RESUMEN
SIRT2 and SIRT3 protein deacetylases maintain genome integrity and stability. However, their mechanisms for maintaining the genome remain unclear. To examine the roles of SIRT2 and SIRT3 in DSB repair, I-SceI-based GFP reporter assays for HR, single-strand annealing (SSA) and nonhomologous end joining (NHEJ) repair were performed under SIRT2- or SIRT3-depleted conditions. SIRT2 or SIRT3 depletion inhibited HR repair equally to RAD52 depletion, but did not affect SSA and NHEJ repairs. SIRT2 or SIRT3 depletion disturbed the recruitment of RAD51 to DSB sites, an essential step for RAD51-dependent HR repair, but not directly through RAD52 deacetylation. SIRT2 or SIRT3 depletion decreased the colocalization of γH2AX foci with RPA1, and thus, they might be involved in initiating DSB end resection for the recruitment of RAD51 to DSB sites at an early step in HR repair. These results show the novel underlying mechanism of the SIRT2 and SIRT3 functions in HR for genome stability.
Asunto(s)
Recombinación Homóloga/genética , Reparación del ADN por Recombinación , Sirtuina 2/metabolismo , Sirtuina 3/metabolismo , Acetilación , Roturas del ADN de Doble Cadena , Proteínas Fluorescentes Verdes/metabolismo , Células HeLa , Histonas/metabolismo , Humanos , Recombinasa Rad51/metabolismo , Proteína Recombinante y Reparadora de ADN Rad52/metabolismoRESUMEN
The p300 and CBP histone acetyltransferases are recruited to DNA double-strand break (DSB) sites where they induce histone acetylation, thereby influencing the chromatin structure and DNA repair process. Whether p300/CBP at DSB sites also acetylate non-histone proteins, and how their acetylation affects DSB repair, remain unknown. Here we show that p300/CBP acetylate RAD52, a human homologous recombination (HR) DNA repair protein, at DSB sites. Using in vitro acetylated RAD52, we identified 13 potential acetylation sites in RAD52 by a mass spectrometry analysis. An immunofluorescence microscopy analysis revealed that RAD52 acetylation at DSBs sites is counteracted by SIRT2- and SIRT3-mediated deacetylation, and that non-acetylated RAD52 initially accumulates at DSB sites, but dissociates prematurely from them. In the absence of RAD52 acetylation, RAD51, which plays a central role in HR, also dissociates prematurely from DSB sites, and hence HR is impaired. Furthermore, inhibition of ataxia telangiectasia mutated (ATM) protein by siRNA or inhibitor treatment demonstrated that the acetylation of RAD52 at DSB sites is dependent on the ATM protein kinase activity, through the formation of RAD52, p300/CBP, SIRT2, and SIRT3 foci at DSB sites. Our findings clarify the importance of RAD52 acetylation in HR and its underlying mechanism.
Asunto(s)
Roturas del ADN de Doble Cadena , Histona Acetiltransferasas/fisiología , Histona Desacetilasas/fisiología , Recombinación Homóloga , Proteína Recombinante y Reparadora de ADN Rad52/metabolismo , Acetilación , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Histona Acetiltransferasas/genética , Histona Desacetilasas/genética , Humanos , Microscopía Fluorescente , Técnicas del Sistema de Dos HíbridosRESUMEN
BACKGROUND: Isohemagglutinins against ABO antigens absent on both recipient and donor red blood cells (RBCs) increase or decrease after ABO-incompatible hematopoietic stem cell transplantation (HSCT). However, few reports have described the changes in the isohemagglutinin titers and the characteristics in patients with recurrent hematologic conditions after ABO-incompatible HSCT. CASE REPORT: A 59-year-old female with acute erythroid leukemia received a peripheral blood stem cell transplant from her HLA-haploidentical daughter. The patient was typed as group O with anti- A (4+) and B (4+) isohemagglutinins, while the donor was typed as group B. The bone marrow cells achieved complete donor cell chimerism on Day 13 after HSCT. On Day 120, the patient showed 97% B RBC type with persistent anti-A (3+) and without anti-B antibodies. On Day 375, her leukemia relapsed, and recipient type O RBCs and anti-B antibodies sequentially reemerged. However, clinicolaboratory hemolysis and erythroid aplasia were not detected in the patient. RESULTS: The post-HSCT sera agglutinated the allo B RBCs, but not the donor B RBCs, while the pre-HSCT sera agglutinated both RBCs. The burst-forming/colony-forming units of erythroid formation from the donor peripheral blood stem cells were impaired by only the pre-HSCT sera and not by the post-HSCT sera. CONCLUSION: To our knowledge, this is the first report investigating the characteristic changes of isohemagglutinins between the pre- and post-HSCT sera in a patient with recurrent acute myeloid leukemia. The present study suggests that the plasma cells producing anti-donor B RBCs in the patient have been selectively eliminated or induced into an anergic state by the post-HSCT immunologic reconstruction.