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Although the survival of children with sickle cell disease (SCD) has dramatically improved over the last decades in the US and Europe, mortality remains high in adults. Moreover, many children and most adults develop a chronic debilitating condition due to organ damage. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the unique curative approach; it allows the cure of more than 95% of children transplanted from a matched related donor (MRD) after a myeloablative conditioning regimen.To date, few studies have addressed the role of HSCT in SCD adults, due to the risk of graft versus host disease (GVHD) and to the toxicity expected in older patients with a higher risk of organ damage. The development of safe, non-myeloablative conditioning regimens that allow stable mixed chimerism and avoid GVHD appears as an attractive option for HSCT to cure adults with severe SCD. The investigators design a prospective multicenter trial targeting patients over 15 years with severe SCD, and compare non-myeloablative transplant (when a matched related donor (MRD) is identified) versus no HSCT (for patients lacking MRD). The main objective is to assess the benefit of HSCT on the 2-year event free survival compared to standard care. The primary endpoint is the 2-year event free survival.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| HLA matched haematopoietic stem cell transplantation | Experimental | Peripheral blood stem cell from matched HLA related donor. |
|
| Control arm | Other | Best standard care : Patients will receive the best standard care according to their situation and their previous treatment: initiation of Hydroxyurea, continuation or optimization of the dose of Hydroxyurea, initiation or continuation of TP, initiation of a new drug proved to improve SCD and having authorization to use in France. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Allogeneic matched related haematopoietic stem cell transplantation | Procedure | Allogeneic matched related haematopoietic stem cell transplantation after a reduced intensity conditioning regimen |
| Measure | Description | Time Frame |
|---|---|---|
| 2 year event-free survival | An event will be defined as :
| 2 years post-inclusion |
| Measure | Description | Time Frame |
|---|---|---|
| Overall survival | 2 years post-inclusion | |
| Number of days requiring hospitalization | Number of days requiring hospitalization at 1 year post-inclusion with exclusion of the 5 first months post-inclusion |
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Inclusion criteria
Exclusion Criteria
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Nathalie Dhedin | Contact | +33142385127 | nathalie.dhedin@aphp.fr | |
| Sylvie Chevret | Contact | +33142499742 | sylvie.chevret@paris7.jussieu.fr |
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| Standard arm | Other | In the standard arm, patients who will not be transplanted, will receive the best standard care according to their situation and their previous treatment: initiation of hydroxyurea, continuation or optimization of the dose of hydroxyurea, initiation or continuation of transfusion program, initiation of a new drug proved to improve SCD and having authorization to use in France |
|
| 1 year |
| Number of days requiring hospitalization | Number of days requiring hospitalization at 2 years post-inclusion with exclusion of the 5 first months post-inclusion | 2 years post-inclusion |
| Number of vaso-occlusive crisis (VOC) requiring hospitalization | 1 year post-inclusion |
| Number of vaso-occlusive crisis (VOC) requiring hospitalization | 2 years post-inclusion |
| Number of acute chest syndrome (ACS) requiring hospitalization | 1 year post-inclusion |
| Number of acute chest syndrome (ACS) requiring hospitalization | 2 years post-inclusion |
| Number of hospitalizations in intensive care unit | 1 year post-inclusion |
| Number of hospitalizations in intensive care unit | 2 years post-inclusion |
| Number of priapism | 1 year post-inclusion |
| Number of priapism | 2 years post-inclusion |
| Number of stroke episodes | 1 year post-inclusion |
| Number of stroke episodes | 2 years post-inclusion |
