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We report the case of a 48-year-old man who presented with fatigue and weight loss. A local physician observed elevated alkaline phosphatase levels, anemia, thrombocytopenia, and renal dysfunction. Fever also appeared, and the patient was admitted to our hospital. Computed tomography revealed hepatosplenomegaly, pleural and ascitic fluid, and left axillary lymphadenopathy. Bone marrow biopsy indicated hyperplasia with increased megakaryocytes and reticulin fibrosis. Axillary lymph node biopsy showed Castleman's disease-like features. Liver biopsy revealed proliferation of reticulin fibrosis. Therefore, TAFRO syndrome was diagnosed and treatment with 1 mg/kg prednisolone was started. Anemia and thrombocytopenia improved, and after 24 weeks of treatment, serum hyaluronic acid and type IV collagen decreased to the normal range. Bone marrow biopsy after 18 weeks of treatment showed decreased reticular fibers. In TAFRO syndrome, improvement of liver and bone marrow fibrosis can be expected with adequate intervention, and serum hyaluronic acid and type IV collagen are useful for evaluating fibrosis.
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Prednisolona , Humanos , Masculino , Persona de Mediana Edad , Prednisolona/administración & dosificación , Enfermedad de Castleman/tratamiento farmacológico , Enfermedad de Castleman/patología , Fibrosis , Resultado del Tratamiento , SíndromeRESUMEN
To evaluate the specific prognostic value of CAs, we conducted an analysis of 923 symptomatic multiple myeloma patients. Among this cohort, 480 patients had complete data set of high-risk CAs by interphase fluorescent in situ hybridization at diagnosis. In the high-risk group analysis, the median OS of patients without CAs (n = 338, 72 %) was 6.5 years, patients with del(17p) (n = 42, 9 %) was 4.4 years, patients with t(4;14) or t(14;16) (n = 72, 15 %) was 4.4 years, and patients with double-positive CAs(del(17p) and t(4;14) or t(14;16)) (n = 18, 4 %) was 2.1 years (p = 0.032). Patients with double-positive CAs had a significantly worse prognosis.
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To investigate the real-world clinical outcomes and management of novel drug-containing therapies for newly diagnosed multiple myeloma (MM) patients, we retrospectively analyzed data on the first-line treatment for newly diagnosed transplant-ineligible MM patients from Kansai Myeloma Forum, a registry network in Japan. A total of 598 patients treated with novel drugs between March 2007 and February 2018 were analyzed. Regimens used were VD (n = 305), Rd (n = 103), VMP (n = 97), VCD (n = 71), and VRd (n = 22). Younger patients tended to receive VRd or VCD, whereas the regimen with the highest median patient age was Rd. More than three-quarters of patients in the Rd group received a reduced dose of lenalidomide. The Rd and VRd groups had a relatively high incidence of infection and skin complications, and the VMP group had the highest incidence of peripheral neuropathy. Overall response rate did not differ significantly between regimens. Multivariate analysis in all patients revealed several poor prognostic factors, such as poor performance status. Novel drug-containing regimens for newly diagnosed MM showed a durable response with manageable AEs in the real-world setting.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Estudios Retrospectivos , Bortezomib/uso terapéutico , Quimioterapia de Inducción , Dexametasona/efectos adversos , Supervivencia sin Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
STATEMENT OF SIGNIFICANCE: Loss of TFL, found in several types of lymphoma, induces excessive CXCL13 secretion through RNA dysregulation contributing to body weight loss and early death in lymphoma model mice. Follicular lymphoma (FL) is associated with overexpressed BCL-2 and other genetic aberrations, including 6q-. We identified a novel gene on 6q25, "Transformed follicular lymphoma (TFL)," from a transformed FL. TFL regulates several cytokines via mRNA degradation, which has been suggested to underlie resolving inflammation. Fluorescence in situ hybridization revealed a deletion of TFL occurred in 13.6% of various B-cell lymphoma samples. We developed VavP-bcl2 transgenic, TFL deficit mice (Bcl2-Tg/Tfl -/-) to seek how TFL affects disease progression in this lymphoma model. While Bcl2-Tg mice developed lymphadenopathy and died around 50 weeks, Bcl2-Tg/Tfl -/- mice lost body weight around 30 weeks and died about 20 weeks earlier than Bcl2-Tg mice. Furthermore, we found a unique B220-IgM+ cell population in the bone marrow of Bcl2-Tg mice. cDNA array in this population revealed that Cxcl13 mRNA in Bcl2-Tg/Tfl -/- mice expressed significantly higher than Bcl2-Tg mice. In addition, bone marrow extracellular fluid and serum showed an extremely high Cxcl13 concentration in Bcl2-Tg/Tfl -/- mice. Among bone marrow cells, the B220-IgM+ fraction was the main producer of Cxcl13 in culture. A reporter assay demonstrated TFL regulates CXCL-13 via induction of 3'UTR mRNA degradation in B lineage cells. These data suggest Tfl regulates Cxcl13 in B220-IgM+ cells in the bone marrow, and a very high concentration of serum Cxcl13 arising from these cells may contribute to early death in lymphoma-bearing mice. Since several reports have suggested the association of CXCL13 expression with lymphoma, these findings provide new insights into cytokine regulation via TFL in lymphoma.
