Plerixafor is a stem cell mobilising agent, and when administered along with G-CSF has been shown to improve CD34+ stem cell collections in lymphoma and multiple myeloma patients compared to G-CSF alone. Patients who ...Plerixafor is a stem cell mobilising agent, and when administered along with G-CSF has been shown to improve CD34+ stem cell collections in lymphoma and multiple myeloma patients compared to G-CSF alone. Patients who failed to mobilize <2.0 × 10</span><sup><span style="font-family:Verdana;">6</span></sup><span style="font-family:Verdana;"> cells/kg on Day 1 collection received Plerixafor and G CSF for further collections. Study population was divided into two groups as plerixafor yes (PY) who are poor mobilizers and Plerixafor No (PN) who are good mobilizers. Out of 49 patients, 28 patients were in PY group and 21 patients in PN group. Median value of apheresis CD34 of day 1 was 1.75 (range 0.258 to 8.52) in PY group and 2.63 (range 1.06 to 6.29) in PN group and that of day 2 was 3.845 (range 0.317 to 13.89) in PY group and 3.18 (range 0.88 to 6.348) in PN group. Median value of total apheresis CD34 was 8.10 (range 4.33 to 18.66) in PY group and 7.58 (range 4.06 to 9.8) in PN group. Median day of neutrophil engraftment was 11.5 (range 9 - 22) in PY group and 11 (range 9 - 36) in PN group whereas median day of platelet engraftment was 14 (range 9 - 98) in PY group and 13 (range 11 - 98) in PN group. It can be concluded that the use of plerixafor not only enabled poor mobilizers of Lymphoma and Multiple Myeloma to collect adequate stem cells to proceed to ASCT, but also had early neutrophil and platelet engraftment which was comparable with good mobilizers.展开更多
Here, we report that chemokine-mimetic plerixafor derivatives could govern tumor-specific delivery and functional effects of nanomaterials. Reduced graphene oxide （rGO） nanosheets were used as a model functional nan...Here, we report that chemokine-mimetic plerixafor derivatives could govern tumor-specific delivery and functional effects of nanomaterials. Reduced graphene oxide （rGO） nanosheets were used as a model functional nanomaterial, and plerixafor-conjugated lipid （PL/rGO） or a benzylcyclam derivative of plerixafor- conjugated lipid （BPL/rGO） was physically adsorbed onto the surface of rGO. The cellular uptake of surface-modified rGO was dependent on overexpression of the CXCR4 chemokine receptor on cancer cells. In KB cells, the binding affinity of BPL/rGO for CXCR4 was 6.8-fold greater than that of PL/rGO. Notably, cellular uptake patterns correlated with in vitro photothermal anticancer efficacy. The tumor distribution of BPL/rGO was higher than that of PL/rGO and plain rGO in mice bearing CXCR4-overexpressing tumors, whereas the distribution of the various rGO forms was similar in mice harboring CXCR4-negative tumors. Moreover, complete photothermal tumor ablation was observed in BPL/rGO- treated mice bearing CXCR4-positive KB cell tumors, but not in CXCR4-negative MCF-7 cell tumors. These results provide evidence that BPL can be used to enhance the delivery of nanomaterials to CXCR4-overexpressing tumors. Chemokine-mimetic BPL can be further applied for nanomaterial-based delivery of photosensitizers, anticancer drugs, or diagnostic tumor imaging agents in CXCR4-overexpressing cancer patients.展开更多
Engraftment syndrome(ES)is one of the most common complications in the early phase after autologous hematopoietic stem cell transplantation(ASCT),and we aimed to evaluate the incidence and risk factors for ES patients...Engraftment syndrome(ES)is one of the most common complications in the early phase after autologous hematopoietic stem cell transplantation(ASCT),and we aimed to evaluate the incidence and risk factors for ES patients receiving ASCT in the era of plerixafor-based mobilization.A total of 294 were enrolled,and 16.0%(n=47)experienced ES after ASCT.The main clinical manifestations were fever(100%),diarrhea(78.7%),skin rash(23.4%),and hypoxemia/pulmonary edema(12.8%).Plerixafor-based mobilization was associated with higher counts of CD3^(+)cells,CD4^(+)cells,and CD8^(+)cells in grafts.In univariate analysis of the total cohort,age≥60 years,receiving ASCT at complete remission(CR),higher number of mononuclear cell(MNC),CD3^(+)cell counts,CD4^(+)cells as well as CD8^(+)cells transfused and plerixafor-based mobilization were associated with ES after ASCT.Multivariate analysis showed that age≥60 years(P=0.0014),receiving ASCT at CR(P=0.002),and higher number of MNC transfused(P=0.026)were associated with ES in total cohort.In plasma cell disease subgroup,age≥60 years(P=0.013),plerixafor-based mobilization(P=0.036),and receiving ASCT at CR(P=0.002)were associated with ES.Patients with more risk factors had a higher risk of ES.The 1-year probabilities of relapse,non-relapse mortality,and survival were comparable between patients with and without ES.Thus,plerixafor-based mobilization may influence the composition of T lymphocytes in grafts and increase the risk of ES,particularly in patients with plasma cell disease.展开更多