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/inmunología , Incompatibilidad de Grupos Sanguíneos/inmunología , Isoanticuerpos/sangre , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre de Sangre Periférica , Eritrocitos/inmunología , Femenino , Humanos , Leucemia Mieloide Aguda/inmunología , Persona de Mediana Edad , Recurrencia , Trasplante HomólogoAsunto(s)
Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Linfoma de Células B de la Zona Marginal , Linfoma Folicular , Humanos , Linfoma Folicular/complicaciones , Linfoma Folicular/patología , Yeyuno/patología , Células Plasmáticas/patología , Linfoma de Células B de la Zona Marginal/patologíaRESUMEN
OBJECTIVES: We conducted a phase-II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP) in Japan (IMIDAS PART 2 study). METHODS: Seventy-nine patients were administered 100 mg dasatinib once daily. We examined pretreatment and post-treatment influences of various factors. The BCR-ABL1 international scale (IS), halving time (HT) and reduction rate of BCR-ABL1 transcript within the initial 1 or 3 months of therapy (RR-BCR-ABL11m,3m ) were the post-treatment factors investigated to predict the molecular response. RESULTS: The estimated major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4% and 35.4%, respectively, at 12 months. Grade 3/4 non-haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post-treatment factors at 3 months predicted DMR by univariate analysis. However, RR-BCR-ABL13m was the only significant landmark for predicting DMR by multivariate analysis. CONCLUSIONS: Primary treatment of CML-CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR-BCR-ABL13m was found to be a more useful predictor of DMR than HT-BCR-ABL1 and BCR-ABL1 IS.
Asunto(s)
Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Expresión Génica , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Dasatinib/administración & dosificación , Dasatinib/efectos adversos , Femenino , Humanos , Leucemia Mieloide de Fase Crónica/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Three-dimensional (3-D) aggregate culturing is useful for investigating the functional properties of mesenchymal stem/stromal cells (MSCs). For 3-D MSC analysis, however, pre-expansion of MSCs with two-dimensional (2-D) monolayer culturing must first be performed, which might abolish their endogenous properties. To avoid the need for 2-D expansion, we used prospectively isolated mouse bone marrow (BM)-MSCs and examined the differences in the biological properties of 2-D and 3-D MSC cultures. The BM-MSCs self-assembled into aggregates on nanoculture plates (NCP) that have nanoimprinted patterns with a low-cellular binding texture. The 3-D MSCs proliferated at the same rate as 2-D-cultured cells by only diffusion culture and secreted higher levels of pro-angiogenic factors such as vascular endothelial growth factor and hepatocyte growth factor (HGF). Conditioned medium from 3-D MSC cultures promoted more capillary formation than that of 2-D MSCs in an in vitro tube formation assay. Matrigel-implanted 3-D MSC aggregates tended to induce angiogenesis in host mice. The 3-D culturing on NCP induced alpha-fetoprotein (AFP) expression in MSCs without the application of AFP- or endodermal-inducible factors, possibly via an HGF-autocrine mechanism, and maintained their differentiation ability for adipocytes, osteocytes, and chondrocytes. Prospectively isolated mouse BM-MSCs expressed low/negative stemness-related genes including Oct3/4, Nanog, and Sox2, which were not enhanced by NCP-based 3-D culturing, suggesting that some of these cells differentiate into meso-endodermal layer cells. Culturing of prospectively isolated MSCs on NCP in 3-D allows the analysis of the biological properties of more closely endogenous BM-MSCs and might contribute to tissue engineering and repair.