| LDH count | Changes in LDH | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Percentage of patients with an aminotransferase value higher than five times the normal value | Changes in aminotransferase | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Percentage of patients with a gamma-GT value higher than five times the normal value | Changes in gamma-GT | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Percentage of patients with an Alkaline phosphatase value higher than five times the normal value | Changes in alkaline phosphatase | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Percentage of patients with a bilirubin value higher than three times the normal value | Changes in bilirubin | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Percentage of patients with a prothrombin value less than 70% | Changes in TP | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Activated partial thromboplastin time higher than 1.5 times the normal value | Changes in TCK | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Rate of hemoglobin | Changes in hemoglobin level | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Hematocrit | Changes in hematocrit | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Mean corpuscular volume | Changes in mean corpuscular volume | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Hemoglobin variants | Changes of percentage of hemoglobin variants | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Reticulocyte count | Changes in percentage of reticulocyte | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| White blood cells count | Changes in white blood cells | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Platelets counts | Changes in platelet counts | every 3 months (from inclusion to 24 months) and at Month 1, Month 2 and Month 3 in the transplant arm |
| Microalbuminuria/creatininuria ratio | at 3 months |
| Microalbuminuria/creatininuria ratio | at 6 months |
| Microalbuminuria/creatininuria ratio | at 12 months |
| Microalbuminuria/creatininuria ratio | at 24 months |
| Ferritin level | at 3 months |
| Ferritin level | at 6 months |
| Ferritin level | at 12 months |
| Ferritin level | at 24 months |
| Transferrin saturation level | at 3 months |
| Percentage of transferrin saturation | at 6 months |
| Percentage of transferrin saturation | at 12 months |
| Percentage of transferrin saturation | at 24 months |
| LH count | Gonadic function will be measured using LH | at 24 months |
| FSH count | Gonadic function will be measured using FSH | at 24 months |
| Testosterone count | Gonadic function will be measured using testosterone level in men | at 24 months |
| Spermogram | Gonadic function will be measured using spermogram in men | at 24 months |
| Oestrogen count | Gonadic function will be measured using oestrogen level in women | at 24 months |
| AMH count | Gonadic function will be measured using AMH level in women | at 24 months |
| Incidence of amenorrhea | Gonadic function will be measured using incidence of amenorrhea in women | at 24 months |
| Number of parity | at 24 months |
| Percentage of patients with a proliferative retinopathy | Changes in retinopathy status (appearance, disappearance, improvement, aggravation) | at 12 months |
| Percentage of patients with a proliferative retinopathy | Changes in retinopathy status (appearance, disappearance, improvement, aggravation) | at 24 months |
| Percentage of patients with a hemorrhagic retinopathy | Changes in retinopathy status (appearance, disappearance, improvement, aggravation) | at 12 months |
| Percentage of patients with a hemorrhagic retinopathy | Changes in retinopathy status (appearance, disappearance, improvement, aggravation) | at 24 months |
| Percentage of patients with retinal detachment | Changes in retinopathy status (appearance, disappearance, improvement, aggravation) | at 12 months |
| Percentage of patients with retinal detachment | Changes in retinopathy status (appearance, disappearance, improvement, aggravation) | at 24 months |
| Proportion of patients with keratitis | Changes in retinopathy status (appearance, disappearance, improvement, aggravation) | at 12 months |
| Proportion of patients with keratitis | Changes in retinopathy status (appearance, disappearance, improvement, aggravation) | at 24 months |
| Proportion of patients with uveitis | Changes in retinopathy status (appearance, disappearance, improvement, aggravation) | at 12 months |
| Proportion of patients with uveitis | Changes in retinopathy status (appearance, disappearance, improvement, aggravation) | at 24 months |
| Tricuspid regurgitant jet velocity | Heart function will be assessed by a transthoracic echocardiography and using tricuspid régurgitant jet velocity | at 12 months |
| Tricuspid regurgitant jet velocity | Heart function will be assessed by a transthoracic echocardiography and using tricuspid régurgitant jet velocity | at 24 months |
| Left atrial dimension | Heart function will be assessed by a transthoracic echocardiography using left atrial dimension indexed to body surface | at 12 months |
| Left atrial dimension | Heart function will be assessed by a transthoracic echocardiography using left atrial dimension indexed to body surface | at 24 months |
