1.Efficacy and Safety of Plerixafor Combined with G-CSF for Autologous Peripheral Blood Hematopoietic Stem Cell Mobilization in Lymphoma Patients.
Fang-Shu GUAN ; Dong-Hua HE ; Yi LI ; Yi ZHANG ; Gao-Feng ZHENG ; Yuan-Yuan ZHU ; Jing-Song HE ; En-Fan ZHANG ; Zhen CAI ; Yi ZHAO
Journal of Experimental Hematology 2023;31(4):1056-1060
OBJECTIVE:
To investigate the efficacy and safety of plerixafor combined with granulocyte colony-stimulating factor (G-CSF) in mobilizing peripheral blood hematopoietic stem cells in patients with lymphoma.
METHODS:
The clinical data of lymphoma patients who received autologous hematopoietic stem cell mobilization using plerixafor combined with G-CSF from January 2019 to December 2021 were retrospectively analyzed. The patients received 3 kinds of mobilization regimens: front-line steady-state mobilization, preemptive intervention, and recuse mobilization. The acquisition success rate, excellent rate of collection, and incidence of treatment-related adverse reaction were counted. The influence of sex, age, disease remission status, bone marrow involvement at diagnosis, chemotherapy lines, number of chemotherapy, platelet count and number of CD34+ cells on the day before acquisition in peripheral blood on the collection results were analyzed to identify the risk factors associated with poor stem cell collection.
RESULTS:
A total of 43 patients with lymphoma were enrolled, including 7 cases who received front-line steady-state mobilization, 19 cases who received preemptive intervention, and 17 cases who received recuse mobilization. The overall acquisition success rate was 58.1% (25/43) after use of plerixafor combined with G-CSF, and acquisition success rate of front-line steady-state mobilization, preemptive intervention, and recuse mobilization was 100%, 57.9%(11/19), and 41.2%(7/17), respectively. The excellent rate of collection was 18.6%(8/43). A total of 15 patients experienced mild to moderate treatment-related adverse reactions. The number of CD34+ cells < 5 cells/μl in peripheral blood on the day before collection was an independent risk factor affecting stem cell collection.
CONCLUSIONS
Plerixafor combined with G-CSF is a safe and effective mobilization regimen for patients with lymphoma. The number of CD34+ cells in peripheral blood on the day before collection is an predictable index for the evaluation of stem cell collection.
Humans
;
Antigens, CD34/metabolism*
;
Granulocyte Colony-Stimulating Factor/therapeutic use*
;
Hematopoietic Stem Cell Mobilization/methods*
;
Hematopoietic Stem Cell Transplantation
;
Heterocyclic Compounds/therapeutic use*
;
Lymphoma/drug therapy*
;
Multiple Myeloma/drug therapy*
;
Retrospective Studies
;
Transplantation, Autologous
2.Comparison of Plerixafor or Cyclophosphamide Combined with G-CSF in Mobilization of Peripheral Blood Stem Cells in Multiple Myeloma.
Wan-Ting LI ; Liang-Ming MA ; Yu LIAN ; Quan-Gang WANG ; Zhong-Jie GAO ; Shuang ZHAO
Journal of Experimental Hematology 2023;31(5):1403-1409
OBJECTIVE:
To compare the efficacy of plerixafor (PXF) combined with granulocyte colony-stimulating factor (G-CSF) (PXF+G-CSF) and cyclophosphamide (Cy) combined with G-CSF (Cy+G-CSF) in the mobilization of peripheral blood stem cells (PBSCs) in patients with multiple myeloma (MM).
METHODS:
The clinical data of 41 MM patients who underwent PBSC mobilization using PXF+G-CSF (18 cases) or Cy+G-CSF (23 cases) in Shanxi Bethune Hospital from January 2019 to December 2021 were retrospectively analyzed, including the count of collected CD34+ cells, acquisition success rate, failure rate, and optimal rate. The correlation of sex, age, disease type, DS staging, ISS staging, number of chemotherapy cycle, disease status before mobilization, and mobilization regimen with the collection results was analyzed, and the adverse reactions, length of hospital stay, and hospitalization costs were compared between the two mobilization regimens.