BACKGROUND The purpose of this paper is to demonstrate a practical stem cell collection method that provides sufficient stem cells for autologous stem cell transplantation(ASCT)in multiple myeloma(MM)patients despite ...BACKGROUND The purpose of this paper is to demonstrate a practical stem cell collection method that provides sufficient stem cells for autologous stem cell transplantation(ASCT)in multiple myeloma(MM)patients despite low peripheral CD34(pCD34)counts and to describe the benefits of this method for MM patients with limited resources.AIM To demonstrate a practical method for stem cell collection.METHODS Stem cell collection data on the last 300 patients at a community cancer center in Washington were reviewed.We report on the methods of collection,including medi-cations used and timing,used by the blood blank as well as their outcomes.The three MM patients with initially very low pCD34 counts all successfully underwent stem cell collection in a single trip to the transplant center for their ASCT.RESULTS Three patients whose pre-collection pCD34 counts were the lowest and less than 2.5 cells/μL were identified.These patients had the commonality of having multiple barriers to transportation and likely would have been able to make only one trip for the stem cell collections.CONCLUSION Despite particularly low pre-collection peripheral blood CD34 counts,successful autologous stem cell collection in MM patients is feasible by routinely adding plerixafor to granulocyte-colony stimulating factor on day 4 of mobilization.There is limited analysis demonstrating that sufficient stem cells for one or more transplants can be collected using this method.This practical and novel approach may benefit the high number of MM patients who face limited resources,finances,long travel times,and social support.These results are highly relevant to physicians treating similar patients.展开更多
Chemokine 12(CXCL12), also known as stromal cell derived factor-1(SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand...Chemokine 12(CXCL12), also known as stromal cell derived factor-1(SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer treatment.Chemokine 12(CXCL12), also known as stromal cell derived factor-1(SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer treatment.展开更多
The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use ...The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells(HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the selfrenewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.展开更多
Testicular germ cell cancer(TGCC) is rare form of malignant disease that occurs mostly in young man between age 15 and 40. The worldwide incidence of TGCC is 1.5 per 100000 man with the highest rates in North Europe. ...Testicular germ cell cancer(TGCC) is rare form of malignant disease that occurs mostly in young man between age 15 and 40. The worldwide incidence of TGCC is 1.5 per 100000 man with the highest rates in North Europe. After discovery of cisplatin cure rates of TGCC are very favorable between 90%-95% and unlike most solid tumors, cure rate for metastatic TGCC is around 80%. Metastatic TGCC is usually treated with 3-4 cycles of bleomycin, etoposide, cisplatinum chemotherapy with or without retroperitoneal surgery and cure rates with this approach are between 41% in poor risk group and 92% in good risk group of patients. Cure rates are lower in relapsed and refractory patients and many of them will die from the disease if not cured with first line chemotherapy. High dose chemotherapy(HDCT) approach was used for the first time during the 1980 s. Progress in hematology allowed the possibility to keep autologous haematopoietic stem cells alive ex-vivo at very low temperatures and use them to repopulate the bone marrow after sub-lethal dose of intesive myeloablative chemotherapy. Despite the fact that there is no positive randomized study to prove HDCT concept, cure rates in relapsed TGCC are higher after high dose therapy then in historical controls in studies with conventional treatment. Here we review clinical studies in HDCT for TGCC, possibilities of mobilising sufficient number of stem cells and future directions in the treatment of this disease.展开更多