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Linfoma Folicular , Linfoma no Hodgkin , Animales , Ratones , Caquexia , Quimiocina CXCL13/genética , Inmunoglobulina M , Hibridación Fluorescente in Situ , Linfoma Folicular/genética , Ratones Transgénicos , Recurrencia Local de Neoplasia , Proteínas Proto-Oncogénicas c-bcl-2/genéticaRESUMEN
Background: Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab. Objectives: We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status. Design: We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database. Methods: We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database. Results: In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower ß2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen. Conclusion: We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/µl; 1 point for <200/µl) or WBC counts (0 points for ⩾3500/µl; 1 point for <3500/µl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p < 0.001). To confirm this concept, our results will need to be validated in other cohorts.
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RNA in extracellular vesicles (EVs) are uptaken by cells, where they regulate fundamental cellular functions. EV-derived mRNA in recipient cells can be translated. However, it is still elusive whether "naked nonvesicular extracellular mRNA" (nex-mRNA) that are not packed in EVs can be uptaken by cells and, if so, whether they have any functions in recipient cells. Here, we show the entrance of nex-mRNA in the nucleus, where they exert a translation-independent function. Human nex-interleukin-1ß (IL1ß)-mRNA outside cells proved to be captured by RNA-binding zinc finger CCCH domain containing protein 12D (ZC3H12D)-expressing human natural killer (NK) cells. ZC3H12D recruited to the cell membrane binds to the 3'-untranslated region of nex-IL1ß-mRNA and transports it to the nucleus. The nex-IL1ß-mRNA in the NK cell nucleus upregulates antiapoptotic gene expression, migration activity, and interferon-γ production, leading to the killing of cancer cells and antimetastasis in mice. These results implicate the diverse actions of mRNA.
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Núcleo Celular/metabolismo , Espacio Extracelular/metabolismo , ARN Mensajero/metabolismo , Regiones no Traducidas 3' , Animales , Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Membrana Celular/metabolismo , Medios de Cultivo Condicionados/metabolismo , Endorribonucleasas/metabolismo , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Células Asesinas Naturales/metabolismo , Ratones , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/farmacología , Proteínas de Unión al ARN/metabolismoRESUMEN
The mobilization efficiency of hematopoietic stem/progenitor cells from bone marrow (BM) to circulation by granulocyte colony-stimulating factor (G-CSF) is dramatically dispersed in humans and mice with no mechanistic lead for poor mobilizers. The regulatory mechanism for mobilization efficiency by dietary fat was assessed in mice. Fat-free diet (FFD) for 2 weeks greatly increased mobilization compared to normal diet (ND). The BM mRNA level of peroxisome proliferator-activated receptor δ (PPARδ), a receptor for lipid mediators, was markedly up-regulated by G-CSF in mice fed with ND and displayed strong positive correlation with widely scattered mobilization efficiency. It was hypothesized that BM fat ligand for PPARδ might inhibit mobilization. The PPARδ agonist inhibited mobilization in mice fed with ND and enhanced mobilization by FFD. Treatment with the PPARδ antagonist and chimeric mice with PPARδ+/- BM showed enhanced mobilization. Immunohistochemical staining and flow cytometry revealed that BM PPARδ expression was enhanced by G-CSF mainly in mature/immature neutrophils. BM lipid mediator analysis revealed that G-CSF treatment and FFD resulted in the exhaustion of ω3-polyunsaturated fatty acids such as eicosapentaenoic acid (EPA). EPA induced the up-regulation of genes downstream of PPARδ, such as carnitine palmitoyltransferase-1α and angiopoietin-like protein 4 (Angptl4), in mature/immature neutrophils in vitro and inhibited enhanced mobilization in mice fed with FFD in vivo. Treatment of wild-type mice with the anti-Angptl4 antibody enhanced mobilization together with BM vascular permeability. Collectively, PPARδ signaling in BM mature/immature neutrophils induced by dietary fatty acids negatively regulates mobilization, at least partially, via Angptl4 production.