RESULTS:
The 41 patients underwent 97 mobilization collections, and the median number of CD34+ cells collected was 6.09 (0-34.07)×106/kg. The acquisition success rate, optimal rate, and failure rate was 90.2%, 56.1%, and 9.8%, respectively. Univariate analysis showed that sex, age, disease type, and disease stage had no significant correlation with the number of CD34+ cells collected and acquisition success rate (P >0.05), but the patients with better disease remission than partial remission before mobilization were more likely to obtain higher CD34+ cell count (P <0.05). The PXF+G-CSF group had a larger number of CD34+ cells and higher acquisition success rate in the first collection than Cy+G-CSF group (both P <0.05), and had lower infection risk and shorter length of hospital stay during mobilization (both P <0.05), but the economic burden increased (P <0.05).
CONCLUSION
PXF+G-CSF used for PBSC mobilization in MM patients has high first acquisition success rate, large number of CD34+ cells, less number of collection times, and short length of hospital stay, but the economic cost is heavy.
Humans
;
Antigens, CD34/metabolism*
;
Cyclophosphamide/therapeutic use*
;
Granulocyte Colony-Stimulating Factor/therapeutic use*
;
Hematopoietic Stem Cell Mobilization/methods*
;
Hematopoietic Stem Cell Transplantation
;
Heterocyclic Compounds/therapeutic use*
;
Multiple Myeloma/drug therapy*
;
Peripheral Blood Stem Cells/metabolism*
;
Retrospective Studies
3.Efficiency and safety analysis of Plerixafor combined with granulocyte colony-stimulating factor on autologous hematopoietic stem cell mobilization in lymphoma.
Meng Meng JI ; Yi Ge SHEN ; Ji Chang GONG ; Wei TANG ; Xiao Qian XU ; Zhong ZHENG ; Si Yuan CHEN ; Yang HE ; Xin ZHENG ; Lin Di ZHAO ; Wei Lin ZHAO ; Wen WU
Chinese Journal of Hematology 2023;44(2):112-117
Objective: To evaluate the advantages and safety of Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) in autologous hematopoietic stem cell mobilization of lymphoma. Methods: Lymphoma patients who received autologous hematopoietic stem cell mobilization with Plerixafor in combination with G-CSF or G-CSF alone were obtained. The clinical data, the success rate of stem cell collection, hematopoietic reconstitution, and treatment-related adverse reactions between the two groups were evaluated retrospectively. Results: A total of 184 lymphoma patients were included in this analysis, including 115 cases of diffuse large B-cell lymphoma (62.5%) , 16 cases of classical Hodgkin's lymphoma (8.7%) , 11 cases of follicular non-Hodgkin's lymphoma (6.0%) , 10 cases of angioimmunoblastic T-cell lymphoma (5.4%) , 6 cases of mantle cell lymphoma (3.3%) , and 6 cases of anaplastic large cell lymphoma (3.3%) , 6 cases of NK/T-cell lymphoma (3.3%) , 4 cases of Burkitt's lymphoma (2.2%) , 8 cases of other types of B-cell lymphoma (4.3%) , and 2 cases of other types of T-cell lymphoma (1.1%) ; 31 patients had received radiotherapy (16.8%) . The patients in the two groups were recruited with Plerixafor in combination with G-CSF or G-CSF alone. The baseline clinical characteristics of the two groups were basically similar. The patients in the Plerixafor in combination with the G-CSF mobilization group were older, and the number of recurrences and third-line chemotherapy was higher. 100 patients were mobilized with G-CSF alone. The success rate of the collection was 74.0% for one day and 89.0% for two days. 84 patients in the group of Plerixafor combined with G-CSF were recruited successfully with 85.7% for one day and 97.6% for two days. The success rate of mobilization in the group of Plerixafor combined with G-CSF was substantially higher than that in the group of G-CSF alone (P=0.023) . The median number of CD34(+) cells obtained in the mobilization group of Plerixafor combined with G-CSF was 3.9×10(6)/kg. The median number of CD34(+) cells obtained in the G-CSF Mobilization group alone was 3.2×10(6)/kg. The number of CD34(+) cells collected by Plerixafor combined with G-CSF was considerably higher than that in G-CSF alone (P=0.001) . The prevalent adverse reactions in the group of Plerixafor combined with G-CSF were grade 1-2 gastrointestinal reactions (31.2%) and local skin redness (2.4%) . Conclusion: The success rate of autologous hematopoietic stem cell mobilization in lymphoma patients treated with Plerixafor combined with G-CSF is significantly high. The success rate of collection and the absolute count of CD34(+) stem cells were substantially higher than those in the group treated with G-CSF alone. Even in older patients, second-line collection, recurrence, or multiple chemotherapies, the combined mobilization method also has a high success rate of mobilization.
