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Cancers May 2024Daratumumab is being increasingly integrated into first-line multiple myeloma (MM) induction regimens, leading to improved response depth and longer progression-free...
Daratumumab is being increasingly integrated into first-line multiple myeloma (MM) induction regimens, leading to improved response depth and longer progression-free survival. Autologous stem cell transplantation (ASCT) is commonly performed as a consolidation strategy following first-line induction in fit MM patients. We investigated a cohort of 155 MM patients who received ASCT after first-line induction with or without daratumumab (RVd, = 110; D-RVd, = 45), analyzing differences in stem cell mobilization, apheresis, and engraftment. In the D-RVd group, fewer patients successfully completed mobilization at the planned apheresis date (44% vs. 71%, = 0.0029), and more patients required the use of rescue plerixafor (38% vs. 28%, = 0.3052). The median count of peripheral CD34+ cells at apheresis was lower (41.37 vs. 52.19 × 10/L, = 0.0233), and the total number of collected CD34+ cells was inferior (8.27 vs. 10.22 × 10/kg BW, = 0.0139). The time to recovery of neutrophils and platelets was prolonged (12 vs. 11 days, = 0.0164; and 16 vs. 14 days, = 0.0002, respectively), and a higher frequency of erythrocyte transfusions (74% vs. 51%, = 0.0103) and a higher number of platelet concentrates/patients were required (4 vs. 2; = 0.001). The use of daratumumab during MM induction might negatively impact stem cell mobilization and engraftment in the context of ASCT.
PubMed: 38791933
DOI: 10.3390/cancers16101854 -
Cancers May 2024Peripheral blood stem cell transplantation (PBSCT) is an important therapeutic measure for both hematologic and non-hematologic diseases. For PBSCT to be successful,...
Peripheral blood stem cell transplantation (PBSCT) is an important therapeutic measure for both hematologic and non-hematologic diseases. For PBSCT to be successful, sufficient CD34 cells need to be mobilized and harvested. Although risk factors associated with poor mobilization in patients with hematologic diseases have been reported, studies of patients with non-hematologic diseases and those receiving plerixafor are rare. To identify factors associated with poor mobilization, data from autologous PBSC harvest (PBSCH) in 491 patients were retrospectively collected and analyzed. A multivariate analysis revealed that in patients with a hematologic disease, an age older than 60 years (odds ratio [OR] 1.655, 95% confidence interval [CI] 1.049-2.611, = 0.008), the use of myelotoxic agents (OR 4.384, 95% CI 2.681-7.168, < 0.001), and a low platelet count (OR 2.106, 95% CI 1.205-3.682, = 0.009) were associated with poor mobilization. In patients with non-hematologic diseases, a history of radiation on the pelvis/spine was the sole associated factor (OR 12.200, 95% CI 1.934-76.956, = 0.008). Among the group of patients who received plerixafor, poor mobilization was observed in 19 patients (19/134, 14.2%) and a difference in the mobilization regimen was noted among the good mobilization group. These results show that the risk factors for poor mobilization in patients with non-hematologic diseases and those receiving plerixafor differ from those in patients with hematologic diseases; as such, non-hematologic patients require special consideration to enable successful PBSCH.
PubMed: 38791900
DOI: 10.3390/cancers16101821 -
Blood Science (Baltimore, Md.) Jul 2024Engraftment syndrome (ES) is one of the most common complications in the early phase after autologous hematopoietic stem cell transplantation (ASCT), and we aimed to...
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 ( = .0014), receiving ASCT at CR ( = .002), and higher number of MNC transfused ( = .026) were associated with ES in total cohort. In plasma cell disease subgroup, age ≥60 years ( = .013), plerixafor-based mobilization ( = .036), and receiving ASCT at CR ( = .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.
PubMed: 38779304
DOI: 10.1097/BS9.0000000000000190 -
Cell Death & Disease May 2024Regenerating gene family member 4 (Reg4) has been implicated in acute pancreatitis, but its precise functions and involved mechanisms have remained unclear. Herein, we...
Regenerating gene family member 4 (Reg4) has been implicated in acute pancreatitis, but its precise functions and involved mechanisms have remained unclear. Herein, we sought to investigate the contribution of Reg4 to the pathogenesis of pancreatitis and evaluate its therapeutic effects in experimental pancreatitis. In acute pancreatitis, Reg4 deletion increases inflammatory infiltrates and mitochondrial cell death and decreases autophagy recovery, which are rescued by the administration of recombinant Reg4 (rReg4) protein. In chronic pancreatitis, Reg4 deficiency aggravates inflammation and fibrosis and inhibits compensatory cell proliferation. Moreover, C-X-C motif ligand 12 (CXCL12)/C-X-C motif receptor 4 (CXCR4) axis is sustained and activated in Reg4-deficient pancreas. The detrimental effects of Reg4 deletion are attenuated by the administration of the approved CXCR4 antagonist plerixafor (AMD3100). Mechanistically, Reg4 mediates its function in pancreatitis potentially via binding its receptor exostosin-like glycosyltransferase 3 (Extl3). In conclusion, our findings suggest that Reg4 exerts a therapeutic effect during pancreatitis by limiting inflammation and fibrosis and improving cellular regeneration.