| Left ventricular dimension | Heart function will be assessed by a transthoracic echocardiography using left ventricular dimension indexed to body surface | at 12 months |
| Left ventricular dimension | Heart function will be assessed by a transthoracic echocardiography using left ventricular dimension indexed to body surface | at 24 months |
| Ventricular mass index value | Heart function will be assessed by a transthoracic echocardiography using ventricular mass index | at 12 months |
| Ventricular mass index value | Heart function will be assessed by a transthoracic echocardiography using ventricular mass index | at 24 months |
| Left ventricular ejection fraction | Heart function will be assessed by a transthoracic echocardiography using left ventricular ejection fraction | at 12 months |
| Left ventricular ejection fraction | Heart function will be assessed by a transthoracic echocardiography using left ventricular ejection fraction | at 24 months |
| Forced Expiratory Volume in one second (FEV) | Lung function will be evaluated Forced Expiratory Volume in one second (FEV) , % | at 12 months |
| Forced Expiratory Volume in one second (FEV) | Lung function will be evaluated Forced Expiratory Volume in one second (FEV) , % | at 24 months |
| DLCO | Lung function will be evaluated using DLCO the diffusion capacity of carbon monoxide | at 12 months |
| DLCO | Lung function will be evaluated using DLCO the diffusion capacity of carbon monoxide | at 24 months |
| Forced vital capacity | Lung function will be evaluated using forced vital capacity (FVC) | at 12 months |
| Forced vital capacity | Lung function will be evaluated using forced vital capacity (FVC) | at 24 months |
| 6 minutes walk test | Lung function will be evaluated using 6 minutes walk test | at 12 months |
| 6 minutes walk test | Lung function will be evaluated using 6 minutes walk test | at 24 months |
| Number of new episodes of avascular osteonecrosis | at 24 months |
| Number of patients for each location of new episodes of avascular osteonecrosis | Location of new episodes of avascular osteonecrosis will be assessed using radiography and magnetic resonance imaging | at 24 months |
| Fractures | Number of new episodes of fractures | at 24 months |
| Central nervous system function | Central nervous system function will be assessed using magnetic resonance Imaging with ARM/MRI | at 12 months |
| Central nervous system function | Central nervous system function will be assessed using magnetic resonance Imaging with ARM/MRI | at 24 months |
| Iron overload | Iron overload will be assessed using liver and heart magnetic resonance Imaging in patients with ferritin > 1000 microg/L | at inclusion |
| Iron overload | Iron overload will be assessed using liver and heart magnetic resonance Imaging in patients with ferritin > 1000 microg/L | at 12 months |
| Iron overload | Iron overload will be assessed using liver and heart magnetic resonance Imaging in patients with ferritin > 1000 microg/L | at 24 months |
| Red blood cell packed transfused | Number of red blood cell packed transfused from 6 months post-inclusion (pre and early post-transplant transfusion are a standard of care and may not be counted) | at 24 months |
| Number of delayed hemolytic transfusion reaction (DHTR) | DHTR will be defined as associated with hemoglobinuria/dark urine in the month following transfusion +/- bone pain with increased hemolytic markers and drop in HbA or new RBC allo-Ab | at 3 months |
| Number of delayed hemolytic transfusion reaction (DHTR) | DHTR will be defined as associated with hemoglobinuria/dark urine in the month following transfusion +/- bone pain with increased hemolytic markers and drop in HbA or new RBC allo-Ab | at 6 months |
| Number of delayed hemolytic transfusion reaction (DHTR) | DHTR will be defined as associated with hemoglobinuria/dark urine in the month following transfusion +/- bone pain with increased hemolytic markers and drop in HbA or new RBC allo-Ab | at 12 months |
| Number of delayed hemolytic transfusion reaction (DHTR) | DHTR will be defined as associated with hemoglobinuria/dark urine in the month following transfusion +/- bone pain with increased hemolytic markers and drop in HbA or new RBC allo-Ab | at 24 months |
| Proportion of patients with new RBC alloantibodies | New RBC alloantibodies will be assessed using blood test | at 3 months |
| Proportion of patients with new RBC alloantibodies | New RBC alloantibodies will be assessed using blood test | at 6 months |
| Proportion of patients with new RBC alloantibodies | New RBC alloantibodies will be assessed using blood test | at 12 months |
