, patients were stratified based on MRD levels at two different time points: after end of induction, before HSCT or at any other time point during the follow-up for patients who did not undergo HSCT. Three groups were defined: Group-1: negative at both time points (n= 23), Group-2: positive at 1 time point (n= 13) and Group-3: positive at both time points (n= 21). Patients who relapsed before receiving HSCT were considered Group-3. Twenty-five patients underwent HSCT: 13 of them from Group-1, 9 from Group-2 (2 had positive MRD previous to receive HSCT) and 3 patients from Group-3. HSCT was performed with matched familiar donor in 16 cases and matched unrelated donor in 9 cases. Results: The distribution of events according to receiving or not HSCT was: 5 died due to transplant related mortality (TRM), 9 relapsed after receiving HSCT and 16 during treatment with chemotherapy. With a median follow-up of 16 (range: 6-67) months, overall 3-year EFS probability (EFSp) (SE) was 32 (8)%. The 3-year EFSp was 75 (11)% for Group-1, 24 (14)% for Group-2 and 0% for Group-3 (p-value <0.00001). Comparing patients who did not receive HSCT vs. patients who did, EFSp (SE) was 32 (12)% and 29 (11)% respectively (p-value: non-significant). The EFSp (SE) according to MRD groups in patients who underwent HSCT was: Group-1: 53 (19)%, Group-2: 14 (13)% and 0% for Group-3 (p-value: 0.06). Conclusions: MRD quantification by flow-cytometry demonstrated to be a significant prognostic factor for relapsed ALL. Both, TRM and death in CR rates, were high and should be decreased by improving supportive measures. MRD determination by flow-cytometry in patients who underwent HSCT showed a trend to achieve a better EFSp, thus representing a relevant tool for stratifying relapsed ALL patients in order to achieve a better selection of patients to receive HSCT. Disclosures No relevant conflicts of interest to declare.

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