RESUMEN
Haematopoietic stem cells (HSCs) are a rare cell type that reconstitute the entire blood and immune systems after transplantation and can be used as a curative cell therapy for a variety of haematological diseases1,2. However, the low number of HSCs in the body makes both biological analyses and clinical application difficult, and the limited extent to which human HSCs can be expanded ex vivo remains a substantial barrier to the wider and safer therapeutic use of HSC transplantation3. Although various reagents have been tested in attempts to stimulate the expansion of human HSCs, cytokines have long been thought to be essential for supporting HSCs ex vivo4. Here we report the establishment of a culture system that allows the long-term ex vivo expansion of human HSCs, achieved through the complete replacement of exogenous cytokines and albumin with chemical agonists and a caprolactam-based polymer. A phosphoinositide 3-kinase activator, in combination with a thrombopoietin-receptor agonist and the pyrimidoindole derivative UM171, were sufficient to stimulate the expansion of umbilical cord blood HSCs that are capable of serial engraftment in xenotransplantation assays. Ex vivo HSC expansion was further supported by split-clone transplantation assays and single-cell RNA-sequencing analysis. Our chemically defined expansion culture system will help to advance clinical HSC therapies.
Asunto(s)
Técnicas de Cultivo de Célula , Proliferación Celular , Citocinas , Células Madre Hematopoyéticas , Humanos , Proliferación Celular/efectos de los fármacos , Células Clonales/citología , Células Clonales/efectos de los fármacos , Células Clonales/metabolismo , Sangre Fetal/citología , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Técnicas de Cultivo de Célula/métodos , Albúminas , Caprolactama , Polímeros , Receptores de Trombopoyetina , Trasplante Heterólogo , Análisis de Expresión Génica de una Sola CélulaRESUMEN
BACKGROUND: Haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with post-transplant cyclophosphamide (PTCy) is an important therapeutic option for patients lacking an HLA-matched donor. However, the significance of CD34+ cell dose in grafts has not been fully elucidated. OBJECTIVE: We aimed to explore the impact of CD34+ cell dose on outcomes after haplo-PBSCT with PTCy. STUDY DESIGN: We retrospectively investigated 111 consecutive patients who underwent haplo-PBSCT with PTCy or HLA-matched PBSCT from related donors. RESULTS: There were no statistically significant differences in 3-year overall survival (p = 0.559) or progression-free survival (p = 0.974) between haplo-PBSCT and matched PBSCT. Delayed neutrophil engraftment and a lower incidence of graft-versus-host disease were observed in haplo-PBSCT. The median dose of CD34+ cells was 4.9 × 106 /kg in 57 haplo-PBSCT and 4.5 × 106 /kg in 54 matched PBSCTs. Importantly, patients who underwent haplo-PBSCT with the administration of CD34+ cell at a dose of ≥4.0 × 106 /kg significantly had improved OS (p = 0.015) and decreased incidence of disease relapse (p = 0.001) without increasing incidence of GVHD. CONCLUSION: Our data suggest that a higher dose of CD34+ cells in haplo-PBSCT with PTCy positively impacts the outcomes without an increase of GVHD.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre de Sangre Periférica , Humanos , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Estudios Retrospectivos , Japón , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
A 64-year-old woman presented with fine motor impairment in both hands. MRI revealed a contrast-enhanced lesion in the medulla oblongata. Lymphoid cells with abnormal blebs were observed and a CD4+/CD8+ double positive (DP) T cell population was detected by flow cytometry (FCM) in the bone marrow (BM) and the peripheral blood (PB). CLEC16A::IL2 fusion gene was identified by whole exome sequencing with DNA prepared from DP T cells. Clonal rearrangement of the T-cell receptor gene and expression of TCL1A protein were detected. This led to a diagnosis of T-cell prolymphocytic leukemia (T-PLL) with central nervous system (CNS) infiltration. Abnormal cells in BM and PB became undetectable on microscopy and FCM, and the CNS lesion disappeared on MRI after second-line therapy with alemtuzumab. Meanwhile, the CLEC16A::IL2 fusion mRNA remained detectable in PB. Allogeneic hematopoietic stem-cell transplantation was performed, and the fusion mRNA has now been undetectable for more than 5 years since transplantation. This is the first report of a T-PLL case with a CLEC16A::IL2 fusion gene.