RESUMEN
Aggressive natural killer cell leukemia (ANKL) is a rare lymphoid neoplasm frequently associated with Epstein-Barr virus, with a disastrously poor prognosis. Owing to the lack of samples from patients with ANKL and relevant murine models, comprehensive investigation of its pathogenesis including the tumor microenvironment (TME) has been hindered. Here we established 3 xenograft mice derived from patients with ANKL (PDXs), which enabled extensive analysis of tumor cells and their TME. ANKL cells primarily engrafted and proliferated in the hepatic sinusoid. Hepatic ANKL cells were characterized by an enriched Myc-pathway and proliferated faster than those in other organs. Interactome analyses and in vivo CRISPR-Cas9 analyses revealed transferrin (Tf)-transferrin receptor 1 (TfR1) axis as a potential molecular interaction between the liver and ANKL. ANKL cells were rather vulnerable to iron deprivation. PPMX-T003, a humanized anti-TfR1 monoclonal antibody, showed remarkable therapeutic efficacy in a preclinical setting using ANKL-PDXs. These findings indicate that the liver, a noncanonical hematopoietic organ in adults, serves as a principal niche for ANKL and the inhibition of the Tf-TfR1 axis is a promising therapeutic strategy for ANKL.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Leucemia Linfocítica Granular Grande , Leucemia Prolinfocítica de Células T , Animales , Humanos , Ratones , Proliferación Celular , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4 , Leucemia Linfocítica Granular Grande/patología , Hígado/patología , Transferrinas , Microambiente TumoralRESUMEN
Neurological complications after hematopoietic stem cell transplantation (HSCT) are frequently life-threatening, and their clinical management can be highly challenging. In the case of central nervous system lesions post-HSCT, a definitive diagnosis is often difficult to reach because many different causative and contributing conditions may be present, including bacterial, fungal, or viral infections; original disease relapse; and post-transplant lymphoproliferative disorder (PTLD). Here, we report a case of a 32-year-old male patient with Philadelphia chromosomepositive acute lymphoid leukemia who underwent three HSCTs and was then diagnosed with primary central nervous system (PCNS) PTLD by brain biopsy. The third HSCT was a haplo-identical peripheral blood stem cell transplantation from his mother, with post-transplant high-dose cyclophosphamide and tacrolimus used as graft-versus-host disease prophylaxis. Four months after the HSCT, multiple small ring lesions were detected in the parabasal ganglia of the patient's brain during magnetic resonance imaging. A lesion biopsy indicated Epstein-Barr virus (EBV)-positive, diffuse large B-cell lymphoma. Because the patient had no evidence of systemic lymphadenopathy, we diagnosed him with PCNS-PTLD. There was no EBV DNA in this patient's cerebrospinal fluid. The diagnosis of PCNS-PTLD by EBV DNA polymerase chain reaction is difficult and highlights the importance of a brain biopsy to diagnose PCNS-PTLD, especially in cases showing no EBV DNA in the cerebrospinal fluid. Although a rare condition, it is essential to locate and analyze cases of PCNS-PTLD after HSCT to establish the optimal strategy for treatment or prophylaxis.
RESUMEN
A recent study reported that treatment-free remission (TFR) of chronic myeloid leukemia (CML) after dasatinib (Das) treatment was significantly associated with natural killer (NK) cell proliferation in the peripheral blood. However, biomarkers to predict lymphocytosis or successful TFR are not well characterized. In order to clarify individual differences in NK cell responses among patients treated with Das, we retrospectively analyzed the association between polymorphisms in the natural killer group 2D receptor [NKG2D; also known as killer cell lectin like receptor K1 (KLRK1)] gene and clinical outcomes in 31 patients treated with Das as first-line treatment for CML. Patients with the NKG2D HNK1/HNK1 (high-cytotoxic activity-related allele on NKG2D hb-1) haplotype achieved MR4.5 more quickly than those with other haplotypes [hazard ratio (HR) 4.39; 95% confidence interval (CI) 2.75-118.6; P = 0.004]. In addition, NK cells with the NKG2D HNK1 allele exhibited enhanced phosphorylation of vav guanine nucleotide exchange factor 1 (VAV1) at Tyr174. These data suggest that NKG2D gene polymorphisms may represent candidate biomarkers for the prediction of TFR following Das treatment.