| Proportion of patients with new RBC alloantibodies | New RBC alloantibodies will be assessed using blood test | at 24 months |
| Percentage of patients with an oral opioid consumption | at 3 months |
| Percentage of patients with an oral opioid consumption | at 6 months |
| Percentage of patients with an oral opioid consumption | at 12 months |
| Percentage of patients with an oral opioid consumption | at 24 months |
| Quality of life evaluated using MOS SF36 questionnaire | Quality of life evaluated using MOS SF36 questionnaire (Medical Outcomes Study - 36-Item Short Form Health Survey). SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. Items are grouped into three categories: functional status, well-being, overall health assessment. In two dimensions, the answer is binary (yes / no) and in the other 6 in ordinal quality (3 to 6 possible answers). For each dimension, the scores for the different items are coded and then summed and transformed linearly on a scale ranging from 0 to 100. A physical composite score and a mental composite score can be calculated according to an established algorithm | at 3 months |
| Quality of life evaluated using MOS SF36 questionnaire | Quality of life evaluated using MOS SF36 questionnaire (Medical Outcomes Study - 36-Item Short Form Health Survey). SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. Items are grouped into three categories: functional status, well-being, overall health assessment. In two dimensions, the answer is binary (yes / no) and in the other 6 in ordinal quality (3 to 6 possible answers). For each dimension, the scores for the different items are coded and then summed and transformed linearly on a scale ranging from 0 to 100. A physical composite score and a mental composite score can be calculated according to an established algorithm | at 6 months |
| Quality of life evaluated using MOS SF36 questionnaire | Quality of life evaluated using MOS SF36 questionnaire (Medical Outcomes Study - 36-Item Short Form Health Survey). SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. Items are grouped into three categories: functional status, well-being, overall health assessment. In two dimensions, the answer is binary (yes / no) and in the other 6 in ordinal quality (3 to 6 possible answers). For each dimension, the scores for the different items are coded and then summed and transformed linearly on a scale ranging from 0 to 100. A physical composite score and a mental composite score can be calculated according to an established algorithm | at 12 months |
| Quality of life evaluated using MOS SF36 questionnaire | Quality of life evaluated using MOS SF36 questionnaire (Medical Outcomes Study - 36-Item Short Form Health Survey). SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. Items are grouped into three categories: functional status, well-being, overall health assessment. In two dimensions, the answer is binary (yes / no) and in the other 6 in ordinal quality (3 to 6 possible answers). For each dimension, the scores for the different items are coded and then summed and transformed linearly on a scale ranging from 0 to 100. A physical composite score and a mental composite score can be calculated according to an established algorithm | at 24 months |
| Depression and Anxiety status | Depression and anxiety will be assessed using Hospital Anxiety and Depression Scale (HADS) questionnaire. The HAD scale is a self-assessment scale for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. HADS is a self-administered scale of 14 items which assessed levels of depression and anxiety, divided into 2 subscales of 7 items (Anxiety or HADS-A, Depression or HADS-D). Each item is scored on a scale of 0 to 3. A score is generated for each of the two sub-scales (sum of the 7 items, ranging from 0 to 21). Limit scores, for each of the scores, distinguish: non-cases or asymptomatic ones (score ≤ 7); probable or borderline cases (score 8-10); clearly or clinically symptomatic cases (score ≥ 11). | at 3 months |
| Depression and Anxiety status | HADS is a self-administered scale of 14 items which assessed levels of depression and anxiety, divided into 2 subscales of 7 items (Anxiety or HADS-A, Depression or HADS-D). Each item is scored on a scale of 0 to 3. A score is generated for each of the two sub-scales (sum of the 7 items, ranging from 0 to 21). Limit scores, for each of the scores, distinguish: non-cases or asymptomatic ones (score ≤ 7); probable or borderline cases (score 8-10); clearly or clinically symptomatic cases (score ≥ 11). | at 6 months |
