Subject(s)
Antibodies, Monoclonal/adverse effects , Databases, Factual , Graft vs Host Disease/chemically induced , Hodgkin Disease/therapy , Risk Management , Stem Cell Transplantation , Allografts , Antibodies, Monoclonal/administration & dosage , Female , Humans , Male , Nivolumab , United States , United States Food and Drug AdministrationABSTRACT
The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.
Subject(s)
Breast Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Inhibitor of Differentiation Protein 1/metabolism , Insulin-Like Growth Factor II/metabolism , Neoplasm Recurrence, Local/pathology , Neoplastic Stem Cells/pathology , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Carcinogenesis , Female , Humans , Inhibitor of Differentiation Protein 1/genetics , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor II/genetics , Mice , Mice, Nude , NF-kappa B/genetics , NF-kappa B/metabolism , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/metabolism , Neoplastic Stem Cells/metabolism , Phosphatidylinositol 3-Kinase/genetics , Phosphatidylinositol 3-Kinase/metabolism , Prognosis , Signal Transduction , Spheroids, Cellular , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction.
Subject(s)
Fibrinolysin/antagonists & inhibitors , Graft vs Host Disease/prevention & control , Inflammation Mediators/antagonists & inhibitors , Matrix Metalloproteinase 9/metabolism , Animals , Base Sequence , Biological Transport , Cell Line , DNA Primers , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Female , Graft vs Host Disease/enzymology , Graft vs Host Disease/mortality , Humans , Mice , Mice, Inbred C57BL , Reverse Transcriptase Polymerase Chain Reaction , Severity of Illness IndexABSTRACT
Donor-recipient sex incompatibility has been associated with transplant outcomes in allogeneic hematopoietic SCT. Such outcomes might be because mHA encoded by Y chromosome genes could be immunological targets for allogeneic T cells and B cells to induce GVHD, GVL effect and graft failure. However, its effect on the outcome of cord blood transplantation (CBT) is yet to be clarified. We retrospectively analyzed 191 adult patients who received single-unit CBT after myeloablative conditioning for malignant disease in our institute. In multivariate analysis, male recipients with female donors had a higher incidence of extensive chronic GVHD (hazard ratio (HR) 2.97, P=0.02), and female recipients with male donors had a lower incidence of platelet engraftment (HR 0.56, P=0.02) compared with female recipients with female donors as the reference. Nevertheless, there was no increase in mortality following sex-incompatible CBT. These data suggested that donor-recipient sex compatibility does not have a significant impact on survival after myeloablative CBT for hematological malignancies.
Subject(s)
Cord Blood Stem Cell Transplantation/adverse effects , Cord Blood Stem Cell Transplantation/methods , Graft vs Host Disease/etiology , Hematologic Neoplasms/therapy , Adolescent , Adult , B-Lymphocytes/immunology , Chromosomes, Human, Y , Cord Blood Stem Cell Transplantation/mortality , Female , Graft vs Host Disease/immunology , Graft vs Host Disease/mortality , Hematologic Neoplasms/mortality , Histocompatibility/immunology , Humans , Male , Middle Aged , Minor Histocompatibility Antigens/immunology , Proportional Hazards Models , Retrospective Studies , Sex Distribution , T-Lymphocytes/immunology , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methods , Transplantation, Homologous , Young AdultABSTRACT
BACKGROUND: Acute kidney injury (AKI) is a common medical complication after myeloablative allogeneic stem cell transplantation (SCT). We have previously performed a retrospective analysis of AKI after cord blood transplantation (CBT) in adults, and found that the maximum of vancomycin (VCM) trough levels were significantly higher in patients with AKI. Following these results, we have monitored VCM serum trough concentrations more strictly, to not exceed 10.0 mg/L, since 2008. METHODS: In this report, we performed an analysis of AKI in a new group of 38 adult patients with hematological malignancies treated with unrelated CBT after myeloablative conditioning between January 2008 and July 2011. RESULTS: Cumulative incidence of AKI at day 100 after CBT was 34% (95% confidence interval 19-50). The median of the maximum value of VCM trough was 8.8 (4.5-12.2) mg/L. In multivariate analysis, no factor was associated with the incidence of AKI. No transplant-related mortality was observed. The probability of disease-free survival at 2 years was 83%. CONCLUSION: These findings suggest that strict monitoring of VCM serum trough concentrations has a beneficial effect on outcomes of CBT.