Humans
;
Granulocyte Colony-Stimulating Factor/therapeutic use*
;
Hematopoietic Stem Cell Mobilization/methods*
;
Hematopoietic Stem Cell Transplantation
;
Heterocyclic Compounds/adverse effects*
;
Lymphoma/drug therapy*
;
Lymphoma, T-Cell/therapy*
;
Multiple Myeloma/drug therapy*
;
Retrospective Studies
;
Transplantation, Autologous
4.Efficacy and safety of autologous hematopoietic stem cell transplantation in elderly multiple myeloma patients: a single center retrospective study.
Bei Hui HUANG ; Juan LI ; Wai Yi ZOU ; Jun Ru LIU ; Jing Li GU ; Xiao Zhe LI ; Mei Lan CHEN ; Li Fen KUANG
Chinese Journal of Hematology 2022;43(2):141-145
Objective: To evaluate the efficacy and safety of autologous hematopoietic stem cell transplantation (auto-HSCT) in elderly patients (≥65 years old) with multiple myeloma (MM) . Methods: From June 1, 2006 to July 31, 2020, 22 MM patients (≥65 years old) who were diagnosed in the First Affiliated Hospital, Sun Yat-sen University and received novel drug induction followed by auto-HSCT were analyzed retrospectively. These patients were evaluated for important organ functions before transplantation, and the International Myeloma Working Group frail score was used in 2016 to screen out transplant-eligible patients. Results: The median (interquartile range, IQR) age at the time of transplantation of the 22 patients was 66.75 (IQR 4.50) years. A total of 20 patients received stem cell mobilization. The median number of mononuclear cells collected was 4.53×10(8)/kg, that of CD34(+) cells was 3.37×10(6)/kg, and the median number of apheresis procedures performed was 2. After stem cell transfusion, the median time of neutrophil implantation was 11 days, that of platelet implantation was 13 days, and the treatment-related mortality was 0 at 100 days after transplantation. The median follow-up was 48.7 months. The median time to progression time was not reached, and the median overall survival time was 111.8 months. Conclusion: Auto-HSCT is a safe and effective treatment for selected elderly patients of 65 years or older with MM.
Aged
;
Hematopoietic Stem Cell Mobilization/methods*
;
Hematopoietic Stem Cell Transplantation/adverse effects*
;
Humans
;
Multiple Myeloma/drug therapy*
;
Retrospective Studies
;
Transplantation, Autologous/methods*
;
Treatment Outcome
5.Ifosfamide, Cisplatin or Carboplatin, and Etoposide (ICE)-based Chemotherapy for Mobilization of Autologous Peripheral Blood Stem Cells in Patients with Lymphomas.
Ping ZHOU ; Peng LIU ; Sheng-Yu ZHOU ; Xiao-Hui HE ; Xiao-Hong HAN ; Yan QIN ; Sheng YANG ; Chang-Gong ZHANG ; Lin GUI ; Jia-Rui YAO ; Li-Ya ZHAO ; Shu-Xiang ZHANG ; Yan SUN ; Yuan-Kai SHI
Chinese Medical Journal 2015;128(18):2498-2504
BACKGROUNDHigh-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a promising approach for lymphomas. This study aimed to evaluate the effect of ifosfamide, cisplatin or carboplatin, and etoposide (ICE)-based regimen as a mobilization regimen on relapsed, refractory, or high-risk aggressive lymphoma.
METHODSFrom June 2001 to May 2013, patients with lymphomas who mobilized by ICE-based regimen for ASCT were analyzed in this retrospective study. The results of the autologous peripheral blood stem cells collection, toxicity, engraftment after ICE-based mobilization regimen were analyzed in this study. Furthermore, risk factors for overall survival (OS) and progression free survival (PFS) were evaluated by univariate analysis.