Asunto(s)
Células de la Médula Ósea/citología , Técnicas de Cultivo de Célula/métodos , Separación Celular/métodos , Imagenología Tridimensional , Células Madre Mesenquimatosas/citología , Nanotecnología/métodos , Animales , Biomarcadores/metabolismo , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Agregación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Tamaño de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Rastreo Celular , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , Neovascularización Fisiológica/efectos de los fármacosRESUMEN
Occult hepatitis B virus (HBV) infection is a clinical challenge, but its relationship to clinicopathologic features and the risk of progression to malignant lymphoma (ML) are poorly defined. We estimated the prevalence of HBV infection of 1,358 patients with newly diagnosed ML. HBV infection was more prevalent in ML than in control patients. The occult HBV infection group had a higher median onset age, no liver or spleen involvement, and higher prevalence of diffuse large B-cell lymphoma than the other groups, indicating that occult HBV infection is a distinct clinicopathologic entity. J. Med. Virol. 88:2206-2210, 2016. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Infecciones Asintomáticas , Hepatitis B/complicaciones , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Infecciones Asintomáticas/epidemiología , ADN Viral/genética , Femenino , Hepatitis B/epidemiología , Anticuerpos contra la Hepatitis B/sangre , Virus de la Hepatitis B/aislamiento & purificación , Humanos , Japón/epidemiología , Linfoma/epidemiología , Linfoma de Células B Grandes Difuso/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Adulto JovenAsunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Brentuximab Vedotina/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células T Periférico/tratamiento farmacológico , Rituximab/uso terapéutico , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células T Periférico/complicaciones , Linfocitos T Colaboradores-Inductores/efectos de los fármacosRESUMEN
Radiocesium nuclides, used as a gamma ray source in various types of industrial equipments and found in nuclear waste, are strictly controlled to avoid their leakage into the environment. When large amounts of radiocesium are accidentally incorporated into the human body, decorporation therapy should be considered. Although standard decorporation methods have been studied since the 1960s and were established in the 1970s with the drug Radiogardase(®) (a Prussian blue preparation), application of recent advances in pharmacokinetics and ethical standards could improve these methods. Here we designed a modern dosage form of hydrogel containing cesium-absorbents to alleviate intestinal mucosa irritation due to the cesium-binding capacity of the absorbents. The effectiveness of the dosage form on fecal excretion was confirmed by quantitative mouse experiments. The total cesium excretion rate of the crystal form (1.37±0.09) was improved by the hydrogel form (1.52±0.10) at the same dose of Prussian blue, with a longer gastrointestinal tract transit time. Using a mouse model, we compared the effects of several drugs on fecal and urinary excretion of internal cesium, without the use of absorbents. Only phenylephrine hydrochloride significantly enhanced cesium excretion (excretion rate of 1.17±0.08) via the urinary pathway, whereas none of the diuretic drugs tested had this effect. These findings indicate that modifying the dosage form of cesium absorbents is important for the decorporation of internal radiocesium contamination.
Asunto(s)
Antídotos/farmacología , Radioisótopos de Cesio/farmacocinética , Ferrocianuros/farmacología , Óxido Ferrosoférrico/farmacología , Alcohol Polivinílico/farmacología , Adsorción , Animales , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/metabolismo , Absorción Intestinal/efectos de los fármacos , Ratones Endogámicos C3H , MicroesferasRESUMEN
A 46-year-old man was diagnosed with acute myelomonocytic leukemia involving inv(16)(p13.1q22) in August 2007. He received a human leukocyte antigen-identical, ABO major-mismatched (donor: A, recipient: O) bone marrow transplantation from an unrelated donor in June 2009. Cyclosporin A (CsA) and short-course methotrexate were used for graft versus host disease prophylaxis. Although granulocyte and platelet engraftment were achieved, the patient exhibited persistent anemia and was dependent on red blood cell (RBC) transfusions. Bone marrow aspiration on day 63 revealed the near absence of erythroid precursors, a finding consistent with pure red cell aplasia. No CBFß-MYH11 transcripts were detected. The recipient's anti-A IgM antibody titer was 1:64, and his anti-A IgG antibody titer was 1:1024. The discontinuation of CsA, and the initiation of rituximab and donor lymphocyte infusions were all ineffective against his anemia. He was treated with high-dose dexamethasone (DEXA) (40 mg/day DEXA, days 657-660, days 757-760; 20 mg/day DEXA, days 764-767, days 772-775) in April 2010. A follow-up examination performed at 7 months after the high-dose DEXA treatment showed the patient's anti-A antibody titer to have dropped to an undetectable level. His hemoglobin levels also returned to normal (Hb: 13.4 g/dl), and he no longer required RBC transfusions.