Subject(s)
Acute Kidney Injury/etiology , Anti-Bacterial Agents/adverse effects , Cord Blood Stem Cell Transplantation/adverse effects , Drug Monitoring , Vancomycin/adverse effects , Acute Kidney Injury/metabolism , Adolescent , Adult , Anti-Bacterial Agents/pharmacokinetics , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Transplantation Conditioning/adverse effects , Vancomycin/pharmacokinetics , Young AdultSubject(s)
Hemophilia A/complications , Joint Diseases/surgery , Mesenchymal Stem Cell Transplantation , Adult , Cell Culture Techniques , Feasibility Studies , Hemarthrosis/complications , Humans , Joint Diseases/etiology , Mesenchymal Stem Cells/cytology , Middle Aged , Transplantation, Autologous , Young AdultABSTRACT
We analyzed the disease-specific outcomes of adult patients with advanced myelodysplastic syndrome (MDS) treated with cord blood transplantation (CBT) after myeloablative conditioning. Between August 1998 and June 2009, 33 adult patients with advanced MDS were treated with unrelated CBT. The diagnoses at transplantation included refractory anemia with excess blasts (n=7) and MDS-related secondary AML (sAML) (n=26). All patients received four fractionated 12 Gy TBI and chemotherapy as myeloablative conditioning. The median age was 42 years, the median weight was 55 kg and the median number of cryopreserved nucleated cells was 2.51 × 10(7) cells per kg. The cumulative incidence of neutrophil recovery at day 50 was 91%. Neutrophil recovery was significantly faster in sAML patients (P=0.04). The cumulative incidence of plt recovery at day 200 was 88%. Plt recovery was significantly faster in CMV seronegative patients (P<0.001). The cumulative incidence of grade II-IV acute GVHD (aGVHD) and extensive-type chronic GVHD was 67 and 34%, respectively. Degree of HLA mismatch had a significant impact on the incidence of grade II-IV aGVHD (P=0.021). TRM and relapse at 5-years was 14 and 16%, respectively. The probability of EFS at 5 years was 70%. No factor was associated with TRM, relapse and EFS. These results suggest that adult advanced MDS patients without suitable related or unrelated BM donors should be considered as candidates for CBT.
Subject(s)
Cord Blood Stem Cell Transplantation , Myelodysplastic Syndromes/surgery , Transplantation Conditioning , Adult , Cause of Death , Cord Blood Stem Cell Transplantation/adverse effects , Cord Blood Stem Cell Transplantation/mortality , Disease-Free Survival , Female , Graft vs Host Disease/etiology , Hematopoiesis , Humans , Male , Middle Aged , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/mortalityABSTRACT
BACKGROUND: Tumour-initiating cells (TICs) or cancer stem cells can exist as a small population in malignant tissues. The signalling pathways activated in TICs that contribute to tumourigenesis are not fully understood. METHODS: Several breast cancer cell lines were sorted with CD24 and CD44, known markers for enrichment of breast cancer TICs. Tumourigenesis was analysed using sorted cells and total RNA was subjected to gene expression profiling and gene set enrichment analysis (GSEA). RESULTS: We showed that several breast cancer cell lines have a small population of CD24(-/low)/CD44(+) cells in which TICs may be enriched, and confirmed the properties of TICs in a xenograft model. GSEA revealed that CD24(-/low)/CD44(+) cell populations are enriched for genes involved in transforming growth factor-beta, tumour necrosis factor, and interferon response pathways. Moreover, we found the presence of nuclear factor-kappaB (NF-kappaB) activity in CD24(-/low)/CD44(+) cells, which was previously unrecognised. In addition, NF-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) prevented tumourigenesis of CD24(-/low)/CD44(+) cells in vivo. CONCLUSION: Our findings suggest that signalling pathways identified using GSEA help to identify molecular targets and biomarkers for TIC-like cells.