High-dose chemotherapy(HDCT)with autologous hematopoietic stem cell transplantation has been explored and has played an important role in the management of patients with high-risk germ cell tumors(GCTs)who failed to b...High-dose chemotherapy(HDCT)with autologous hematopoietic stem cell transplantation has been explored and has played an important role in the management of patients with high-risk germ cell tumors(GCTs)who failed to be cured by conventional chemotherapy.Hematopoietic stem cells(HSCs)collected from the peripheral blood,after appropriate pharmacologic mobilization,have largely replaced bone marrow as the principal source of HSCs in transplants.As it is currently common practice to perform tandem or multiple sequential cycles of HDCT,it is anticipated that collection of large numbers of HSCs from the peripheral blood is a prerequisite for the success of the procedure.Moreover,the CD34+cell dose/kg of body weight infused after HDCT has proven to be a major determinant of hematopoietic engraftment,with patients who receive>2×106 CD34+cells/kg having consistent,rapid,and sustained hematopoietic recovery.However,many patients with relapsed/refractory GCTs have been exposed to multiple cycles of myelosuppressive chemotherapy,which compromises the efficacy of HSC mobilization with granulocyte colony-stimulating factor with or without chemotherapy.Therefore,alternative strategies that use novel agents in combination with traditional mobilizing regimens are required.Herein,after an overview of the mechanisms of HSCs mobilization,we review the existing literature regarding studies reporting various HSC mobilization approaches in patients with relapsed/refractory GCTs,and finally report newer experimental mobilization strategies employing novel agents that have been applied in other hematologic or solid malignancies.展开更多
文摘Plerixafor is a stem cell mobilising agent, and when administered along with G-CSF has been shown to improve CD34+ stem cell collections in lymphoma and multiple myeloma patients compared to G-CSF alone. Patients who failed to mobilize <2.0 × 10</span><sup><span style="font-family:Verdana;">6</span></sup><span style="font-family:Verdana;"> cells/kg on Day 1 collection received Plerixafor and G CSF for further collections. Study population was divided into two groups as plerixafor yes (PY) who are poor mobilizers and Plerixafor No (PN) who are good mobilizers. Out of 49 patients, 28 patients were in PY group and 21 patients in PN group. Median value of apheresis CD34 of day 1 was 1.75 (range 0.258 to 8.52) in PY group and 2.63 (range 1.06 to 6.29) in PN group and that of day 2 was 3.845 (range 0.317 to 13.89) in PY group and 3.18 (range 0.88 to 6.348) in PN group. Median value of total apheresis CD34 was 8.10 (range 4.33 to 18.66) in PY group and 7.58 (range 4.06 to 9.8) in PN group. Median day of neutrophil engraftment was 11.5 (range 9 - 22) in PY group and 11 (range 9 - 36) in PN group whereas median day of platelet engraftment was 14 (range 9 - 98) in PY group and 13 (range 11 - 98) in PN group. It can be concluded that the use of plerixafor not only enabled poor mobilizers of Lymphoma and Multiple Myeloma to collect adequate stem cells to proceed to ASCT, but also had early neutrophil and platelet engraftment which was comparable with good mobilizers.
文摘Here, we report that chemokine-mimetic plerixafor derivatives could govern tumor-specific delivery and functional effects of nanomaterials. Reduced graphene oxide （rGO） nanosheets were used as a model functional nanomaterial, and plerixafor-conjugated lipid （PL/rGO） or a benzylcyclam derivative of plerixafor- conjugated lipid （BPL/rGO） was physically adsorbed onto the surface of rGO. The cellular uptake of surface-modified rGO was dependent on overexpression of the CXCR4 chemokine receptor on cancer cells. In KB cells, the binding affinity of BPL/rGO for CXCR4 was 6.8-fold greater than that of PL/rGO. Notably, cellular uptake patterns correlated with in vitro photothermal anticancer efficacy. The tumor distribution of BPL/rGO was higher than that of PL/rGO and plain rGO in mice bearing CXCR4-overexpressing tumors, whereas the distribution of the various rGO forms was similar in mice harboring CXCR4-negative tumors. Moreover, complete photothermal tumor ablation was observed in BPL/rGO- treated mice bearing CXCR4-positive KB cell tumors, but not in CXCR4-negative MCF-7 cell tumors. These results provide evidence that BPL can be used to enhance the delivery of nanomaterials to CXCR4-overexpressing tumors. Chemokine-mimetic BPL can be further applied for nanomaterial-based delivery of photosensitizers, anticancer drugs, or diagnostic tumor imaging agents in CXCR4-overexpressing cancer patients.