Topics: Animals; Pancreatitis-Associated Proteins; Fibrosis; Mitochondria; Pancreatitis; Mice; Receptors, CXCR4; Humans; Mice, Inbred C57BL; Cyclams; Male; Mice, Knockout; Benzylamines; Chemokine CXCL12; Cell Proliferation; Signal Transduction; Autophagy; Pancreas; Cell Death
PubMed: 38769308
DOI: 10.1038/s41419-024-06738-y -
Journal of Research in Pharmacy Practice 2023Diffuse large B-cell lymphoma is the most prevalent form of non-Hodgkin's lymphoma that is usually treated with chemoimmunotherapy. If the disease proves refractory or...
Successful Stem Cell Mobilization and CD34+ Cell Collection in a Poor Mobilizer: A Case Report Utilizing a Combination of Recombinant Growth Colony Stimulating Factor, Recombinant Human Growth Factor, and Plerixafor.
Diffuse large B-cell lymphoma is the most prevalent form of non-Hodgkin's lymphoma that is usually treated with chemoimmunotherapy. If the disease proves refractory or recurrent, the primary treatment approach involves high-dose chemotherapy with bone marrow transplantation. The collection of peripheral blood stem cells before transplantation plays a vital role in the treatment process, necessitating the mobilization of blood stem cells from the bone marrow to the peripheral blood. Despite using standard methods such as granulocyte colony-stimulating factor (G-CSF), chemotherapy, and plerixafor, some patients cannot collect an optimal count of CD34+ cells for transplantation. Managing these patients with poor mobilization poses significant challenges. In this article, we present a case of a poor mobilizer patient who achieved prosperous mobilization by using recombinant human G-CSF, recombinant human growth hormone, and plerixafor.
PubMed: 38716322
DOI: 10.4103/jrpp.jrpp_46_23 -
ACS Biomaterials Science & Engineering May 2024The laminar flow profiles in microfluidic systems coupled to rapid diffusion at flow streamlines have been widely utilized to create well-controlled chemical gradients...
The laminar flow profiles in microfluidic systems coupled to rapid diffusion at flow streamlines have been widely utilized to create well-controlled chemical gradients in cell cultures for spatially directing cell migration. However, within hydrogel-based closed microfluidic systems of limited depth (≤0.1 mm), the biomechanical cues for the cell culture are dominated by cell interactions with channel surfaces rather than with the hydrogel microenvironment. Also, leaching of poly(dimethylsiloxane) (PDMS) constituents in closed systems and the adsorption of small molecules to PDMS alter chemotactic profiles. To address these limitations, we present the patterning and integration of a PDMS-free open fluidic system, wherein the cell-laden hydrogel directly adjoins longitudinal channels that are designed to create chemotactic gradients across the 3D culture width, while maintaining uniformity across its ∼1 mm depth to enhance cell-biomaterial interactions. This hydrogel-based open fluidic system is assessed for its ability to direct migration of U87 glioma cells using a hybrid hydrogel that includes hyaluronic acid (HA) to mimic the brain tumor microenvironment and gelatin methacrylate (GelMA) to offer the adhesion motifs for promoting cell migration. Chemotactic gradients to induce cell migration across the hydrogel width are assessed using the chemokine CXCL12, and its inhibition by AMD3100 is validated. This open-top hydrogel-based fluidic system to deliver chemoattractant cues over square-centimeter-scale areas and millimeter-scale depths can potentially serve as a robust screening platform to assess emerging glioma models and chemotherapeutic agents to eradicate them.
Topics: Humans; Glioma; Cell Movement; Hydrogels; Chemotaxis; Cell Line, Tumor; Cell Culture Techniques, Three Dimensional; Tumor Microenvironment; Chemokine CXCL12; Cyclams; Cell Culture Techniques; Hyaluronic Acid; Gelatin; Benzylamines; Brain Neoplasms
PubMed: 38652035
DOI: 10.1021/acsbiomaterials.4c00041 -
Hematology, Transfusion and Cell Therapy Mar 2024High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) improved 5-year overall survival rates in relapsed/refractory germ cell tumors...