Subject(s)
Breast Neoplasms/pathology , CD24 Antigen/analysis , Cell Separation/methods , Gene Expression Profiling , Hyaluronan Receptors/analysis , Neoplasm Proteins/analysis , Neoplastic Stem Cells/physiology , Animals , Benzamides/pharmacology , Benzamides/therapeutic use , Biomarkers , Breast Neoplasms/genetics , Cyclohexanones/pharmacology , Cyclohexanones/therapeutic use , Female , Genetic Vectors/pharmacology , Humans , Mice , Mice, Inbred NOD , Mice, SCID , NF-kappa B/antagonists & inhibitors , NF-kappa B/physiology , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/physiology , Neoplastic Stem Cells/chemistry , Neoplastic Stem Cells/transplantation , Oligonucleotide Array Sequence Analysis , Signal Transduction/physiology , Transduction, Genetic , Xenograft Model Antitumor AssaysABSTRACT
We analyzed the disease-specific outcomes of adult ALL treated with cord blood transplantation (CBT) after myeloablative conditioning. Between October 2000 and November 2007, 27 adult patients with ALL were treated with unrelated CBT. All patients received four fractionated 12 Gy TBI and chemotherapy as myeloablative conditioning. The median age was 36 years, the median weight was 57 kg and the median number of nucleated cells was 2.47 x 10(7)/kg. All patients received a single and HLA-mismatched cord blood unit. The cumulative incidence of neutrophil recovery at day 30 and platelet recovery at day 200 was 92.6 and 92.3%, respectively. With a median follow-up of 47 months, the probability of EFS at 5 years was 57.2%. The 5-year cumulative incidence of TRM and relapse was 3.7 and 27.4%, respectively. These results suggest that unrelated CBT after myeloablative conditioning could be safely and effectively used for adult patients with ALL.
Subject(s)
Cord Blood Stem Cell Transplantation/methods , Fetal Blood/cytology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Transplantation Conditioning/methods , Adolescent , Adult , Female , Graft vs Host Disease , Humans , Incidence , Male , Middle Aged , Recurrence , Retrospective Studies , Transplantation, HomologousSubject(s)
Antibodies, Antineutrophil Cytoplasmic/blood , Glomerulonephritis/etiology , Scleroderma, Systemic/complications , Aged , Diagnosis, Differential , Female , Glomerulonephritis/blood , Glomerulonephritis/diagnosis , Glomerulonephritis/drug therapy , Glucocorticoids/therapeutic use , Humans , Methylprednisolone/therapeutic use , Prednisolone/therapeutic use , Scleroderma, Systemic/blood , Scleroderma, Systemic/drug therapySubject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/mortality , Adolescent , Adult , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 6/genetics , Disease-Free Survival , Female , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Retrospective Studies , Survival Rate , Translocation, Genetic/genetics , Transplantation, HomologousABSTRACT
The incidence of pneumonia caused by Pneumocystis carinii (PCP) (organism now renamed Pneumocystis jiroveci) during the early period after cord blood transplantation (CBT) was studied in 120 adults. Initially 89 patients (74%) received oral administration of 2 single-strength trimethoprim-sulfamethoxazole (TMP-SMZ) tablets twice daily from day -21. In 45 of 89 patients (51%), TMP-SMZ administration for a scheduled duration was completed. In the remaining 44 patients (49%), however, TMP-SMZ administration was discontinued prior to day -3 because of toxicity. Among these patients, 42 subsequently received aerosolized pentamidine (AP) on a median of day -13 (range, -20 to -6). Thirty-one patients (26%) received AP without TMP-SMZ administration on a median of day -14 (range, -21 to -9). None of the 120 patients were diagnosed with PCP within 100 days or 2 years after CBT; however, one patient who received AP before CBT but no prophylaxis after CBT developed cerebral toxoplasmosis on day +91. Pre-transplant prophylaxis against PCP did not significantly affect transplantation-related mortality or disease-free survival at 2 years after CBT. The results suggest that PCP during the early period after CBT can be effectively prevented by any pre-transplant prophylactic method.