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Prolinfocítica de Células T , Femenino , Humanos , Persona de Mediana Edad , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/metabolismo , Leucemia Prolinfocítica de Células T/terapia , Interleucina-2/metabolismo , Alemtuzumab , ARN Mensajero , Proteínas de Transporte de Monosacáridos , Lectinas Tipo C/genéticaRESUMEN
For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 104 /µL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3-24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105 /µL; p = 0.022) or low CD4/CD8 ratios (Asunto(s)
Linfoma de Células B Grandes Difuso
, Receptores Quiméricos de Antígenos
, Humanos
, Receptores Quiméricos de Antígenos/uso terapéutico
, Linfocitos T
, Estudios de Cohortes
, Japón/epidemiología
, Clorhidrato de Bendamustina/uso terapéutico
, Receptores de Antígenos de Linfocitos T/uso terapéutico
, Linfoma de Células B Grandes Difuso/tratamiento farmacológico
, Inmunoterapia Adoptiva
, Factores de Riesgo
RESUMEN
Graft failure and delayed hematopoietic recovery are the major limitations of cord-blood transplantation (CBT). Romiplostim, a thrombopoietin-receptor agonist, promotes megakaryopoiesis and multilineage hematopoiesis in aplastic anemia. The decreased number of hematopoietic stem cells in the early phase after CBT and aplastic anemia share certain characteristics. Therefore, we hypothesized that romiplostim administration immediately after CBT may promote multilineage hematopoietic recovery. We investigated the safety and preliminary efficacy of administering romiplostim a day after CBT. This phase 1 dose-escalation study included six adults with hematologic malignancies in remission. Romiplostim was administered subcutaneously within 7 days after single-unit CBT, initially at doses of 5 µg/kg or 10 µg/kg in three patients, then once a week for 14 weeks or until platelet recovery. The maximum dose was 20 µg/kg. The median number of romiplostim administrations was 6 (range, 3-15). Romiplostim-related adverse events included bone pain (3/6) and injection site reaction (1/6). Non-hematological grade ≥ 3 toxicities were observed in four patients; febrile neutropenia was the most common (4/6). All patients achieved neutrophil engraftment and the median time was 14 days (range, 12-32). Platelet counts ≥ 50 × 109 /L were recorded in all patients except for one who died on day 48; the median time was 34 days (range, 29-98). No relapse, thrombosis, or bone marrow fibrosis was observed during a median follow-up of 34 months. Romiplostim may be safely administered in the early phase of CBT. Further phase 2 trial is warranted for its efficacy evaluation. Trial registration number: UMIN000033799, August 18, 2018.
Asunto(s)
Anemia Aplásica , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Trombopoyetina/efectos adversos , Recurrencia Local de NeoplasiaRESUMEN
OBJECTIVES: Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporin A is the standard treatment for aplastic anemia (AA). However, the efficacy of repeated IST with rabbit ATG (rATG) as salvage therapy remains unclear in patients with relapsed or refractory AA. METHODS: We retrospectively evaluated the efficacy and safety of IST2 with rATG (IST2-rATG) in 19 consecutive patients with relapsed or refractory AA who received first-line IST with rATG in two centers between 2009 and 2020. RESULTS: The overall 6-month response rate of the patients was 58%. The response rates were similar between patients with relapsed and refractory AA. The presence of glycophosphatidylinositol-deficient blood cells was associated with a better response to IST2-rATG. Despite retreatment with the same rATG, serum disease and severe allergic reactions were not observed. CONCLUSION: IST2-rATG is effective and safe for the treatment of adult patients with relapsed and refractory AA after receiving first-line IST with rATG.