High-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT) improved 5-year overall survival rates in relapsed/refractory germ cell tumors (GCTs) from 10% to 52%. Nearly 30% of GCT patients are deemed poor mobilizers after receiving several lines of prior therapy. There is limited data available regarding upfront plerixafor use in GCT patients. We predicted upfront plerixafor use would increase the amount of stem cells collected preventing subsequent mobilizations and improve time to curative therapy. A retrospective, single center, chart review of adult GCT patients who received plerixafor upfront for mobilization at a single center between January 1, 2013 and August 31, 2021 was performed. The primary objective was to evaluate the rate of successful peripheral blood CD34 cell collections. Secondary objectives consisted of describing the impact of plerixafor use on mobilization and assessing auto-HSCT related outcomes. Sixteen patients received plerixafor upfront after an average of three prior lines of therapy (range: 2-5 lines). Successful collection (≥4 × 10 CD34 cells/Kg collected within four days) was achieved in 15 (94%) patients in a median of one apheresis day (interquartile range: 1-2 days). All patients proceeded to an initial auto-HSCT and 12 patients (75%) completed both transplants as planned. Survival at 12 months was 50%. The significantly higher amount of CD34 cells collected over less apheresis days demonstrated the clinical utility of upfront plerixafor and its potential to facilitate more efficient stem cell mobilization. There is a need for larger randomized studies with upfront plerixafor use in this unique patient population.
PubMed: 38485549
DOI: 10.1016/j.htct.2023.12.008 -
Hua Xi Kou Qiang Yi Xue Za Zhi = Huaxi... Feb 2024This study aimed to investigate the effects of sitagliptin on the proliferation, apoptosis, inflammation, and osteogenic differentiation of human periodontal ligament...
Effects of sitagliptin activation of the stromal cell-derived factor-1/CXC chemokine receptor 4 signaling pathway on the proliferation, apoptosis, inflammation, and osteogenic differentiation of human periodontal ligament stem cells induced by lipopolysaccharide.
OBJECTIVES
This study aimed to investigate the effects of sitagliptin on the proliferation, apoptosis, inflammation, and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) in lipopolysaccharide (LPS)-induced inflammatory microenvironment and its molecular mechanism.
METHODS
hPDLSCs were cultured and treated with different concentrations of sitagliptin to detect cell viability and subsequently determine the experimental concentration of sitagliptin. An hPDLSCs inflammation model was established after 24 h of stimulation with 1 µg/mL LPS and divided into blank, control, low-concentration sitagliptin (0.5 µmol/L), medium-concentration sitagliptin (1 µmol/L), and high-concentration sitagliptin (2 µmol/L), high-concentrationsitagliptin+stromal cell derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) pathway inhibitor (AMD3100) (2 µmol/L+10 µg/mL) groups. A cell-counting kit-8 was used to detect the proliferation activity of hPDLSCs after 24, 48, and 72 h culture. The apoptosis of hPDLSCs cultured for 72 h was detected by flow cytometry. After inducing osteogenic differentiation for 21 days, alizarin red staining was used to detect the osteogenic differentiation ability of hPDLSCs. The alkaline phosphatase (ALP) activity in hPDLSCs was determined using a kit. The levels of inflammatory factors [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6] in the supernatant of hPDLSCs culture were detected by enzyme-linked immunosorbent assay. The mRNA expressions of osteogenic differentiation genes [Runt-associated transcription factor 2 (RUNX2), osteocalcin (OCN), osteopontin (OPN)], SDF-1 and CXCR4 in hPDLSCs were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Western blot analysis was used to determine SDF-1 and CXCR4 protein expression in hPDLSCs.
RESULTS
Compared with the blank group, the proliferative activity, number of mineralized nodules, staining intensity, ALP activity, and RUNX2, OCN, OPN mRNA, SDF-1, and CXCR4 mRNA and protein expression levels of hPDLSCs in the control group significantly decreased. The apoptosis rate and levels of TNF-α, IL-1β, and IL-6 significantly increased (<0.05). Compared with the control group, the proliferative activity, number of mineralized nodule, staining intensity, ALP activity, and RUNX2, OCN, OPN mRNA, SDF-1, and CXCR4 mRNA and protein expression levels of hPDLSCs in low-, medium-, and high-concentration sitagliptin groups increased. The apoptosis rate and levels of TNF-α, IL-1β, and IL-6 decreased (<0.05). AMD3100 partially reversed the effect of high-concentration sitagliptin on LPS-induced hPDLSCs (<0.05).
CONCLUSIONS
Sitagliptin may promote the proliferation and osteogenic differentiation of hPDLSCs in LPS-induced inflammatory microenvironment by activating the SDF-1/CXCR4 signaling pathway. Furthermore, it inhibited the apoptosis and inflammatory response of hPDLSCs.