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Médula Ósea , PPAR delta , Animales , Células de la Médula Ósea , Factor Estimulante de Colonias de Granulocitos , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas , Ratones , PPAR delta/genéticaRESUMEN
Fibroblast growth factor 23 (FGF-23) hormone is produced by bone-embedded osteocytes and regulates phosphate homeostasis in kidneys. We found that administration of granulocyte colony-stimulating factor (G-CSF) to mice induced a rapid, substantial increase in FGF-23 messenger RNA in bone marrow (BM) cells. This increase originated mainly from CD45-Ter119+CD71+ erythroblasts. FGF-23 protein in BM extracellular fluid was markedly increased during G-CSF-induced hematopoietic progenitor cell (HPC) mobilization, but remained stable in the blood, with no change in the phosphate level. Consistent with the BM hypoxia induced by G-CSF, low oxygen concentration induced FGF-23 release from human erythroblast HUDEP-2 cells in vitro. The efficient mobilization induced by G-CSF decreased drastically in both FGF-23-/- and chimeric mice with FGF-23 deficiency, only in hematopoietic cells, but increased in osteocyte-specific FGF-23-/- mice. This finding suggests that erythroblast-derived, but not bone-derived, FGF-23 is needed to release HPCs from BM into the circulation. Mechanistically, FGF-23 did not influence CXCL-12 binding to CXCR-4 on progenitors but interfered with their transwell migration toward CXCL-12, which was canceled by FGF receptor inhibitors. These results suggest that BM erythroblasts facilitate G-CSF-induced HPC mobilization via FGF-23 production as an intrinsic suppressor of chemoattraction.
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Eritroblastos/citología , Factores de Crecimiento de Fibroblastos/metabolismo , Células Madre Hematopoyéticas/citología , Animales , Células Cultivadas , Eritroblastos/metabolismo , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Hematopoyesis , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas/metabolismo , Humanos , Masculino , Ratones Endogámicos C57BL , ARN Mensajero/genética , Regulación hacia ArribaRESUMEN
We retrospectively analyzed 51 patients with solitary plasmacytoma diagnosed from October 2002 to September 2018 from a cohort of 3575 patients with plasma cell dyscrasias registered in the Kansai Myeloma Forum. Twenty-seven patients had solitary bone plasmacytoma (SBP) and 24 had extramedullary plasmacytoma (EMP), with prevalence of 0.8% and 0.7%, respectively. The most frequent M protein was IgG (40%) in SBP, whereas non-secretory proteins were most frequent (50%) in EMP. Five-year overall survival was 78.2% in SBP and 80.8% in EMP (P = 0.894). Among patients with SBP, 44% progressed to MM with a median time of 10.5 months (2.4-93.3 months), whereas 8% of EMP patients progressed to MM with a median time of 18.6 months (13.0-24.2 months). The most frequent treatment was radiotherapy (41%) or observation (41%) in SBP, and chemotherapy (54%) in EMP. No statistically significant difference was observed upon univariate analysis of prognostic factors including age, sex, performance status, and IgG M protein. Our results suggest that there are biological differences between SBP and EMP in real-world settings.