Asunto(s)
Anemia Aplásica , Suero Antilinfocítico , Humanos , Adulto , Suero Antilinfocítico/uso terapéutico , Anemia Aplásica/diagnóstico , Anemia Aplásica/tratamiento farmacológico , Estudios Retrospectivos , Terapia de Inmunosupresión , Ciclosporina , Inmunosupresores/uso terapéutico , Resultado del TratamientoRESUMEN
A 51-year-old man with the chief complaint of glove- and stocking-type dysesthesia for >3 years was diagnosed with Waldenström's macroglobulinemia (WM) based on IgM-type M-proteinemia, bone marrow infiltration of plasmacytoid B cells, multiple lymphadenopathies, and splenomegaly. A nerve conduction examination suggested demyelinating neuropathy. Serum anti-myelin-associated glycoprotein antibody was negative. Sural nerve biopsy showed myelin thinning, suggesting demyelination. Axonal damage and tumor cell infiltration in the intrafascicular epineurium were also observed. After chemotherapies with rituximab and bendamustine, M-proteinemia and lymphadenopathies disappeared. However, abnormalities in the nerve conduction examination and dysesthesia were only slightly alleviated. As articles describing patients with WM with peripheral nerve infiltration are limited, we report this case with a literature review.
Asunto(s)
Linfadenopatía , Enfermedades del Sistema Nervioso Periférico , Macroglobulinemia de Waldenström , Masculino , Humanos , Persona de Mediana Edad , Macroglobulinemia de Waldenström/complicaciones , Macroglobulinemia de Waldenström/tratamiento farmacológico , Parestesia/complicaciones , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/patología , Rituximab/uso terapéutico , Linfadenopatía/complicaciones , Inmunoglobulina MRESUMEN
Sequencing technology has identified aplastic anemia (AA) not only as an autoimmune bone marrow failure syndrome, but also as a clonal hematopoietic disease. Here, we present a case in which an ASXL1-mutated clone was predominantly expanded during the treatment of AA. A 58-year-old man with chronic glomerulonephritis on maintenance hemodialysis presented with pancytopenia. The findings of bone marrow biopsy indicated a hypoplastic bone marrow. Magnetic resonant imaging showed fatty changes in the bone marrow. The patient was eventually diagnosed with severe AA. He was treated with anti-human thymocyte globulin, cyclosporine, granulocyte colony-stimulating factor, and the thrombopoietin receptor agonist (TPO-RA) eltrombopag. After switching to another TPO-RA, romiplostim, the neutrophil, reticulocyte, and platelet counts gradually improved, and blood transfusion was not needed 1 year after treatment. Mutational analyses revealed that reconstituted hematopoietic cells originated from the ASXL1-mutated clone. Nevertheless, the patient's blood cell counts remained normal 2 years after treatment.
Asunto(s)
Anemia Aplásica , Masculino , Humanos , Persona de Mediana Edad , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/genética , Médula Ósea , Terapia de Inmunosupresión , Células Madre Hematopoyéticas , Suero Antilinfocítico , Trastornos de Fallo de la Médula Ósea , Células Clonales , Proteínas RepresorasRESUMEN
A 61-year-old female was referred to our hospital because of pancytopenia and febrile neutropenia. On admission, computed tomography showed mild hepatosplenomegaly and intra-abdominal abscess formation in the right pelvic region; however, no lymphadenopathy was found. Bone marrow (BM) examination showed severe fibrosis by silver staining. Several small- to medium-sized lymphocytes with a constriction in the nuclei were observed, exhibiting CD3 (-), CD10 (-), CD20 (+), BCL-2 (+-), and CD138 (+-). Genetic testing revealed that BM cells were positive for MYD88 mutation and positive for IgH rearrangement, whereas neither JAK2 nor CALR mutation was positive. A diagnosis of BM infiltration of lymphoplasmacytic lymphoma (LPL) was made. Rituximab monotherapy was administered once a week for four times. BM examination 4 weeks after the end of treatment showed that lymphoma cells had disappeared and that myelofibrosis had been almost gone. The MYD88 mutation of BM turned out to be negative at that moment.
