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INTRODUCTION: Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series. METHODS AND ANALYSIS: This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over. ETHICS AND DISSEMINATION: This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians. TRIAL REGISTRATION NUMBER: jRCTs041210027.
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Dexametasona , Histiocitose de Células de Langerhans , Ácido Zoledrônico , Humanos , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/mortalidade , Criança , Adolescente , Japão , Adulto , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Adulto Jovem , Ácido Zoledrônico/uso terapêutico , Masculino , Feminino , Ensaios Clínicos Fase II como Assunto , Pré-Escolar , Conservadores da Densidade Óssea/uso terapêuticoRESUMO
BACKGROUND: In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. METHODS: We conducted a post-marketing all-case surveillance to study the safety and efficacy of ponatinib in clinical practice, focusing on arterial occlusive events. RESULTS: Data from 724 patients were collected for 2 years from the initiation of ponatinib. The arterial occlusive events were reported in 6.49% (47/724) with an exposure-adjusted incidence rate of 6.8/100 person-years. The risks associated with arterial occlusive events were age and comorbidities including hypertension and diabetes. At 104 weeks, the cumulative major molecular response rate in patients with chronic-phase chronic myeloid leukemia was 67.2% and the complete cytogenetic response in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was 80.0%. Furthermore, the estimated 1-year overall survival rate was 98.5% for chronic-phase chronic myeloid leukemia and 68.6% for Philadelphia chromosome-positive acute lymphoblastic leukemia. CONCLUSIONS: This surveillance demonstrated that ponatinib has a favorable safety and efficacy profile in Japanese patients and also showed the necessity of closely monitoring arterial occlusive events in older adults and patients with predisposing factors for atherosclerosis.
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Arteriopatias Oclusivas , Imidazóis , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Vigilância de Produtos Comercializados , Piridazinas , Humanos , Imidazóis/efeitos adversos , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Piridazinas/efeitos adversos , Piridazinas/uso terapêutico , Piridazinas/administração & dosagem , Masculino , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Idoso , Japão/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto , Idoso de 80 Anos ou mais , Arteriopatias Oclusivas/induzido quimicamente , Arteriopatias Oclusivas/epidemiologia , Adulto Jovem , Adolescente , Resultado do Tratamento , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêuticoRESUMO
Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated1-7. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells remain unclear. Here we show the potency and mechanisms of action and resistance of the EZH1-EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations. Integrative single-cell analyses showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. Acquired mutations at the PRC2-compound interface result in the propagation of clones with increased H3K27me3 expression. In patients free of PRC2 mutations, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation in the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies.
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Histonas , Linfoma , Adulto , Humanos , Histonas/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Metilação , Cromatina/genéticaRESUMO
The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulator 3 (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Células-Tronco Neoplásicas/patologia , Linhagem Celular Tumoral , Proteínas de Membrana , Proteínas de Neoplasias/genéticaRESUMO
Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs. However, little is known about the mechanism by which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3-/- mice was shown to depend on Toll-like receptor 7 (TLR7), which senses a combination of nucleosides and oligoribonucleotides (ORNs). TLR7 increased phagocyte numbers by driving the proliferation of Ly6Chi immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3-/- mice. Downstream of TLR7, FcRγ and DAP10 were required for monocyte proliferation. Histiocytosis is accompanied by inflammation in SLC29A3 disorders. However, TLR7 in nucleoside-laden splenic monocytes failed to activate inflammatory responses. Enhanced production of proinflammatory cytokines was observed only after stimulation with ssRNAs, which would increase lysosomal ORNs. Patient-derived monocytes harboring the G208R SLC29A3 mutation showed enhanced survival and proliferation in a TLR8-antagonist-sensitive manner. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders.