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Neoplasias Óseas , Plasmacitoma , Sistema de Registros , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/epidemiología , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Neoplasias Óseas/terapia , Progresión de la Enfermedad , Femenino , Humanos , Inmunoglobulina G , Japón/epidemiología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/etiología , Proteínas de Mieloma , Plasmacitoma/epidemiología , Plasmacitoma/mortalidad , Plasmacitoma/patología , Plasmacitoma/terapia , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Myelofibrosis in myeloproliferative neoplasms (MPNs) with mutations such as JAK2V617F is an unfavorable sign for uncontrollable disease progression in the clinic and is complicated with osteosclerosis whose pathogenesis is largely unknown. Because several studies have revealed that macrophages are an indispensable supporter for bone-forming osteoblasts, we speculated that macrophages might play a significant role in the proliferation of collagen-producing myofibroblasts in marrow fibrotic tissues. Here, we show that myelofibrosis critically depends on macrophages whose differentiation is skewed by vitamin D receptor (VDR) signaling. In our novel myelofibrosis model established by transplantation of VDR+/+ hematopoietic stem/progenitor cells into VDR-/- mice, donor-derived F4/80+ macrophages proliferated together with recipient-derived α-smooth muscle actin-positive myofibroblasts, both of which comprised fibrotic tissues with an indistinguishable spindle-shaped morphology. Interfering VDR signals, such as low vitamin D diet and VDR deficiency in donor cells as well as macrophage depletion prevented myelofibrosis in this model. These interventions also ameliorated myelofibrosis in JAK2V617F-driven murine MPNs likely in a transforming growth factor-ß1- or megakaryocyte-independent manner. These results suggest that VDR and macrophages may be novel therapeutic targets for MPNs with myelofibrosis.
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Diferenciación Celular , Macrófagos/patología , Osteosclerosis/etiología , Mielofibrosis Primaria/etiología , Receptores de Calcitriol , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas , Xenoinjertos , Humanos , Ratones , Ratones Noqueados , Miofibroblastos/patología , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/patología , Mielofibrosis Primaria/prevención & control , Receptores de Calcitriol/metabolismo , Transducción de Señal , Deficiencia de Vitamina DRESUMEN
Background: Transformed follicular lymphoma (TFL, ZC3H12D) was identified as a candidate tumor suppressor gene that contributes to cell-cycle arrest through regulation of Rb phosphorylation, but the clinical impact of TFL is unknown. The goal of this study was to evaluate the prognostic significance of TFL expression in advanced endometrial cancer.Methods: Tissue samples were obtained from 103 patients with Federation Internationale des Gynaecologistes et Obstetristes stage III-IV endometrial cancer. Associations between TFL expression and outcomes were evaluated using the Kaplan-Meier method and multivariate Cox proportional hazards regression models.Results: There were 24 TFL-low cases (23.3%) and the 10-year progression-free survival (PFS) and overall survival (OS) in these cases were lower than those for patients with normal TFL expression in univariate analysis (PFS, P = 0.003; OS, P = 0.106). In multivariate analysis, TFL status was a significant predictor for PFS [HR = 2.76; 95% confidence interval (CI), 1.45-5.28; P = 0.002] and OS (HR = 1.94; 95% CI, 0.91-4.11; P = 0.085), adjusted for covariates. The TFL gene maps to human chromosome 6q25.1, where estrogen receptor alpha (ERα) gene ESR1 is also located. Lack of ERα expression is a poor prognostic factor in early endometrial cancer. Among 41 ERα-low patients, 10-year PFS was significantly lower in 15 TFL-low cases (univariate analysis, P = 0.055; multivariate analysis, HR = 4.70; 95% CI, 1.68-13.20; P = 0.003).Conclusions: We identified TFL as a strong independent prognostic factor, regardless of ERα status.Impact: An investigation of the mechanism underlying tumor suppression by TFL may lead to new therapies for patients with advanced endometrial cancer. Cancer Epidemiol Biomarkers Prev; 27(8); 963-9. ©2018 AACR.