RESULTSThe stem cells were mobilized using ICE-based regimen plus rituximab or ICE-based regimen alone in 12 patients and 54 patients, respectively. The results of stem cell mobilization were excellent. Ninety-seven percentages of the patients had the stem cell collection of at least 2.0 × 10 6 CD34 + cells/kg and 68% had at least 5 × 10 6 CD34 + cells/kg. Fifty-eight percentage of the patients experienced Grade 4 neutropenia, 20% developed febrile neutropenia, and only 12% had Grade 4 thrombocytopenia. At a median follow-up of 63.8 months, the 5-year PFS and OS were 64.4% and 75.3%, respectively.
CONCLUSIONICE is a powerful regimen for stem cell mobilization in patients with lymphomas.
Adolescent ; Adult ; Antineoplastic Agents ; therapeutic use ; Carboplatin ; therapeutic use ; Child ; Cisplatin ; therapeutic use ; Etoposide ; therapeutic use ; Female ; Hematopoietic Stem Cell Mobilization ; methods ; Humans ; Ifosfamide ; therapeutic use ; Lymphoma ; drug therapy ; Male ; Middle Aged ; Retrospective Studies ; Stem Cell Transplantation ; methods ; Transplantation, Autologous ; Young Adult
6.Exogenous VEGF promotes hematopoietic stem cell mobilization.
Xiao-Jian ZHU ; Yi LI ; Yong YOU ; Qing LI ; Chen ZENG ; Zhao-Dong ZHONG ; Ping ZOU
Journal of Experimental Hematology 2014;22(1):154-159
This study was aimed to investigate the effect of exogenous VEGF on hematopoietic stem cell mobilization and immune system. The C57BL/6J mice were randomly divided into the normal control group, VEGF short-term group (5 d) and VEGF long-term group (27 d). Mice in the experimental group were injected ip with VEGF (100 ng/d); mice in control group were injected ip with PBS. The white blood cell (WBC) count and the ratio of lymphocyte in the peripheral blood at different time point were assayed by hemacytometer. The percentage of hematopoietic stem cell (HSC), lymphocyte subgroup, regulatory T cell (Treg), myeloid-derived suppressor cells (MDSC) in the peripheral blood and spleen of different groups were detected by flow cytometry. The morphological changes of spleen and spleen index of mice in the control and long-term group were observed by microscopy. The results showed that the absolute number of WBC in the peripheral blood of mice significantly increased after injection of VEGF, and the peak value was at day 3. The percentage of Lin(-)Sca-1(+)CD117(+) cells in the peripheral blood and spleen of the long-term group were significantly higher than that in the normal control group (P < 0.05). The spleen of the mice in VEGF long-term group was larger than that of the control group, the spleen index also increased (P < 0.05), and remarkable extramedullary hematopoietic signs were found in the HE stained sections. There was no significant change in the total ratio of lymphocytes in the peripheral blood after injection, but the percentage of CD3(+) cells and the CD3(+)/B220(+) ratio in the long-term group deceased; the percentages of Treg and Gr-1(+)CD11b(+) MDSC in the experimental groups increased (P < 0.05), which more significantly increased in the long-term group than that in the short-term group (P < 0.05). It is concluded that the exogenous VEGF promotes hematopoietic stem cell mobilization, and at same time up-regulates the many kinds of suppressive immune cell levels which leads to changes of immuno-function.
Animals
;
Hematopoietic Stem Cell Mobilization
;
methods
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Spleen
;
cytology
;
T-Lymphocytes, Regulatory
;
Vascular Endothelial Growth Factor A
;
pharmacology
7.Effect of dexamethasone on G-CSF mobilization of peripheral blood stem cells in healthy donors and hematopoietic reconstruction in the recipients.