Asunto(s)
Dexametasona/uso terapéutico , Aplasia Pura de Células Rojas/tratamiento farmacológico , Sistema del Grupo Sanguíneo ABO , Dexametasona/administración & dosificación , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Persona de Mediana Edad , Aplasia Pura de Células Rojas/terapia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
BACKGROUND: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib-resistant or imatinib-intolerant chronic myeloid leukemia (CML). METHODS: From 2009 to 2011, 54 CML-chronic phase (CP) patients with resistance (n = 40) or intolerance (n = 25) to imatinib were registered to undergo dasatinib treatment. Eleven patients showed both resistance and intolerance to imatinib. Coincidentally, the resistance criteria in this study were the same as a non-optimal response to tyrosine kinase inhibitors (TKIs) as defined in the European LeukemiaNet (ELN) 2013 recommendations. RESULTS: The overall incidence rate of major molecular response (MMR) at 12 months was 62.3% (n = 47). Forty patients with resistance to imatinib who were 'warning' and 'failure' patients based on the ELN 2013 recommendations were assessed; cumulative MMR and MR(4.5) rates were 62.5% (n = 39) and 21.0% (n = 40), respectively, at 12 months. Twelve patients who showed a BCR-ABL transcript level >1% on the international scale did not achieve a MMR or discontinued dasatinib treatment because of insufficient effects. With regard to safety issues, grade 3/4 non-hematologic adverse events (AEs) were infrequent. CONCLUSIONS: Patients with non-optimal responses (who meet ELN 2013 warning and failure criteria) to imatinib should be switched quickly to dasatinib, which is less toxic in CML-CP patients, to improve their prognoses. A BCR-ABL1 IS of <1% at 3 months of dasatinib administration is a landmark for good therapeutic outcome.
Asunto(s)
Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/efectos adversos , Estimación de Kaplan-Meier , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Exosomes mediate intercellular communication, and mesenchymal stem cells (MSC) or their secreted exosomes affect a number of pathophysiologic states. Clinical applications of MSC and exosomes are increasingly anticipated. Radiation therapy is the main therapeutic tool for a number of various conditions. The cellular uptake mechanisms of exosomes and the effects of radiation on exosome-cell interactions are crucial, but they are not well understood. Here we examined the basic mechanisms and effects of radiation on exosome uptake processes in MSC. Radiation increased the cellular uptake of exosomes. Radiation markedly enhanced the initial cellular attachment to exosomes and induced the colocalization of integrin CD29 and tetraspanin CD81 on the cell surface without affecting their expression levels. Exosomes dominantly bound to the CD29/CD81 complex. Knockdown of CD29 completely inhibited the radiation-induced uptake, and additional or single knockdown of CD81 inhibited basal uptake as well as the increase in radiation-induced uptake. We also examined possible exosome uptake processes affected by radiation. Radiation-induced changes did not involve dynamin2, reactive oxygen species, or their evoked p38 mitogen-activated protein kinase-dependent endocytic or pinocytic pathways. Radiation increased the cellular uptake of exosomes through CD29/CD81 complex formation. These findings provide essential basic insights for potential therapeutic applications of exosomes or MSC in combination with radiation.