Topics: Humans; Periodontal Ligament; Lipopolysaccharides; Core Binding Factor Alpha 1 Subunit; Receptors, CXCR4; Tumor Necrosis Factor-alpha; Interleukin-6; Osteogenesis; Signal Transduction; Inflammation; Stem Cells; RNA, Messenger; Apoptosis; Cell Proliferation; Stromal Cells; Cell Differentiation; Cells, Cultured; Cyclams; Benzylamines
PubMed: 38475949
DOI: 10.7518/hxkq.2024.2023213 -
Cell Communication and Signaling : CCS Mar 2024The incidence of multiple myeloma (MM), a type of blood cancer affecting monoclonal plasma cells, is rising. Although new drugs and therapies have improved patient... (Review)
Review
BACKGROUND
The incidence of multiple myeloma (MM), a type of blood cancer affecting monoclonal plasma cells, is rising. Although new drugs and therapies have improved patient outcomes, MM remains incurable. Recent studies have highlighted the crucial role of the chemokine network in MM's pathological mechanism. Gaining a better understanding of this network and creating an overview of chemokines in MM could aid in identifying potential biomarkers and developing new therapeutic strategies and targets.
PURPOSE
To summarize the complicated role of chemokines in MM, discuss their potential as biomarkers, and introduce several treatments based on chemokines.
METHODS
Pubmed, Web of Science, ICTRP, and Clinical Trials were searched for articles and research related to chemokines. Publications published within the last 5 years are selected.
RESULTS
Malignant cells can utilize chemokines, including CCL2, CCL3, CCL5, CXCL7, CXCL8, CXCL12, and CXCL13 to evade apoptosis triggered by immune cells or medication, escape from bone marrow and escalate bone lesions. Other chemokines, including CXCL4, CCL19, and CXCL10, may aid in recruiting immune cells, increasing their cytotoxicity against cancer cells, and inducing apoptosis of malignant cells.
CONCLUSION
Utilizing anti-tumor chemokines or blocking pro-tumor chemokines may provide new therapeutic strategies for managing MM. Inspired by developed CXCR4 antagonists, including plerixafor, ulocuplumab, and motixafortide, more small molecular antagonists or antibodies for pro-tumor chemokine ligands and their receptors can be developed and used in clinical practice. Along with inhibiting pro-tumor chemokines, studies suggest combining chemokines with chimeric antigen receptor (CAR)-T therapy is promising and efficient.
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Chemokines; Signal Transduction; Biomarkers
PubMed: 38475811
DOI: 10.1186/s12964-024-01544-7 -
Annals of Medicine Dec 2024The combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor is one of the approaches for hematopoietic stem cell mobilization in patients with... (Meta-Analysis)
Meta-Analysis
AIM
The combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor is one of the approaches for hematopoietic stem cell mobilization in patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), and Hodgkin's lymphoma (HL). This systematic review and meta-analysis aimed to determine the ability of G-CSF + plerixafor to mobilize peripheral blood (PB) CD34+ cells and examine its safety profile.
METHODS
We performed a database search using the terms 'granulocyte colony stimulating factor', 'G-CSF', 'AMD3100', and 'plerixafor', published up to May 1, 2023. The methodology is described in further detail in the PROSPERO database (CRD42023425760).
RESULTS
Twenty-three studies were included in this systematic review and meta-analysis. G-CSF + plerixafor resulted in more patients achieving the predetermined apheresis yield of CD34+ cells than G-CSF alone (OR, 5.33; 95%, 4.34-6.55). It was further discovered that G-CSF + plerixafor could mobilize more CD34+ cells into PB, which was beneficial for the next transplantation in both randomized controlled (MD, 18.30; 95%, 8.74-27.85) and single-arm (MD, 20.67; 95%, 14.34-27.00) trials. Furthermore, G-CSF + plerixafor did not cause more treatment emergent adverse events than G-CSF alone (OR, 1.25; 95%, 0.87-1.80).
CONCLUSIONS
This study suggests that the combination of G-CSF and plerixafor, resulted in more patients with MM, NHL, and HL, achieving the predetermined apheresis yield of CD34+ cells, which is related to the more effective mobilization of CD34+ cells into PB.
Topics: Humans; Hematopoietic Stem Cell Mobilization; Multiple Myeloma; Granulocyte Colony-Stimulating Factor; Heterocyclic Compounds; Lymphoma; Lymphoma, Non-Hodgkin; Hematopoietic Stem Cells; Transplantation, Autologous; Benzylamines; Hematopoietic Stem Cell Transplantation
PubMed: 38470973
DOI: 10.1080/07853890.2024.2329140