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Histiocitose , Receptor 7 Toll-Like , Animais , Camundongos , Citocinas/genética , Histiocitose/genética , Mutação/genética , Nucleosídeos , Receptor 7 Toll-Like/genética , Receptor 8 Toll-Like/genéticaRESUMO
Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal expansion of CD1a+ CD207+ myeloid dendritic cells. The features of LCH are mainly described in children and remain poorly defined in adults; therefore, we conducted a nationwide survey to collect clinical data from 148 adult patients with LCH. The median age at diagnosis was 46.5 (range: 20-87) years with male predominance (60.8%). Among the 86 patients with detailed treatment information, 40 (46.5%) had single system LCH, whereas 46 (53.5%) had multisystem LCH. Moreover, 19 patients (22.1%) had an additional malignancy. BRAF V600E in plasma cell-free DNA was associated with a low overall survival (OS) rate and the risk of the pituitary gland and central nervous system involvement. At a median follow-up of 55 months from diagnosis, six patients (7.0%) had died, and the four patients with LCH-related death did not respond to initial chemotherapy. The OS probability at 5 years post-diagnosis was 90.6% (95% confidence interval: 79.8-95.8). Multivariate analysis showed that patients aged ≥60 years at diagnosis had a relatively poor prognosis. The probability of event-free survival at 5 years was 52.1% (95% confidence interval: 36.6-65.5), with 57 patients requiring chemotherapy. In this study, we first revealed the high rate of relapse after chemotherapy and mortality of poor responders in adults as well as children. Therefore, prospective therapeutic studies of adults with LCH using targeted therapies are needed to improve outcomes in adults with LCH.
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Histiocitose de Células de Langerhans , Neoplasias , Criança , Humanos , Masculino , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/terapia , Intervalo Livre de Progressão , MutaçãoRESUMO
Gene editing using engineered nucleases frequently produces unintended genetic lesions in hematopoietic stem cells (HSCs). Gene-edited HSC cultures thus contain heterogeneous populations, the majority of which either do not carry the desired edit or harbor unwanted mutations. In consequence, transplanting edited HSCs carries the risks of suboptimal efficiency and of unwanted mutations in the graft. Here, we present an approach for expanding gene-edited HSCs at clonal density, allowing for genetic profiling of individual clones before transplantation. We achieved this by developing a defined, polymer-based expansion system and identifying long-term expanding clones within the CD201+CD150+CD48-c-Kit+Sca-1+Lin- population of precultured HSCs. Using the Prkdcscid immunodeficiency model, we demonstrate that we can expand and profile edited HSC clones to check for desired and unintended modifications, including large deletions. Transplantation of Prkdc-corrected HSCs rescued the immunodeficient phenotype. Our ex vivo manipulation platform establishes a paradigm to control genetic heterogeneity in HSC gene editing and therapy.
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Edição de Genes , Transplante de Células-Tronco Hematopoéticas , Heterogeneidade Genética , Células-Tronco Hematopoéticas , Fenótipo , Células ClonaisRESUMO
Cancer pain is a significant issue in terminally ill cancer patients (TICPs). The fentanyl patch (FP) is used extensively for treating cancer pain, but FP requirements vary between patients. We aimed to identify determinants of FP requirements in TICPs and propose effective pain relief using a FP. In a retrospective chart review, we investigated cancer patients admitted to our hospital from April 2012 to July 2015 and used FP until death. The time course of FP use in TICPs until death was examined. The primary endpoint was the final dose of FP use (FDFP). In total, 79 patients were included the analysis. FDFP was inversely correlated with age (R= -0.262, p = 0.20; Spearman test). FDFP tended to be higher in males than in females and was significantly higher in patients with pancreatic cancer than in patients without pancreatic cancer (p = 0.017; Welch's test). FP adjustments were more frequent in the last 60 days of life in patients with pancreatic cancer than in patients with other malignancies (P for interaction = 0.002; mixed effect model). In conclusion, younger age, and pancreatic cancer were associated with higher FP requirements in TICPs. TICPs with pancreatic cancer required more frequent FP adjustment near death.
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Dor do Câncer , Neoplasias , Neoplasias Pancreáticas , Masculino , Feminino , Humanos , Fentanila , Analgésicos Opioides/uso terapêutico , Dor do Câncer/tratamento farmacológico , Doente Terminal , Estudos Retrospectivos , Neoplasias/complicações , Neoplasias Pancreáticas/complicações , Neoplasias PancreáticasRESUMO
We investigated the role of Hoip, a catalytic subunit of linear ubiquitin chain assembly complex (LUBAC), in adult hematopoiesis and myeloid leukemia by using both conditional deletion of Hoip and small-molecule chemical inhibitors of Hoip. Conditional deletion of Hoip led to significantly longer survival and marked depletion of leukemia burden in murine myeloid leukemia models. Nevertheless, a competitive transplantation assay showed the reduction of donor-derived cells in the bone marrow of recipient mice was relatively mild after conditional deletion of Hoip. Although both Hoip-deficient hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) impaired the maintenance of quiescence, conditional deletion of Hoipinduced apoptosis in LSCs but not HSCs in vivo. Structure-function analysis revealed that LUBAC ligase activity and the interaction of LUBAC subunits were critical for the propagation of leukemia. Hoip regulated oxidative phosphorylation pathway independently of nuclear factor kappa B pathway in leukemia, but not in normal hematopoietic cells. Finally, the administration of thiolutin, which inhibits the catalytic activity of Hoip, improved the survival of recipients in murine myeloid leukemia and suppressed propagation in the patient-derived xenograft model of myeloid leukemia. Collectively, these data indicate that inhibition of LUBAC activity may be a valid therapeutic target for myeloid leukemia.