Asunto(s)
Exosomas/efectos de la radiación , Integrina beta1/metabolismo , Células Madre Mesenquimatosas/efectos de la radiación , Tetraspanina 28/metabolismo , Línea Celular , Dinamina II/metabolismo , Exosomas/metabolismo , Rayos gamma , Técnicas de Silenciamiento del Gen , Humanos , Cadenas alfa de Integrinas/metabolismo , Integrina beta1/análisis , Integrina beta1/genética , Sistema de Señalización de MAP Quinasas , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Estrés Oxidativo , Tetraspanina 28/análisis , Tetraspanina 28/genéticaAsunto(s)
Cromosomas Humanos Par 6 , Cromosomas Humanos Par 9 , Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica , Síndrome de Sweet , Translocación Genética , Tirosina Quinasa 3 Similar a fms , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 6/metabolismo , Cromosomas Humanos Par 9/genética , Cromosomas Humanos Par 9/metabolismo , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Síndrome de Sweet/genética , Síndrome de Sweet/metabolismo , Síndrome de Sweet/patología , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Immune checkpoint inhibitors (ICI) are promising therapeutic agents for relapsed or refractory classical Hodgkin's lymphoma (RRcHL). This retrospective study evaluated patients with RRcHL registered in the clinical research program Tohoku-Hematology-Forum-26, between 2016 and 2020, and treated with ICI in 14 centers in Northeast Japan. We analyzed the usage, efficacy, and safety of ICI therapy (ICIT). Among a total of 27 patients with RRcHL, 21 and nine were treated with nivolumab and/or pembrolizumab, respectively. The best response was complete response (CR), partial response (PR), stable disease (SD), and progressive disease in 11 (40.8%), seven (25.9%), eight (29.6%), and one (3.7%) patient, respectively. In all patients undergoing ICIT, the 2-year progression-free survival and 2-year overall survival (OS) were 48.6% and 87.4%, respectively. The 2-year OS for patients with CR, PR, and SD were 100%, 68.6%, and 87.5%, respectively. A total of 36 events of immune-related adverse events (irAEs) or immune-related like adverse events (irlAEs) were observed in 19 of the 27 patients (70.4%). Two thirds of these irAEs or irlAEs were grade 1-2 and controllable. During the observation period, ICIT was discontinued in 22 of 27 (81.4%) patients due to CR, inadequate response, irAE and patient circumstances in five (22.7%), seven (31.8%), eight (36.4%) and two patients (9.1%), respectively. Therapy-related mortality-associated irAE were observed in only one patient during ICIT. These results suggest that ICIT for RRcHL is effective and safe in real-world settings. The optimal timing of induction and duration of ICIT remains to be established.
Asunto(s)
Células Clonales/patología , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4/aislamiento & purificación , Linfadenopatía Inmunoblástica/virología , Linfoma de Células T/virología , Células Madre Neoplásicas/patología , Células Plasmáticas/virología , Anciano de 80 o más Años , Antígenos CD/análisis , Antígenos de Neoplasias/análisis , Linfocitos B/patología , Linfocitos B/virología , Médula Ósea/patología , Células Clonales/virología , Diagnóstico Diferencial , Infecciones por Virus de Epstein-Barr/sangre , Resultado Fatal , Reordenamiento Génico de Cadena Pesada de Linfocito B , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Humanos , Linfadenopatía Inmunoblástica/sangre , Linfadenopatía Inmunoblástica/diagnóstico , Linfadenopatía Inmunoblástica/patología , Ganglios Linfáticos/patología , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células T/sangre , Linfoma de Células T/diagnóstico , Linfoma de Células T/patología , Masculino , Células Madre Neoplásicas/virología , Células Plasmáticas/patología , Linfocitos T/patología , Linfocitos T/virologíaAsunto(s)
Plaquetas/metabolismo , Síndrome de Plaquetas Grises/diagnóstico , Complicaciones Hematológicas del Embarazo/diagnóstico , Adulto , Antígenos CD/metabolismo , Células Sanguíneas/metabolismo , Células Sanguíneas/patología , Degranulación de la Célula , Femenino , Humanos , Inmunofenotipificación , EmbarazoRESUMEN
BACKGROUND Nocardia infections have rarely been reported in hematopoietic stem cell transplantation (HSCT) patients, who usually receive the prophylactic use of sulfamethoxazole/trimethoprim (ST) against Pneumocystis jiroveci. However, the ST prophylaxis, sensitive to Nocardia species, sometimes induces renal toxicities. Therefore, alternative prophylactic or therapeutic drugs are required for nocardiosis in HSCT patients. CASE REPORT A 34-year-old Japanese man with acute mixed phenotypic leukemia with t(9; 22) received allogenic peripheral blood HSCT from a haplo-identical sibling donor. He developed graft versus host disease (GVHD) with grade II, and was treated with prednisolone and cyclosporine A with concurrent ciprofloxacin, fluconazole, valacyclovir, and ST. However, the prophylactic ST was ceased because of its renal