Subject(s)
Antifungal Agents/administration & dosage , Cord Blood Stem Cell Transplantation/adverse effects , Pentamidine/administration & dosage , Pneumocystis carinii , Pneumonia, Pneumocystis/prevention & control , Trimethoprim, Sulfamethoxazole Drug Combination/administration & dosage , Administration, Inhalation , Administration, Oral , Adolescent , Adult , Antifungal Agents/adverse effects , Drug Administration Schedule , Female , Hematologic Diseases/therapy , Humans , Incidence , Male , Middle Aged , Pentamidine/adverse effects , Pneumonia, Pneumocystis/epidemiology , Pneumonia, Pneumocystis/etiology , Retrospective Studies , Tokyo/epidemiology , Trimethoprim, Sulfamethoxazole Drug Combination/adverse effects , Young AdultABSTRACT
We analysed 86 patients with CML who received unrelated cord blood transplantation (UCBT), identified through a registry of the Japan Cord Blood Bank Network. At transplantation, the median patient age was 39 years (range, 1-67 years); 38 patients were in chronic phase (CP), 13 in the accelerated phase (AP) and 35 in blast crisis (BC). Median duration from diagnosis to UCBT was 1.5 years (range, 0.2-14.6 years). A nucleated cell (NC) dose of more than 3.0 x 10(7) per kg was sufficient to achieve neutrophil (91%) and platelet recovery (86%), whereas the lower dose of NC achieved only 60 and 61%, respectively. The duration and type of pre-transplant treatment did not affect neutrophil or platelet recovery. Results of multivariate analysis indicated that older patients (>50 years) had a higher incidence of transplant-related mortality. Advanced-disease stage and lower doses of NCs were significantly associated with lower leukaemia-free and event-free survival. At 2-year survival for patients in CP, AP and BC was 71, 59 and 32%, respectively (P=0.0004). A pre-transplant European Group for Blood and Marrow Transplantation scoring system was effective in predicting the outcome of UCBT. We conclude that UCBT is a reasonable alternative therapy for patients with CML.
Subject(s)
Cord Blood Stem Cell Transplantation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Adolescent , Adult , Aged , Child , Child, Preschool , Cord Blood Stem Cell Transplantation/mortality , Disease-Free Survival , Female , Humans , Infant , Male , Middle Aged , Recurrence , Risk FactorsABSTRACT
The 190 kD (p190) and 210 kD (p210) Bcr-Abl proteins are responsible for the pathophysiology of Philadelphia chromosome (Ph)(+) leukemia. We applied RNA interference (RNAi) to specific killing of p190(+) cells, and determined the optimal sequences for gene silencing in the BCR, junctional and ABL regions of p190, respectively. Then, p190(+) and p210(+) cells were infected with lentiviral vectors encoding these shRNAs, resulting in efficient killing of p190(+) cells, while p210(+) cells were only sensitive to shBCR and shABL. In p190-transformed Ba/F3 cells, silencing of p190 specifically inhibited tyrosine phospohorylation of Stat5 prior to their death, but did not affect phosphorylation of Jak2, Akt or MEK1/2. In contrast, downregulation of p190 by their treatment with 17-allylamino-17-demetoxygeldanamycin (17-AAG) was associated with reduced protein levels of Jak2, Akt and MEK1/2. shRNA targeting p190 collaborated additively with imatinib and 17-AAG in growth inhibition of Ba/F3-p190wt and imatinib-resistant Ba/F3-p190Y253 H cells. Collectively, RNAi-mediated silencing of p190 is a promising option both for delineating signal transduction and for therapeutic application in 190(+) leukemia.