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Leucemia Mieloide , Ubiquitina-Proteína Ligases , Humanos , Animais , Camundongos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , NF-kappa B/metabolismo , ApoptoseRESUMO
(1) Objectives: The effect of cell-processing protocols on the clinical efficacy of bone tissue engineering is not well-known. To maximize efficacy, we optimized the cell-processing protocol for bone-marrow-derived mesenchymal stromal cells for bone tissue engineering. In this study, the efficacy of bone tissue engineering using this modified protocol was compared to that of the original protocol. (2) Materials and Methods: This single-arm clinical study included 15 patients. Cells were obtained from bone marrow aspirates and expanded in culture flasks containing basic fibroblast growth factor. The cells were seeded onto ß-tricalcium phosphate granules and induced into osteogenic cells for two weeks. Then, the cell-scaffold composites were transplanted into patients with severe atrophic alveolar bone. Radiographic evaluations and bone biopsies were performed. The results were compared with those of a previous clinical study that used the original protocol. (3) Results: Panoramic X-ray and computed tomography showed bone regeneration at the transplantation site in all cases. The average bone area in the biopsy samples at 4 months was 44.0%, which was comparable to that in a previous clinical study at 6 months (41.9%) but with much less deviation. No side effects related to cell transplantation were observed. In regenerated bone, 100% of the implants were integrated. (4) Conclusions: Compared to the original protocol, the non-inferiority of this protocol was proven. The introduction of an optimized cell-processing protocol resulted in a comparable quality of regenerated bone, with less fluctuation. Optimized cell-processing protocols may contribute to stable bone regeneration.
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Langerhans cell histiocytosis (LCH) and acute myeloid leukemia (AML) are distinct entities of blood neoplasms, and the exact developmental origin of both neoplasms are considered be heterogenous among patients. However, reports of concurrent LCH and AML are rare. Herein we report a novel case of concurrent LCH and AML which shared same the driver mutations, strongly suggesting a common clonal origin.An 84-year-old female presented with cervical lymphadenopathy and pruritic skin rash on the face and scalp. Laboratory tests revealed pancytopenia with 13% of blasts, elevated LDH and liver enzymes, in addition to generalised lymphadenopathy and splenomegaly by computed tomography. Bone marrow specimens showed massive infiltration of MPO-positive myeloblasts, whereas S-100 and CD1a positive atypical dendritic cell-like cells accounted for 10% of the atypical cells on bone marrow pathology, suggesting a mixture of LCH and AML. A biopsy specimen from a cervical lymph node and the skin demonstrated the accumulation of atypical cells which were positive for S-100 and CD1a. LCH was found in lymph nodes, skin and bone marrow; AML was found in peripheral blood and bone marrow (AML was predominant compared with LCH in the bone marrow). Next generation sequencing revealed four somatic driver mutations (NRAS-G13D, IDH2-R140Q, and DNMT3A-F640fs/-I715fs), equally shared by both the lymph node and bone marrow, suggesting a common clonal origin for the concurrent LCH and AML. Prednisolone and vinblastine were initially given with partial response in LCH; peripheral blood blasts also disappeared for 3 months. Salvage chemotherapy with low dose cytarabine and aclarubicin were given for relapse, with partial response in both LCH and AML. She died from pneumonia and septicemia on day 384. Our case demonstrates a common cell of origin for LCH and AML with a common genetic mutation, providing evidence to support the proposal to classify histiocytosis, including LCH, as a myeloid/myeloproliferative malignancy.