toxicity. He developed a pulmonary nodular lesion with elevated ß-D-glucan and Aspergillus galactomannan antigen. Repeated blood and sputum culture isolated no pathogens. Voriconazole treatment administered once improved these lesions and laboratory findings. One month later, he presented with right pleuritic chest pain and multiple ring-enhancing cavitation lesions along the ribs. A needle biopsy demonstrated Nocardia elegans, which is an extremely rare infection induced by Nocardia species, in the cavitation lesions, shown by 16S rRNA gene sequencing. He was started on doripenem and liposomal amphotericin B, and a subsequent treatment kept him free from Nocardia elegans infection, without any adverse effects, while continuing the cyclosporine A and prednisolone treatment for chronic GVHD. CONCLUSIONS Clarithromycin has fewer adverse effects than ST. This case suggests that clarithromycin is an appropriate alternative and prophylactic therapy for patients with nocardiosis and ST toxicities.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Nocardiosis , Nocardia , Adulto , Claritromicina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Nocardia/genética , ARN Ribosómico 16SRESUMEN
BACKGROUND: Histiocytic sarcoma (HS) is a rare neoplasm showing morphological and immunophenotypic features of mature tissue histiocytes. We report a patient with nodal HS exhibiting prominent reactive eosinophilic infiltration. CASE PRESENTATION: A 68-year-old man presented with intermittent left lower abdominal pain and weight loss over 3 months. A computed tomography scan revealed multiple abdominal nodules. Open biopsy of the mesenteric tumors was performed for definitive diagnosis. Histologically, the tumor was comprised of a diffuse noncohesive proliferation of pleomorphic large cells, including multinucleated cells. Neoplastic cells were positive for histiocytic markers (CD68, CD163, and LIGHT) and PD-L1 but lacked markers of Langerhans cells, follicular dendritic cells, and epithelial cells. Frequent reactive inflammatory cells were intermingled in the background. Interestingly, prominent eosinophilic infiltration was also noted. Spindle neoplastic cells were prone to be present around areas with little to no eosinophilic infiltration and exhibiting fibrosis and lymphatic vessel proliferation. Conversely, polygonal neoplastic cells were prone to be present around areas with relatively large amounts of eosinophilic infiltration without fibrosis or lymphatic vessel proliferation. Immunohistochemically, the tumor cells and reactive eosinophils expressed eotaxin-2 and eotaxin-3, respectively. CONCLUSION: We revealed that eotaxins induced the selective migration of eosinophils into tissues in this case. These eosinophils may affect the tumor remodeling and tumor biology characteristics of HS, such as fibrosis and lymphatic vessel proliferation.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Quimiocina CCL24/metabolismo , Sarcoma Histiocítico/diagnóstico por imagen , Anciano , Biopsia , Eosinófilos/patología , Histiocitos/metabolismo , Sarcoma Histiocítico/patología , Humanos , Inmunohistoquímica , Inmunofenotipificación , Masculino , Tomografía Computarizada por Rayos XAsunto(s)
Crisis Blástica/diagnóstico por imagen , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico por imagen , Imagen por Resonancia Magnética , Neoplasias Primarias Secundarias/diagnóstico por imagen , Neoplasias del Nervio Óptico/diagnóstico por imagen , Sarcoma/diagnóstico por imagen , Adulto , Femenino , Humanos , RadiografíaRESUMEN
BACKGROUND: Comorbidity and relative dose intensity (RDI) have been associated with survival in diffuse large B-cell lymphoma (DLBCL) patients, but both relationships remain unaddressed in the same patients. METHODS: A retrospective review of consecutive DLBCL patients treated from January 2010 to October 2018 was performed. Data for the clinical characteristics of the patients, including the Charlson Comorbidity Index (CCI) and RDI, on their outcomes were evaluated. RESULTS: A total of 211 patients with a median age of 72 years (range 19-90 years) were analyzed. CCI ≥ 2 was associated with poor event-free survival (EFS) and overall survival (OS). RDI < 70% was associated with worse EFS and OS. A multivariate analysis revealed that RDI < 70% was only a poor risk factor for the reduction of OS in elderly DLBCL patients (65 years <) and independent from the presence of CCI. The relationship between CCI and RDI in elderly patients was analyzed in four groups, based on CCI ≥ 2 or less and RDI ≥ 70% or less. The group with CCI ≥ 2 and RDI < 70% had a poorer OS and EFS, as compared to the other three groups. The group with CCI < 2 and RDI ≥ 70% had a superior OS but an identical EFS, as compared to the two groups with CCI < 2 and RDI < 70% and CCI ≥ 2 and RDI ≥ 70%. CONCLUSIONS: CCI ≥ 2 was associated with a poorer outcome, but maintaining RDI ≥ 70% may improve the outcome, especially in elderly DLBCL patients.