基金supported by the National Key Research and Development Program of China(2022YFC2502606)the National Natural Science Foundation of China(No.82170208,82200239)+3 种基金CAMS Innovation Fund for Medical Sciences(No.2022-I2M-C&T-B-121)Tongzhou district Distinguished Young Scholars(No.JCQN2023009)Peking University Health Science Center-University of Michigan College of Medicine Joint Institute for Translational and Clinical Research(BMU2022JI003)the Fundamental Research Funds for the Central Universities.
文摘Engraftment syndrome(ES)is one of the most common complications in the early phase after autologous hematopoietic stem cell transplantation(ASCT),and we aimed to evaluate the incidence and risk factors for ES patients receiving ASCT in the era of plerixafor-based mobilization.A total of 294 were enrolled,and 16.0%(n=47)experienced ES after ASCT.The main clinical manifestations were fever(100%),diarrhea(78.7%),skin rash(23.4%),and hypoxemia/pulmonary edema(12.8%).Plerixafor-based mobilization was associated with higher counts of CD3^(+)cells,CD4^(+)cells,and CD8^(+)cells in grafts.In univariate analysis of the total cohort,age≥60 years,receiving ASCT at complete remission(CR),higher number of mononuclear cell(MNC),CD3^(+)cell counts,CD4^(+)cells as well as CD8^(+)cells transfused and plerixafor-based mobilization were associated with ES after ASCT.Multivariate analysis showed that age≥60 years(P=0.0014),receiving ASCT at CR(P=0.002),and higher number of MNC transfused(P=0.026)were associated with ES in total cohort.In plasma cell disease subgroup,age≥60 years(P=0.013),plerixafor-based mobilization(P=0.036),and receiving ASCT at CR(P=0.002)were associated with ES.Patients with more risk factors had a higher risk of ES.The 1-year probabilities of relapse,non-relapse mortality,and survival were comparable between patients with and without ES.Thus,plerixafor-based mobilization may influence the composition of T lymphocytes in grafts and increase the risk of ES,particularly in patients with plasma cell disease.
文摘BACKGROUND The purpose of this paper is to demonstrate a practical stem cell collection method that provides sufficient stem cells for autologous stem cell transplantation(ASCT)in multiple myeloma(MM)patients despite low peripheral CD34(pCD34)counts and to describe the benefits of this method for MM patients with limited resources.AIM To demonstrate a practical method for stem cell collection.METHODS Stem cell collection data on the last 300 patients at a community cancer center in Washington were reviewed.We report on the methods of collection,including medi-cations used and timing,used by the blood blank as well as their outcomes.The three MM patients with initially very low pCD34 counts all successfully underwent stem cell collection in a single trip to the transplant center for their ASCT.RESULTS Three patients whose pre-collection pCD34 counts were the lowest and less than 2.5 cells/μL were identified.These patients had the commonality of having multiple barriers to transportation and likely would have been able to make only one trip for the stem cell collections.CONCLUSION Despite particularly low pre-collection peripheral blood CD34 counts,successful autologous stem cell collection in MM patients is feasible by routinely adding plerixafor to granulocyte-colony stimulating factor on day 4 of mobilization.There is limited analysis demonstrating that sufficient stem cells for one or more transplants can be collected using this method.This practical and novel approach may benefit the high number of MM patients who face limited resources,finances,long travel times,and social support.These results are highly relevant to physicians treating similar patients.