Hua-Sheng LIU ; Xiao-Ning WANG ; Hai-Bo LIU ; Xin LIU ; Peng-Cheng HE ; Li-Mei CHEN ; Jie-Ying XI ; Meng-Chang WANG ; Jin LI ; Hai-Tao ZHANG ; Mei ZHANG
Journal of Experimental Hematology 2013;21(5):1232-1236
This study was aimed to investigate the effects of different mobilization methods on mobilization and collection of peripheral blood stem cells in healthy donors and the adverse effect of collection, as well as hematopoietic construction in recipients. A total of 43 donors between January 2008 and May 2013 were divided into the simple mobilization group and the combined mobilization group. The simple group was subcutaneously injected with 5.0-10.0 µg/(kg·d) recombinant human granulocyte colony-stimulating factor (rhG-CSF), and the combined mobilization group was treated with rhG-CSF and intravenously dripped with 10 mg dexamethasone for 2-4 hours before collection. The acquisition and count of MNC and CD34(+) cells in different groups, the relationship between the stem cells and MNC count in blood before collection, and the adverse reactions were analyzed; the hematopoietic reconstruction of recipients was investigated. The results showed that the hematopoietic stem cell number of the two groups meet the demands. The count of MNC and CD34(+) cells in the simple mobilization group was more than that in the combined mobilization group. The MNC count in two groups positively correlated with peripheral blood MNC count before collection. The decline of hemoglobin and platelet levels was more obvious in the simple mobilization group than that in combined mobilization group. The adverse reactions of collection in the simple mobilization group could be well tolerated and reversed. There was no adverse reaction in the combined mobilization group. The differences of conditioning regimens between two groups were not statistically significant and the hematopoietic reconstruction time of combined group was shorter than that in the simple mobilization group.It is concluded that the adverse reactions in process of collection can be reduced, and enough hematopoietic stem cells can be collected by G-CSF plus dexamethasone in mobilization of peripheral blood stem cells. The count of MNC in peripheral blood before collection can be still used as a reference index to evaluate the acquisition of MNC. Especially the combination with dexamethasone for stem cell mobilization can promote the hematopoietic reconstruction of the recipients.
Adolescent
;
Adult
;
Child
;
Child, Preschool
;
Dexamethasone
;
pharmacology
;
Female
;
Granulocyte Colony-Stimulating Factor
;
pharmacology
;
Hematopoietic Stem Cell Mobilization
;
methods
;
Hematopoietic Stem Cells
;
drug effects
;
Humans
;
Male
;
Middle Aged
;
Peripheral Blood Stem Cell Transplantation
;
methods
;
Recovery of Function
;
Young Adult
8.Evaluation of methods for collection of peripheral blood stem cells in children.
Guomei YIN ; Zhuolan SHEN ; Fei QIN ; Wenbin QIAN
Journal of Zhejiang University. Medical sciences 2013;42(3):350-354
OBJECTIVETo evaluate the methods for collection of peripheral blood stem cells (PBSC) in children.
METHODSPeripheral blood stem cells were collected from 20 child patients and 11 donors. The patients treated with chemotherapy, received G-CSF or GM-CSF and the donors received G-CSF for mobilization. When the peripheral blood (PB) leukocyte count reached to 5 X10(9)/L,the hematopoietic stem cells were collected with CS-3000 Plus, COM TEC or COBE Spectra blood cell separators from patients and donors. For children whose weight <20 kg,HCT <24% or TBV <1 100-1 650 ml,blood cell separators were pre-injected with the same type RBCs irradiated by 25 Gy of gamma-ray and with low flow rate (10-30 ml/min). The number of CD34(+) cell was detected by flow cytometry. The relationship of number of CD34(+) cell with mononuclear cell (MNC) and processed blood volume was analyzed.
RESULTSSuccessful collection of the PBSCs with the CS- 3000 Plus (n=10), the COM TEC (n=3) and the COBE Spectra (n=18) was achieved in all the 31 cases with 1-5 aphereses used. Number of CD34(+) cells was (7.9 ±2.9) X 10(6)/kg and that of MNCs was (7.4 ±3.1) X 10(8)/kg. The total CD34(+) cell count was correlated with MNCs before aphaeresis and processed blood volume.
CONCLUSIONFor collection of high quality PBSCs, the appropriate methods should be chosen according to the body weight, TBV, mobilization of child patients/donors.
Adolescent ; Child ; Child, Preschool ; Cytapheresis ; methods ; Female ; Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cells ; Humans ; Infant ; Male
9.Analysis of influence factors on G-CSF-mobilized hematopoietic stem cells of 191 healthy donors in a mono center.