Asunto(s)
Linfoma de Células B , Mielofibrosis Primaria , Macroglobulinemia de Waldenström , Femenino , Humanos , Persona de Mediana Edad , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Factor 88 de Diferenciación Mieloide/genética , Médula Ósea/patología , Linfoma de Células B/diagnóstico , Rituximab , Macroglobulinemia de Waldenström/complicaciones , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/genéticaRESUMEN
NUP98::DDX10 is a rare fusion gene associated with acute myeloid leukemia (AML), for which the prognosis and indication for allogeneic hematopoietic stem cell transplantation are unknown. A 48-year-old woman was diagnosed with AML harboring NUP98::DDX10. The results of quantitative RT-PCR of the fusion mRNA as a minimal residual disease (MRD) marker guided the treatment. In August 2019, the patient achieved hematological remission following standard remission induction therapy with idarubicin and cytarabine. After four cycles of consolidation therapies, MRD was detected, and she underwent allogeneic stem cell transplantation in May 2020. As MRD persisted in June, the immunosuppressant was stopped and three cycles of azacitidine were administered. Despite this, a hematological relapse occurred in January 2021 that was resistant to high-dose cytarabine and an investigational agent. She died as a result of the disease's progression. Thus, a second thought should be given to the timing of transplantation, the bridging, and the intervention for relapse after transplantation. The cases must be accumulated.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Femenino , Humanos , Persona de Mediana Edad , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamiento farmacológico , Citarabina/uso terapéutico , Neoplasia Residual , Pronóstico , Recurrencia , Proteínas de Complejo Poro Nuclear/genética , ARN Helicasas DEAD-box/genéticaRESUMEN
Cytokine release syndrome (CRS), occurring in more than 70% of HLA-haploidentical hematopoietic stem-cell transplantations with post-transplant cyclophosphamide (PT/CY-haplo), can lead to hemodynamic instability and worsen clinical outcomes. A calcineurin inhibitor is initiated after cyclophosphamide administration in the commonly used PT/CY regimens. Here, we conducted a phase I/II, prospective, single-center trial of PT/CY-haplo to evaluate the safety and efficacy of cyclophosphamide on days 3 and 5 along with cyclosporin and mycophenolate mofetil started from day - 1. Thirty-five adults with hematologic malignancies were enrolled. Myeloablative and reduced-intensity conditioning were used in 25 and 10 patients, respectively. Graft sources were bone marrow in 11 patients and mobilized peripheral blood stem cells in 24 patients. Disease-free survival on day 100, the primary endpoint, was 86% (95% confidence interval (CI), 69-94), which was over the predefined threshold of 50%. Unexpectedly, only 20% (95% CI, 8.4-37) of patients developed fever of > 38 °C early after graft infusion, all CRS grade 1, and all of which resolved just after cyclophosphamide administration. The cumulative incidences of grades II-IV acute graft-versus-host disease (GVHD), III-IV acute GVHD, and moderate-severe chronic GVHD were 23% (95% CI, 11-38), 6% (95% CI, 1-17), and 11% (95% CI, 4-25), respectively. The 3-year overall survival rate was 49% (95% CI, 31-64). Our results suggest that administration of cyclosporine and mycophenolate mofetil prior to PT/CY can reduce the frequency and severity of CRS without increasing GVHD. UMIN Clinical Trial Registry numbers: 000006631 and 000015694.