| Depression and Anxiety status | Depression and anxiety will be assessed using Hospital Anxiety and Depression Scale (HADS) questionnaire. The HAD scale is a self-assessment scale for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. HADS is a self-administered scale of 14 items which assessed levels of depression and anxiety, divided into 2 subscales of 7 items (Anxiety or HADS-A, Depression or HADS-D). Each item is scored on a scale of 0 to 3. A score is generated for each of the two sub-scales (sum of the 7 items, ranging from 0 to 21). Limit scores, for each of the scores, distinguish: non-cases or asymptomatic ones (score ≤ 7); probable or borderline cases (score 8-10); clearly or clinically symptomatic cases (score ≥ 11). | at 12 months |
| Weight | Evolution of weight | at 3 months |
| Weight | Evolution of weight | at 6 months |
| Weight | Evolution of weight | at 12 months |
| Weight | Evolution of weight | at 24 months |
| Number of severe infections | A severe infection will be defined as a CTAE score of grade 3 or 4 | at 24 months |
| GvHD incidence | at 12 months |
| GvHD incidence | at 24 months |
| Grading of GvHD | Grading of GvHD will be assessed using magic consortium 2016 and NIH classification | at 12 months |
| Chimerism in HSCT | Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion | at 1 month |
| Chimerism in HSCT | Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion | at 2 months |
| Chimerism in HSCT | Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion | at 3 months |
| Chimerism in HSCT | Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletionchimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. | at 6 months |
| Chimerism in HSCT | Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion | at 9 months |
| Chimerism in HSCT | Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion | at 12 months |
| Chimerism in HSCT | Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion | at 18 months |
| Chimerism in HSCT | Chimerism in HSCT will be assessed on total blood population and on T subset. In patients transplanted in Paris area, a more extensive centralized chimerism will be performed if donor T lymphocyte chimerism will be under 70% at 3 months post-transplant. Chimerism analysis by PCR microsatellite or by quantitative real-time PCR of insertion/deletion | at 24 months |
| Number of days of hospitalization | Number of days of hospitalization from inclusion | Number of days of hospitalization from inclusion at M24 |
| RBC and WBC adherence | Study of RBC and WBC adherence on lymphocytes subpopulation (including NK-T cells). Modulation of WBC and RBC surface markers by allograft. | at inclusion |
| RBC and WBC adherence | Study of RBC and WBC adherence on lymphocytes subpopulation (including NK-T cells). Modulation of WBC and RBC surface markers by allograft. | at 12 months |
| RBC and WBC adherence | Study of RBC and WBC adherence on lymphocytes subpopulation (including NK-T cells). Modulation of WBC and RBC surface markers by allograft. | at 24 months |
| Expression of RBC and WBC surface markers | Expression of RBC and WBC surface markers on lymphocytes subpopulation | at inclusion |
| Expression of RBC and WBC surface markers | Expression of RBC and WBC surface markers on lymphocytes subpopulation | at 12 months |
| Expression of RBC and WBC surface markers | Expression of RBC and WBC surface markers on lymphocytes subpopulation | at 24 months |
| Mast cell mediator release | Master cell mediator release will be assessed using plasma sample. Modulation of mast cell mediators release by allograft (tryptase, substance P and histamine) | at inclusion |
| Mast cell mediator release | Master cell mediator release will be assessed using plasma sample. Modulation of mast cell mediators release by allograft (tryptase, substance P and histamine) | at 12 months |
| Mast cell mediator release | Master cell mediator release will be assessed using plasma sample. Modulation of mast cell mediators release by allograft (tryptase, substance P and histamine) | at 24 months |
| Inflammatory cytokines | Inflammatory cytokines will be measured using serum sample. Modulation of inflammatory cytokine (TNF-alpha, IL-1, IL-6...) by allograft | at inclusion |
| Inflammatory cytokines | Inflammatory cytokines will be measured using serum sample. Modulation of inflammatory cytokine (TNF-alpha, IL-1, IL-6...) by allograft | at 12 months |
| Inflammatory cytokines | Inflammatory cytokines will be measured using serum sample. Modulation of inflammatory cytokine (TNF-alpha, IL-1, IL-6...) by allograft | at 24 months |
| ID | Term |
|---|---|
| D000755 | Anemia, Sickle Cell |
| ID | Term |
|---|---|
| D000745 | Anemia, Hemolytic, Congenital |
| D000743 | Anemia, Hemolytic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D006453 | Hemoglobinopathies |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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