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Transformación Celular Neoplásica/patología , Neoplasias Endometriales/mortalidad , Linfoma Folicular/fisiopatología , Adulto , Anciano , Terapia Combinada , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Epstein-Barr virus (EBV) causes various diseases in the elderly, including B-cell lymphoma such as Hodgkin's lymphoma and diffuse large B-cell lymphoma. Here, we show that EBV acts in trans on noninfected macrophages in the tumor through exosome secretion and augments the development of lymphomas. In a humanized mouse model, the different formation of lymphoproliferative disease (LPD) between 2 EBV strains (Akata and B95-8) was evident. Furthermore, injection of Akata-derived exosomes affected LPD severity, possibly through the regulation of macrophage phenotype in vivo. Exosomes collected from Akata-lymphoblastoid cell lines reportedly contain EBV-derived noncoding RNAs such as BamHI fragment A rightward transcript (BART) micro-RNAs (miRNAs) and EBV-encoded RNA. We focused on the exosome-mediated delivery of BART miRNAs. In vitro, BART miRNAs could induce the immune regulatory phenotype in macrophages characterized by the gene expressions of interleukin 10, tumor necrosis factor-α, and arginase 1, suggesting the immune regulatory role of BART miRNAs. The expression level of an EBV-encoded miRNA was strongly linked to the clinical outcomes in elderly patients with diffuse large B-cell lymphoma. These results implicate BART miRNAs as 1 of the factors regulating the severity of lymphoproliferative disease and as a diagnostic marker for EBV+ B-cell lymphoma.
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Infecciones por Virus de Epstein-Barr/complicaciones , Exosomas/virología , Herpesvirus Humano 4/genética , Inflamación/virología , Linfoma/virología , ARN Viral/genética , Animales , Carcinogénesis/genética , Carcinogénesis/inmunología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Exosomas/genética , Exosomas/inmunología , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Inflamación/etiología , Inflamación/genética , Inflamación/inmunología , Linfoma/etiología , Linfoma/genética , Linfoma/inmunología , Ratones , MicroARNs/análisis , MicroARNs/genética , ARN Viral/análisis , Análisis de Secuencia de ARN , Microambiente TumoralRESUMEN
Determinants of the efficacy and safety of pomalidomide (POM) monotherapy or POM plus dexamethasone (DEX) (POM/DEX) for relapsed and refractory multiple myeloma (RRMM) were examined retrospectively in a real-world clinical practice setting in Japan. The subjects were 108 patients registered with the Kansai Myeloma Forum, who were treated with either POM or POM/DEX. Of these, 79 (73%), 73 (68%), and 58 (54%) were resistant to bortezomib (BTZ), lenalidomide (LEN), and both BTZ and LEN, respectively. The median overall survival (OS) was not reached. The median time to treatment failure (TTF) was 4.4 months. The best response was recorded in 96 patients, with a 31% overall response rate (ORR) and a 79% rate of achieving at least stable disease. Number of pre-POM regimens ≥ 5, non-IgG-type M-protein, and time from initial therapy to POM or POM/DEX therapy < 2 years were associated with shorter TTF and OS. Frequent (> 10%) severe adverse events included neutropenia (55.1%), thrombocytopenia (33.7%), anemia (30.6%), febrile neutropenia (12.2%), fatigue (11.2%), and anorexia (10.2%). In conclusion, POM and POM/DEX showed substantial efficacy against RRMM, but new combination therapies with POM are needed to improve efficacy further without causing hematologic toxicities.