Asunto(s)
Ciclofosfamida/uso terapéutico , Ciclosporina/uso terapéutico , Síndrome de Liberación de Citoquinas/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Inmunosupresores/uso terapéutico , Ácido Micofenólico/uso terapéutico , Adolescente , Adulto , Anciano , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Síndrome de Liberación de Citoquinas/etiología , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Incidencia , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/efectos adversos , Estudios Prospectivos , Trasplante Haploidéntico/efectos adversos , Adulto JovenRESUMEN
Bing-Neel syndrome (BNS), which presents with a variety of neurological complications, is a rare manifestation of the lymphoplasmacytic lymphoma (LPL) and is characterized by the infiltration of LPL cells into the central nervous system. In this study, we report the case of a patient with BNS, which was confirmed by detecting MYD88 L265P mutation in the cerebrospinal fluid (CSF) cells. A 74-year-old patient was diagnosed with IgG-variant LPL. He achieved a very good partial response to the treatment with rituximab and bendamustine (RB) and was stable for over 5 years, when presenting a slowly progressive motor deficit in the lower limbs. It was difficult to confirm BNS from morphological analysis of the CSF cells. After detecting MYD88 L265P mutation in the CSF cells, he was subsequently diagnosed with BNS and treated with RB and intrathecal chemotherapy, resulting in rapid clinical improvement. With the onset of neurological manifestation during the clinical course of LPL, the detection of MYD88 L265P mutation in the CSF cells could be helpful for the diagnosis and management of BNS.
Asunto(s)
Factor 88 de Diferenciación Mieloide , Macroglobulinemia de Waldenström , Anciano , Humanos , Inmunoglobulina G , Masculino , Mutación , Factor 88 de Diferenciación Mieloide/genética , Rituximab , Macroglobulinemia de Waldenström/diagnóstico , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/genéticaRESUMEN
A 50-year-old man demonstrated markedly increased number of white blood cells, anemia, severe splenomegaly, and bleeding tendency. Bone marrow analysis revealed remarkable hypercellularity; dysplasia in multilineage cells, including megakaryocytes; and fibrosis. He was eventually diagnosed with triple-negative myelofibrosis. A massive hematoma developed at the bone marrow biopsy site. A similar episode recurred after the second bone marrow biopsy. The von Willebrand factor and other coagulation factor activities were within normal ranges. Platelet aggregation analyses demonstrated highly impaired aggregation induced by ADP, collagen, and epinephrine. Treatment with hydroxyurea and ruxolitinib, a JAK inhibitor, was ineffective, and he eventually died on day 144 after hospitalization. Acquired platelet dysfunction uncommonly occurs in patients with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), without precise elucidation of the frequency and underlying mechanism. The onset of bleeding tendency in the current patient suggested that platelet dysfunction may be caused by somatic genetic events. Here, we discuss the mechanisms of acquired platelet dysfunction in MDS or MPN with a literature review.
Asunto(s)
Mielofibrosis Primaria , Humanos , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/tratamiento farmacológicoRESUMEN
Notch signaling plays pivotal roles in both hematopoietic stem/progenitor and their niche cells. Myeloproliferative phenotypes are induced by disruption of Notch signaling in nonhematopoietic bone marrow (BM) cells. Nestin-expressing cells in the BM reportedly represent a component of the hematopoietic stem cell niche. We established mice in which rare Nestin-expressing cells in the BM were marked by green fluorescent protein, and Notch signaling was conditionally disrupted in these cells specifically. We observed impairment of erythropoiesis in the BM accompanying splenomegaly with BM hematopoietic programs in other lineages undisturbed. Transplantation experiments revealed that the microenvironmental rather than the hematopoietic cells were attributable to these phenotypes. We further found that the erythroid-island-forming ability of BM central macrophages was compromised along with the transcriptional upregulation of interleukin-6. Various Inflammatory conditions hamper BM erythropoiesis, which often accompanies extramedullary hematopoiesis. The mouse model demonstrated here may be of relevance to this common pathophysiologic condition. Stem Cells 2019;37:924-936.