Qian WANG ; Lei YUAN ; Hong-Hua LI ; Yu ZHAO ; Wen-Rong HUANG ; Jian BO ; Shu-Hong WANG ; Hai-Yan ZHU ; Li-Ping DOU ; Quan-Shun WANG ; Li YU ; Yu JING
Journal of Experimental Hematology 2013;21(1):169-172
This study was aimed to investigate the factors influencing mobilization efficiency of peripheral hematopoietic stem cells with granulocyte colony stimulating factor (G-CSF) and their impact on healthy donors. 181 donors were mobilized subcutaneously with G-CSF at 5 - 10 µg/(kg·d), and 10 donors were mobilized with G-CSF at 3.3 - 4.9 µg/(kg·d), once 12 h, for 4 - 5 d. Peripheral blood mononuclear cell (MNC) and CD34(+) cell counts were analyzed by flow cytometry. Mobilization-related side effects were also monitored. The results showed that white blood cell counts increased by 6 times averaged after mobilization (P < 0.01). The platelet count obviously decreased (P < 0.01), while the hemoglobin level did not show significant difference. No significant differences were observed in MNC and CD34(+) cell counts between those subjects harvested on the 4th and 5th day after mobilization. Male donors were superior to female ones in cell harvest (P < 0.01). Donor body weight played positive role in cell yield, while impact of age on harvest was not remarkable. Neither MNC nor CD34(+) cell count showed a linear relationship with G-CSF dose. Only slight side effects were observed on the donors in this study. It is concluded that mobilization with G-CSF is sufficient in healthy donors without remarkable side effects.
Adolescent
;
Adult
;
Child
;
Factor Analysis, Statistical
;
Female
;
Granulocyte Colony-Stimulating Factor
;
pharmacology
;
Hematopoietic Stem Cell Mobilization
;
methods
;
Humans
;
Male
;
Middle Aged
;
Peripheral Blood Stem Cell Transplantation
;
methods
;
Tissue Donors
;
Young Adult
10.Effects of the mobilization with AMD3100, granulocyte-colony-stimulating factor (G-CSF) alone and in combination on the immunological function of the lymphocytes in mice.
Yuan KONG ; Ru FENG ; Xiao-jun HUANG
Chinese Journal of Hematology 2012;33(5):358-361
OBJECTIVETo investigate the impact of the mobilization with the antagonist of the stromal cell-derived factor receptor CXCR4 (AMD3100) (plerixafor), granulocyte-colony-stimulating factor (G-CSF) alone and in combination on the proliferation and cytotoxic functions of the murine splenic lymphocytes.
METHODSC57BL/6(H-2(b)) mice, as donors, were mobilized by, AMD3100, G-CSF alone or in combination (n = 10 mice in each group), and phosphate buffered saline (PBS). Then, the proliferation capacity of murine lymphocytes either in response to the phytohemagglutinin (PHA) stimulation or the mixed lymphocytes reaction (MLR) with allo-lymphocytes from the BALB/C(H-2(d)) mice were detected by CCK-8 method. The cytotoxic capacity of murine lymphocytes on Yac-1 tumor cells was examined by LDH assay.
RESULTSThe proliferation capacity and the responsiveness to alloantigen of the lymphocytes derived from the mice spleen mobilized by AMD3100, G-CSF alone or in combination were significantly lower than those by PBS control (P < 0.05), and those combination of AMD 3100 and G-CSF group were significantly lower than in other groups(P < 0.05). At the effector-target ration of 40:1, the cytotoxic capacity of murine lymphocytes in above mobilization groups was lower than in control group, but no statistically significant difference (P > 0.05).
CONCLUSIONBoth the proliferation capacity and the responsiveness to alloantigen of the murine lymphocytes decreases significantly after the mobilization with AMD3100, G-CSF alone or in combination, whereas no significant alternations are demonstrated on the cytotoxic capacity of murine lymphocytes. Further studies are needed to clarify the underlying mechanisms.
Animals ; Cell Proliferation ; Granulocyte Colony-Stimulating Factor ; adverse effects ; pharmacology ; Hematopoietic Stem Cell Mobilization ; methods ; Hematopoietic Stem Cell Transplantation ; methods ; Heterocyclic Compounds ; administration & dosage ; pharmacology ; Lymphocytes ; drug effects ; immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Receptors, CXCR4 ; drug effects ; Sincalide

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