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Dexametasona/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Dexametasona/efectos adversos , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Recurrencia , Sistema de Registros , Estudios Retrospectivos , Talidomida/administración & dosificación , Talidomida/efectos adversos , Trombocitopenia/inducido químicamente , Trombocitopenia/epidemiología , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Azacitidina/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Protoporfiria Eritropoyética/tratamiento farmacológico , Piel/efectos de los fármacos , Anciano , Progresión de la Enfermedad , Humanos , Masculino , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/diagnóstico , Protoporfiria Eritropoyética/diagnóstico , Protoporfiria Eritropoyética/etiología , Piel/patología , Resultado del TratamientoAsunto(s)
Mieloma Múltiple , Talidomida , Anciano , Dexametasona , Humanos , Lenalidomida , Talidomida/análogos & derivadosRESUMEN
Although deregulation of EPHB signaling has been shown to be an important step in colorectal tumorigenesis, the role of EPHB6 in this process has not been investigated. We found here that manipulation of EPHB6 levels in colon cancer cell lines has no effect on their motility and growth on a solid substrate, soft agar or in a xenograft mouse model. We then used an EphB6 knockout mouse model to show that EphB6 inactivation does not efficiently initiate tumorigenesis in the intestinal tract. In addition, when intestinal tumors are initiated genetically or pharmacologically in EphB6+/+ and EphB6-/- mice, no differences were observed in animal survival, tumor multiplicity, size or histology, and proliferation of intestinal epithelial cells or tumor cells. However, reintroduction of EPHB6 into colon cancer cells significantly reduced the number of lung metastasis after tail-vein injection in immunodeficient mice, while EPHB6 knockdown in EPHB6-expressing cells increased their metastatic spread. Consistently, although EPHB6 protein expression in a series of 130 primary colorectal tumors was not associated with patient survival, EPHB6 expression was significantly lower in lymph node metastases compared to primary tumors. Our results indicate that the loss of EPHB6 contributes to the metastatic process of colorectal cancer.
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Biomarcadores de Tumor , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Receptores de la Familia Eph/deficiencia , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Inmunohistoquímica , Ratones , Ratones Noqueados , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Receptores de la Familia Eph/genética , Receptores de la Familia Eph/metabolismoRESUMEN
To test the feasibility of mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis in Japanese patients, we conducted two multicenter prospective phase II trials of allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA-matched related donors (MRD group) with MMF and cyclosporine or HLA 7-8/8 allele-matched unrelated bone-marrow donors (URD group) with MMF and tacrolimus. The cumulative incidences of grade II-IV acute GVHD on day 100, which was the primary endpoint in these trials, were 45.0% (90% CI 25.8-62.5) and 25.8% (90% CI 13.9-39.5) in the MRD (n = 20) and URD (n = 31) groups, respectively. The rates of 3-year overall survival and non-relapse mortality were 80.0 and 15.0% in the MRD group and 74.2 and 6.5% in the URD group, respectively. GVHD prophylaxis with MMF may lead to a lower incidence of severe mucositis and faster neutrophil engraftment compared to that with methotrexate. A pharmacokinetics study of mycophenolic acid (MPA) showed that a relatively higher plasma concentration of MPA was associated with a lower incidence of acute GVHD. In conclusion, the results of these studies suggest that GVHD prophylaxis with MMF may be useful as an alternative in Japanese patients who may benefit from faster engraftment or less severe mucositis after allogeneic HSCT.
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Inhibidores de la Calcineurina/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Histocompatibilidad , Ácido Micofenólico/administración & dosificación , Adulto , Anciano , Femenino , Supervivencia de Injerto/efectos de los fármacos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA/inmunología , Humanos , Japón , Masculino , Persona de Mediana Edad , Mucositis/prevención & control , Hermanos , Trasplante Homólogo , Donante no Emparentado , VoluntariosRESUMEN
Granulocyte colony-stimulating factor (G-CSF) is widely used for peripheral blood stem/progenitor mobilization. G-CSF causes low-grade fever that is ameliorated by nonsteroidal anti-inflammatory drugs (NSAIDs), suggesting the activation of arachidonic acid (AA) cascade. How G-CSF regulated this reaction was assessed. G-CSF treatment in mice resulted in fever, which was canceled in prostaglandin E synthase (mPGES-1)-deficient mice. Mobilization efficiency was twice as high in chimeric mice lacking mPGES-1, specifically in hematopoietic cells, suggesting that prostaglandin E2 (PGE2) from hematopoietic cells modulated the bone marrow (BM) microenvironment. Neutrophils from steady-state BM constitutively expressed mPGES-1 and significantly enhanced PGE2 production in vitro by ß-adrenergic stimulation, but not by G-CSF, which was inhibited by an NSAID. Although neutrophils expressed all ß-adrenergic receptors, only ß3-agonist induced this phenomenon. Liquid chromatography-tandem mass spectrometry traced ß-agonist-induced PGE2 synthesis from exogenous deuterium-labeled AA. Spontaneous PGE2 production was highly efficient in Gr-1high neutrophils among BM cells from G-CSF-treated mice. In addition to these in vitro data, the in vivo depletion of Gr-1high neutrophils disrupted G-CSF-induced fever. Furthermore, sympathetic denervation eliminated both neutrophil priming for PGE2 production and fever during G-CSF treatment. Thus, sympathetic tone-primed BM neutrophils were identified as one of the major PGE2 producers. PGE2 upregulated osteopontin, specifically in preosteoblasts, to retain progenitors in the BM via EP4 receptor. Thus, the sympathetic nervous system regulated neutrophils as an indispensable PGE2 source to modulate BM microenvironment and body temperature. This study provided a novel mechanistic insight into the communication of the nervous system, BM niche components, and hematopoietic cells.