Asunto(s)
Células de la Médula Ósea/metabolismo , Eritropoyesis/genética , Macrófagos/metabolismo , Nestina/genética , Receptores Notch/genética , Esplenomegalia/genética , Animales , Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Linaje de la Célula/genética , Regulación de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Nestina/metabolismo , Receptores Notch/deficiencia , Transducción de Señal , Esplenomegalia/metabolismo , Esplenomegalia/patología , Nicho de Células Madre/genéticaRESUMEN
Immunosuppressive therapy (IST) is the first-line treatment for young patients with severe aplastic anemia (AA) when a human leucocyte antigen (HLA)-matched related donor (MRD) is unavailable. Fulminant AA (FAA) is defined as AA with a complete absence of neutrophils at presentation and no response to granulocyte-colony stimulating factor (G-CSF) treatment. Here we report a 38-year-old male FAA patient who underwent allogeneic stem cell transplantation from an HLA haplotype-mismatched donor as first-line treatment. The patient had no remarkable disease history and was referred to our hospital because of a peritonsillar abscess and severe pancytopenia. Bone marrow biopsy revealed marked hypocellularity without dysplasia. His neutrophil count remained 0.0×109/l following G-CSF administration, and he was diagnosed with FAA. His siblings were not MRDs, but his sister had haploidentical HLAs. After administering a conditioning regimen, the patient received a transplant of peripheral blood stem cells donated by his sister. Neutrophil engraftment was observed on post-transplant day 16, and he experienced acute graft-versus-host disease (grade I, skin stage 1), but no other complications were observed. Hematopoietic stem cell transplantation from an HLA haplotype-mismatched related donor may be a viable option for first-line treatment of FAA when an MRD is unavailable.
Asunto(s)
Anemia Aplásica , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adulto , Anemia Aplásica/terapia , Factor Estimulante de Colonias de Granulocitos , Humanos , Masculino , Acondicionamiento Pretrasplante , Trasplante HaploidénticoRESUMEN
A 46-year-old man who had previously undergone open surgery for renal cell carcinoma (RCC) developed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL). After the induction therapy, he achieved complete molecular remission. However, fever and bilateral buttock pain continued during the consolidation therapy. 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) showed FDG accumulation in both iliac bones and in the sacrum; however, no causative diseases, including relapse of Ph-ALL and RCC, were detected. Iliac bone marrow biopsy revealed bone marrow necrosis (BMN), the etiology of which was presumed to be the leukemia itself and the therapeutic response to chemotherapy. Fever resolution and buttock pain alleviation were observed over the next months. We observed diffuse fibrosis in the bone marrow at day 162 and day 364 after cord blood transplantation. Moreover, the FDG accumulation was significantly reduced on PET-CT. BMN is not widely recognized despite its potential association with hematologic malignancies. Additional cases of BMN should be reviewed to clarify BMN etiology and clinical features.
Asunto(s)
Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Médula Ósea , Quimioterapia de Consolidación , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
Primary central nervous system lymphoma (PCNSL) is a rare subtype of lymphoma that arises within the brain or the eyes. PCNSL recurs within the central nervous system (CNS) in most relapsed cases, whereas extra-CNS relapse is experienced in rare cases. The present study aimed at identifying the presence of common precursor cells (CPC) for primary intra- and relapsed extra-CNS tumors, and further assessing the initiating events in bone marrow (BM). Targeted deep sequencing was carried out for five paired primary intra- and relapsed extra-CNS tumors of PCNSL. Two to five mutations were shared by each pair of intra- and extra-CNS tumors. In particular, MYD88 mutations, L265P in three and P258L in one, were shared by four pairs. Unique somatic mutations were observed in all five intra-CNS tumors and in four out of five extra-CNS tumors. Remarkably, IgH clones in the intra- and the extra-CNS tumors in two pairs were distinct from each other, whereas one pair of tumors shared identical monoclonal IgH rearrangement. In a cohort of 23 PCNSL patients, L265P MYD88 mutations were examined in tumor-free BM mononuclear cells (MNC) in which the PCNSL tumors had L265P MYD88 mutations. L265P MYD88 mutations were detected by a droplet digital PCR method in nine out of 23 bone marrow mononuclear cells. These results suggest that intra- and extra-tumors are derived from CPC with MYD88 mutations in most PCNSL, arising either before or after IgH rearrangement. The initiating MYD88 mutations may occur during B-cell differentiation in BM.