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Introduction: Mesenchymal stromal cells (MSCs) hold the potential for application as cellular therapy products; however, there are many problems that need to be addressed before the use in clinical settings, these include the heterogeneity of MSCs, scalability in MSC production, timing and techniques for MSC administration, and engraftment efficiency and persistency of administered MSCs. In this study, problems regarding immune rejection caused by human leukocyte antigen (HLA) mismatches were addressed. Methods: Umbilical cord-derived MSCs (UC-MSCs) were gene-edited to avoid allogeneic immunity. The HLA class I expression was abrogated by the knock-out of the beta-2-microglobulin (B2M) gene; instead, the B2M-HLA-G fusion gene was knocked-in using the CRISPR/Cas9 system in combination with adeno-associated virus (AAV). Results: Cell surface markers on gene-edited UC-MSCs were not different from those on primary UC-MSCs. The gene-edited UC-MSCs also retained the potential to differentiate into adipocytes, osteoblasts, and chondrocytes. B2M gene knock-out alone protected cells from allogeneic T cell immune responses but were vulnerable to NK cells. B2M gene knock-out in combination with B2M-HLA-G knock-in protected cells from both T cells and NK cells. The B2M-HLA-G knock-in MSCs retained a good immunosuppressive ability and the addition of these cells into the mixing lymphocyte reaction showed a significant inhibition of T cell proliferation. Conclusions: The results of this study demonstrated the possibility that the CRISPR/Cas9 system combined with AAV can be used to effectively disrupt/introduce any gene into UC-MSCs. Our findings suggest that the gene-edited cell line produced here using this method may have a higher ability to escape the cytotoxic activity of immune cells than primary cells, thereby being more advantageous for long-term graft survival.
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Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. Although ABL1-specific tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML, the TKI efficacy depends on the individual patient. In this work, we found that the patients with different nilotinib responses can be classified by using the estimated parameters of our simple dynamical model with two common laboratory findings. Furthermore, our proposed method identified patients who failed to achieve a treatment goal with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêuticoRESUMO
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) characterized by sustained mature neutrophilic leukocytosis. Recently, presence of colony-stimulating factor 3 receptor (CSF3R) mutations has been added to the diagnostic criteria for CNL. Anti-inflammatory effects of the JAK1/2 inhibitor ruxolitinib relieve constitutional symptoms associated with MPN, such as fatigue, night sweats, and fever. We present a case of CNL harboring CSF3R-T618I mutation exacerbated by concomitant bilateral renal abscesses, which was refractory to antibiotics, at the time of initial diagnosis. In this case, ruxolitinib rapidly improved not only CNL but the infection, due to its anti-inflammatory potency.
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Even though hematopoietic stem cell transplantation (HSCT) allows successful treatment for many malignant and non-malignant disorders, its curative potential remains limited by severe side effects, including infections and other transplant-related complications such as graft-versus-host disease (GvHD). This study examined changes in serum proteome via high-performance two-dimensional gel electrophoresis (2-DE) during HSCT to search for diagnostic biomarkers for post-HSCT complications. Longitudinal proteomic analysis revealed proteins related to metabolic complications and hemolytic anemia. Retinol-binding protein 4 (RBP4), a reliable marker of insulin resistance, was identified, and is possibly associated with the onset mechanism of acute graft-versus-host disease (aGvHD) and/or skin GvHD. Although the cause of insulin resistance is not fully understood, it is thought to be associated with adipocytes inflammation induced by RBP4, iron overload and hemolytic anemia after HSCT, as observed in this study. The present study has demonstrated that insulin resistance and metabolic complications could be immediate complications after transplantation and are associated with aGvHD. The biomarkers revealed in this study are promising tools to be used for improving the early diagnosis of HSCT-associated complications, especially aGvHD, possibly even before clinical manifestations.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Resistência à Insulina , Biomarcadores , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Proteômica , Proteínas Plasmáticas de Ligação ao Retinol , Transplante Homólogo/efeitos adversosRESUMO
Severe congenital neutropenia (SCN) is characterized by severe neutropenia and recurrent critical infections. X-linked neutropenia (XLN) is caused by a gain-of-function mutation in the Wiskott-Aldrich syndrome gene (WAS), the product of which (WASp) is expressed only in blood cells, especially during neutrophil maturation. To investigate the mechanism of neutropenia, we established a novel knock-in mouse line expressing WASp-I292T. WASp-I292T neutrophils exhibited activated (dysregulated) actin polymerization. Although WASp-I292T mice did not recapitulate neutropenia, neutrophil levels were increased in the bone marrow, and extramedullary hematopoiesis was observed. Bone marrow neutrophils from WASp-I292T mice exhibited attenuated transmigration. These abnormalities were associated with downregulation of NFκB and TP53 and faulty activation of their downstream pathways.