Asunto(s)
Células de la Médula Ósea/efectos de los fármacos , Dinoprostona/metabolismo , Fiebre/inducido químicamente , Factor Estimulante de Colonias de Granulocitos/farmacología , Neutrófilos/efectos de los fármacos , Agonistas Adrenérgicos beta/farmacología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Línea Celular , Fiebre/genética , Eliminación de Gen , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Masculino , Ratones Endogámicos C57BL , Neutrófilos/citología , Neutrófilos/metabolismo , Prostaglandina-E Sintasas/genética , Prostaglandina-E Sintasas/metabolismo , Receptores Adrenérgicos beta/metabolismoRESUMEN
We identified a novel fusion gene, FOXP1-PDGFRA, in a patient with myeloproliferative neoplasm (MPN) with eosinophilia, harboring the chromosome abnormality t(3;4)(p13;q12). The patient responded well to imatinib and has remained in molecular remission for 3 years. This is the seventh fusion gene involving PDGFRA in MPN with eosinophilia. PDGFRA was truncated in its autoinhibitory domain, as in other PDGFRA-related MPNs, and was fused to FOXP1 at its functional forkhead domain. Comparing genomic DNA with mRNA sequences provides the possibility that the splicing process near the breakpoint junction in the FOXP1-PDGFRA fusion gene may use the normal splice donor site for intron 23a of FOXP1 and the cryptic splice acceptor site in exon 12 of PDGFRA. This is the first report to describe the FOXP1-PDGFRA fusion gene in MPN.
Asunto(s)
Factores de Transcripción Forkhead/genética , Síndrome Hipereosinofílico/genética , Proteínas de Fusión Oncogénica/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Proteínas Represoras/genética , Adulto , Antineoplásicos/uso terapéutico , Análisis Citogenético , Humanos , Síndrome Hipereosinofílico/tratamiento farmacológico , Síndrome Hipereosinofílico/patología , Mesilato de Imatinib/uso terapéutico , Leucemia , Masculino , Proteínas de Fusión Oncogénica/genéticaRESUMEN
Post-transplant lymphoproliferative disorder (PTLD) is a well-known complication after transplantation. A living donor liver transplantation was performed on a 31-year-old man for fulminant hepatitis. He again developed liver dysfunction after 7 months. He was diagnosed as having acute cellular rejection and the steroid pulse therapy introduced resulted in little improvement. He gradually developed a high fever and right axillary lymphadenopathy appeared. Chest computed tomography (CT) was performed revealing small lung nodules and axillary lymphadenopathy. Because his serological status for Epstein-Barr virus was positive, PTLD was highly suspected and immunosuppression treatment was withdrawn with little improvement. One week later, he developed tachycardia. Chest CT was re-performed revealing an infiltration to the left cardiac chamber. For diagnosis, axillary lymph node biopsy was performed and during the procedure, he developed ventricular tachycardia (VT). Immunohistological staining revealed PTLD of T lymphocytes, and chemotherapy was introduced on the same day he developed VT. After two cycles of tetrahydropyranyl, adriamycin, cyclophosphamide, vincristine, prednisolone and etoposide treatment, he completely recovered. This is a first case report of severe PTLD with VT, and our case implies the feasibility of chemotherapy after the appearance of dissemination symptoms.