Asunto(s)
Neoplasias del Sistema Nervioso Central/genética , Linfoma de Células B/genética , Recurrencia Local de Neoplasia , Células Madre Neoplásicas/metabolismo , Anciano , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Femenino , Reordenamiento Génico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Mutación , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Células Madre Neoplásicas/patologíaRESUMEN
A 66-year-old male undergoing maintenance hemodialysis presented with mild thrombocytopenia. He also had aortic valve stenosis and required aortic valve replacement. In addition, he required anticoagulation therapy with warfarin because of chronic subclavian artery occlusion. He was eventually diagnosed with immune thrombocytopenic purpura (ITP), although there were no bleeding tendencies. The patient was preoperatively treated with thrombopoietin receptor agonist (romiplostim®) because of the risk of bleeding complication during cardiac surgery. The platelet count rapidly increased with low-dose romiplostim, and no thrombotic complication occurred. During surgery, no significant bleeding complications were observed. This report suggests that romiplostim is a useful treatment option for the management of bleeding complication during cardiac surgery in a hemodialysis patient with ITP.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Trombopoyetina/uso terapéutico , Anciano , Humanos , Masculino , Recuento de Plaquetas , Receptores de Trombopoyetina/antagonistas & inhibidores , Diálisis RenalRESUMEN
Recent sequencing studies demonstrated the MYD88 L265P mutation in more than 70% of primary central nervous system lymphomas (PCNSL), and the clinical significance of this mutation has been proposed as diagnostic and prognostic markers in PCNSL. In contrast, mutational analyses using cell-free DNAs have been reported in a variety of systemic lymphomas. To investigate how sensitively the MYD88 L265P mutation can be identified in cell-free DNA from PCNSL patients, we carried out droplet digital PCR (ddPCR) and targeted deep sequencing (TDS) in 14 consecutive PCNSL patients from whom paired tumor-derived DNA and cell-free DNA was available at diagnosis. The MYD88 L265P mutation was found in tumor-derived DNA from all 14 patients (14/14, 100%). In contrast, among 14 cell-free DNAs evaluated by ddPCR (14/14) and TDS (13/14), the MYD88 L265P mutation was detected in eight out of 14 (ddPCR) and in 0 out of 13 (TDS) samples, implying dependence on the detection method. After chemotherapy, the MYD88 L265P mutation in cell-free DNAs was traced in five patients; unexpectedly, the mutations disappeared after chemotherapy was given, and they remained undetectable in all patients. These observations suggest that ddPCR can sensitively detect the MYD88 L265P mutation in cell-free DNA and could be used as non-invasive diagnostics, but may not be applicable for monitoring minimal residual diseases in PCNSL.
Asunto(s)
Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/genética , ADN/sangre , Mutación , Factor 88 de Diferenciación Mieloide/genética , Quimioterapia , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Reacción en Cadena de la Polimerasa/métodos , Estudios Retrospectivos , Análisis de Secuencia de ADN , Resultado del TratamientoRESUMEN
CD4+Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft-versus-host disease (GVHD) in murine models of allogeneic hematopoietic stem cell transplantation. We recently demonstrated that a single treatment of the agonistic antibody to DR3 (death receptor 3, αDR3) to donor mice resulted in the expansion of donor-derived Treg and prevented acute GVHD, although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we comprehensively analyzed the immunophenotype of Treg after DR3 signal activation, demonstrating that DR3-activated Treg (DR3-Treg) had an activated/mature phenotype. Furthermore, the CD25+Foxp3+ subpopulation in DR3-Treg showed stronger suppressive effects in vivo. Prophylactic treatment of αDR3 to recipient mice expanded recipient-derived Treg and reduced the severity of GVHD, whereas DR3 activation in mice with ongoing GVHD further promoted donor T-cell activation/proliferation. These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. In conclusion, our data demonstrated that DR3 signaling affects the function of Treg and T-cell activation after alloantigen exposure in a time-dependent manner. These observations provide important information for future clinical testing using human DR3 signal modulation and highlight the critical effect of the state of T-cell activation on clinical outcomes after activation of DR3.