基金supported by the National Natural Science Foundation of China(Nos.81773774,81473231,and 81673461)Science Foundation for Distinguished Young Scholars of Jiangsu Province(No.BK20150028)+3 种基金the National Science and Technology Major Project(No.2017ZX09301014)the Project Program of State Key Laboratory of Natural Medicines,China Pharmaceutical University(No.SKLNMZZCX201823)Program for Changjiang Scholars and Innovative Research Team in University(No.IRT1193)the Open Project of State Key Laboratory Cultivation Base for TCM Quality and Efficacy,Nanjing University of Chinese Medicine(No.TCMQ&E201704)
文摘Chemokine 12(CXCL12), also known as stromal cell derived factor-1(SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer treatment.Chemokine 12(CXCL12), also known as stromal cell derived factor-1(SDF-1) and a member of the CXC chemokine subfamily, is ubiquitously expressed in many tissues and cell types. It interacts specifically with the ligand for the transmembrane G protein-coupled receptors CXCR4 and CXCR7. The CXCL12/CXCR4 axis takes part in a series of physiological, biochemical, and pathological process, such as inflammation and leukocyte trafficking, cancer-induced bone pain, and postsurgical pain, and also is a key factor in the cross-talking between tumor cells and their microenvironment. Aberrant overexpression of CXCR4 is critical for tumor survival, proliferation, angiogenesis, homing and metastasis. In this review, we summarized the role of CXCL12/CXCR4 in cancer, CXCR4 inhibitors under clinical study, and natural product CXCR4 antagonists. In conclusion, the CXCL12/CXCR4 signaling is important for tumor development and targeting the pathway might represent an effective approach to developing novel therapy in cancer treatment.
文摘The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells(HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the selfrenewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.
文摘Testicular germ cell cancer(TGCC) is rare form of malignant disease that occurs mostly in young man between age 15 and 40. The worldwide incidence of TGCC is 1.5 per 100000 man with the highest rates in North Europe. After discovery of cisplatin cure rates of TGCC are very favorable between 90%-95% and unlike most solid tumors, cure rate for metastatic TGCC is around 80%. Metastatic TGCC is usually treated with 3-4 cycles of bleomycin, etoposide, cisplatinum chemotherapy with or without retroperitoneal surgery and cure rates with this approach are between 41% in poor risk group and 92% in good risk group of patients. Cure rates are lower in relapsed and refractory patients and many of them will die from the disease if not cured with first line chemotherapy. High dose chemotherapy(HDCT) approach was used for the first time during the 1980 s. Progress in hematology allowed the possibility to keep autologous haematopoietic stem cells alive ex-vivo at very low temperatures and use them to repopulate the bone marrow after sub-lethal dose of intesive myeloablative chemotherapy. Despite the fact that there is no positive randomized study to prove HDCT concept, cure rates in relapsed TGCC are higher after high dose therapy then in historical controls in studies with conventional treatment. Here we review clinical studies in HDCT for TGCC, possibilities of mobilising sufficient number of stem cells and future directions in the treatment of this disease.
文摘High-dose chemotherapy(HDCT)with autologous hematopoietic stem cell transplantation has been explored and has played an important role in the management of patients with high-risk germ cell tumors(GCTs)who failed to be cured by conventional chemotherapy.Hematopoietic stem cells(HSCs)collected from the peripheral blood,after appropriate pharmacologic mobilization,have largely replaced bone marrow as the principal source of HSCs in transplants.As it is currently common practice to perform tandem or multiple sequential cycles of HDCT,it is anticipated that collection of large numbers of HSCs from the peripheral blood is a prerequisite for the success of the procedure.Moreover,the CD34+cell dose/kg of body weight infused after HDCT has proven to be a major determinant of hematopoietic engraftment,with patients who receive>2×106 CD34+cells/kg having consistent,rapid,and sustained hematopoietic recovery.However,many patients with relapsed/refractory GCTs have been exposed to multiple cycles of myelosuppressive chemotherapy,which compromises the efficacy of HSC mobilization with granulocyte colony-stimulating factor with or without chemotherapy.Therefore,alternative strategies that use novel agents in combination with traditional mobilizing regimens are required.Herein,after an overview of the mechanisms of HSCs mobilization,we review the existing literature regarding studies reporting various HSC mobilization approaches in patients with relapsed/refractory GCTs,and finally report newer experimental mobilization strategies employing novel agents that have been applied in other hematologic or solid malignancies.