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Neutropenia , Vespas , Actinas/metabolismo , Animais , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Hematopoese/genética , Humanos , Camundongos , Neutropenia/genética , Neutrófilos/metabolismo , Proteína da Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/metabolismoRESUMO
This study investigated the safety, efficacy, and immunological influence of allogeneic umbilical cord-derived mesenchymal stromal cells (IMSUT-CORD) processed in serum-free medium and cryoprotectant, for treating steroid-resistant acute graft-versus-host disease (aGVHD). In a phase I dose-escalation trial, IMSUT-CORD were infused intravenously twice weekly over two cycles with up to two additional cycles. Four patients received a dose of 1 × 106 cells/kg, while three received 2 × 106/kg. Of 76 total adverse events, fourteen associated or possibly associated adverse events included 2 cases of a hot flash, headache, and peripheral neuropathy, 1 each of upper abdominal pain, hypoxia, increased γ-GTP, somnolence, peripheral vascular pain at the injection site, thrombocytopenia, hypertension, and decreased fibrinogen. At 16 weeks after the initial IMSUT-CORD infusion, three patients showed complete response (CR), two partial response (PR), one mixed response, and one no response. The overall response rate was 71.4%, and the continuous CR/PR rate was 100% for over 28 days after CR/PR. NK cell count significantly increased and correlated with treatment response, whereas IL-12, IL-17, and IL-33 levels decreased, but did not correlate with treatment response. CCL2 and CCL11 levels increased during IMSUT-CORD therapy. IMSUT-CORD are usable in patients with steroid-resistant aGVHD (UMIN000032819: https://www.umin.ac.jp/ctr ).
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Humanos , Fibrinogênio/uso terapêutico , Doença Enxerto-Hospedeiro/terapia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Guanosina Trifosfato/uso terapêutico , Interleucina-12/uso terapêutico , Interleucina-17/uso terapêutico , Interleucina-33/uso terapêutico , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Esteroides/uso terapêutico , Cordão UmbilicalRESUMO
Histiocytosis is a syndrome characterized by fever, pain, and other symptoms caused by the neoplastic proliferation of atypical cells of the macrophage-dendritic cell lineage and surrounding inflammatory cell infiltration. The diagnosis is confirmed by the immune-histological features of biopsied specimens. From this viewpoint, histiocytosis is divided into Langerhans cell histiocytosis (LCH) (CD1a+/CD207+/CD14±/CD68±) and non-LCH, including Erdheim-Chester disease (ECD), juvenile xanthogranuloma, and Rosai-Dorfman disease (CD1a-/CD207-/CD14++/CD68++). Genetic alterations occur at the cellular level in hematopoietic progenitor cells, and environmental factors are assumed to influence tumor development. The genomic analysis of the lesions involved revealed driver mutations primarily in the MAPK pathway, including BRAF-V600E, and the PI3K pathway. This strongly suggests that abnormalities in these signaling pathways play a role in pathogenesis. Steroids, vinca alkaloids, cytarabine, and cladribine are commonly used to treat histiocytosis. However, efficacy has not been fully confirmed in any of them. In recent years, the efficacy of BRAF inhibitors and MEK inhibitors has been reported mainly in therapy-resistant and refractory cases of LCH and ECD.
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Doença de Erdheim-Chester , Histiocitose de Células de Langerhans , Xantogranuloma Juvenil , Doença de Erdheim-Chester/diagnóstico , Doença de Erdheim-Chester/tratamento farmacológico , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/terapia , Humanos , Mutação , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and frequent progression to leukemia. It has long remained unresolved how MDS cells, which are less proliferative, inhibit normal hematopoiesis and eventually dominate the bone marrow space. Despite several studies implicating mesenchymal stromal or stem cells (MSCs), a principal component of the HSC niche, in the inhibition of normal hematopoiesis, the molecular mechanisms underlying this process remain unclear. Here, we demonstrate that both human and mouse MDS cells perturb bone metabolism by suppressing the osteolineage differentiation of MSCs, which impairs the ability of MSCs to support normal HSCs. Enforced MSC differentiation rescues the suppressed normal hematopoiesis in both in vivo and in vitro MDS models. Intriguingly, the suppression effect is reversible and mediated by extracellular vesicles (EVs) derived from MDS cells. These findings shed light on the novel MDS EV-MSC axis in ineffective hematopoiesis.