Subject(s)
Cell Proliferation/drug effects , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , RNA Interference , STAT5 Transcription Factor/metabolism , Animals , Benzamides , Benzoquinones/pharmacology , Blotting, Western , Cell Survival/drug effects , Cell Survival/physiology , Colony-Forming Units Assay , Fusion Proteins, bcr-abl/metabolism , Hematopoiesis/drug effects , Hematopoiesis/physiology , Imatinib Mesylate , Lactams, Macrocyclic/pharmacology , Lentivirus/genetics , Mice , Piperazines/pharmacology , Precursor Cells, B-Lymphoid/metabolism , Precursor Cells, B-Lymphoid/pathology , Pyrimidines/pharmacology , RNA, Small Interfering/pharmacology , Signal TransductionABSTRACT
Although infusion of cryopreserved bone marrow or peripheral blood stem cell is associated with a variety of symptoms, there have been no reports detailing the data of infusion-related toxicities of cryopreserved cord blood (CB) units. We prospectively evaluated the incidence and significance of infusion-related toxicities in 34 adult patients undergoing unrelated CB transplantation. Cryopreserved CB units were thawed and immediately infused, unfiltered, through a central intravenous catheter without further manipulation. Heart rate, blood pressure, oxygen saturation and clinical symptoms were recorded during and after infusion. Twenty-four percent of patients experienced non-cardiovascular toxicities related to infusion. The incidence of systolic and diastolic hypertension and bradycardia was 58, 64 and 32%, respectively. Although three patients (9%) with severe systolic hypertension after the infusion required treatment with antihypertensive agents, no patients experienced life-threatening side effects or needed discontinuation of CB unit infusion. Patient or transplant characteristics had no effect on the hypertension and bradycardia related to the infusion of CB. These data suggest that infusion of cryopreserved CB without further manipulation after thawing is safe and well tolerated. However, cardiovascular toxicities including hypertension and bradycardia were frequently observed.
Subject(s)
Cord Blood Stem Cell Transplantation/adverse effects , Hematologic Neoplasms/therapy , Adolescent , Adult , Bradycardia/etiology , Cardiac Complexes, Premature/etiology , Cryopreservation , Female , Humans , Hypertension/etiology , Male , Middle Aged , Prospective StudiesABSTRACT
The efficacy and safety of preemptive therapy using ganciclovir (GCV) 5 mg/kg once daily for CMV infection after unrelated cord blood transplantation (CBT) were studied. The initial preemptive therapy with GCV 5 mg/kg once daily led to resolution of CMV antigenemia in 25 of 34 patients (74%). In the remaining 9 patients (26%), antigenemia resolved after dose-escalation of GCV or change to foscarnet therapy. Recurrence of antigenemia was seen in 18 patients (53%). A total of 12 patients received the second preemptive therapy with GCV 5 mg/kg once daily, which led to resolution of antigenemia in 11 of 12 patients (92%). The remaining 1 patient (8%) required change to foscarnet therapy. None of 34 patients developed CMV disease. Neutropenia with an absolute neutrophil number of less than 1 and 0.5 x 10(9) per liter after GCV therapy occurred in 12 (35%) and 1 (3%) patients, respectively, after the initial therapy, and in 2 (17%) and 0 (0%) patients, respectively, after the second therapy. No patients developed neutropenic fever or secondary graft failure after GCV therapy. There were no deaths directly attributable to GCV therapy. The present study suggests that antigenemia-based preemptive strategy using GCV 5 mg/kg once daily is feasible and effective for CBT recipients.