Asunto(s)
Alelos , Biomarcadores de Tumor/genética , Dasatinib/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Proteínas de Neoplasias/genética , Polimorfismo Genético , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We experienced the case of a 56-year-old male with B-lymphoid/myeloid lineage mixed phenotype acute leukemia (MPAL). A cytogenetic analysis of the patient's bone marrow revealed a complex karyotype, including der(9)t(7;9)(q11.2;p13). We identified an aberrant PAX5 transcript, including the exons 1A to 5 and the contiguous intron 5/6 sequence using the 3' rapid amplification of cDNA ends-polymerase chain reaction method, and confirmed their expression in the leukemic cells. Our case suggests that der(9)t(7;9)(q11.2;p13) can cause the truncation of the PAX5 transcript, which is supposed to contribute to the generation of MPAL, in addition to three previously reported types of PAX5 fusion.
RESUMEN
We report a case of HIV-negative Burkitt lymphoma (BL) that relapsed 9 years after complete remission. We performed a polymerase chain reaction analysis of three regions of the VDJ junction of the immunoglobulin heavy chain (IGH) gene and compared the clonality of the first and second BL lesions, which were found to be clonally distinct. The patient received the R-Hyper CVAD/R-MA regimen; however, leukoencephalopathy subsequently developed due to the effect of cytarabine, and the regimen was changed to R-IVAM. The patient achieved complete remission and received high-dose chemotherapy following autologous stem cell transplantation. He maintained the complete remission for 72 months after transplantation. Given this outcome, we suggest that clonally distinct relapse of HIV-negative BL may exhibit a good prognosis.
Asunto(s)
Linfoma de Burkitt/genética , Linfoma de Burkitt/terapia , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/terapia , Recombinación V(D)J , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Secuencia de Bases , Linfoma de Burkitt/patología , Ciclofosfamida/uso terapéutico , Citarabina/uso terapéutico , Dexametasona/uso terapéutico , Doxorrubicina/uso terapéutico , Etopósido/uso terapéutico , Genes de Inmunoglobulinas , Trasplante de Células Madre Hematopoyéticas , Humanos , Ifosfamida/uso terapéutico , Cadenas Pesadas de Inmunoglobulina/genética , Masculino , Metotrexato/uso terapéutico , Datos de Secuencia Molecular , Recurrencia Local de Neoplasia/patología , Inducción de Remisión , Vincristina/uso terapéuticoRESUMEN
PURPOSE: To determine the safety and the appropriate dose of intravenous l-ascorbic acid (AA) in conjunction with chemotherapy for patients with relapsed lymphoma. PATIENTS AND METHODS: Patients with relapsed CD20-positive B-cell non-Hodgkin's lymphoma, who were going to receive the CHASER regimen as salvage therapy, were enrolled and treated with escalating doses of AA administered by drip infusion after the 2nd course of the CHASER regimen. The target plasma concentration immediately after AA administration was >15 mM (264 mg/dl). RESULTS: A serum AA concentration of >15 mM was achieved in 3 sequentially registered patients, all of whom had received a 75 g whole body dose. No obvious adverse drug reaction was observed in the patients. The trial was therefore successfully completed. CONCLUSION: Intravenous AA at a whole body dose of 75 g appears to be safe and sufficient to achieve an effective serum concentration. A phase II trial to evaluate the efficacy of intravenous AA in relapsed/refractory lymphoma patients will now be initiated.
Asunto(s)
Ácido Ascórbico/administración & dosificación , Linfoma de Células B/tratamiento farmacológico , Terapia Recuperativa , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Dexametasona/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Rituximab/administración & dosificación , Resultado del TratamientoAsunto(s)
Crisis Blástica/patología , Eritrocitos/patología , Proteínas de Fusión bcr-abl , Leucemia Mieloide Aguda/patología , Fagocitosis , Crisis Blástica/genética , Crisis Blástica/metabolismo , Eritrocitos/metabolismo , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Persona de Mediana EdadAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Leucemia-Linfoma de Células T del Adulto/diagnóstico por imagen , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Bazo/diagnóstico por imagen , Resultado Fatal , Femenino , Humanos , Persona de Mediana Edad , Neoplasia Residual , Cintigrafía , Resultado del TratamientoAsunto(s)
Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Anciano , Humanos , MasculinoRESUMEN
Acquired aplastic anemia is a rare hematopoietic stem-cell disorder that results in pancytopenia and hypocellular bone marrow. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. Acquired aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy such as antithymocyte globulin or cyclosporine. We present a rare case report of a 68-year old patient with acquired severe aplastic anemia with repeated cerebral infarctions at the beginning of immunosuppressive therapy. He started immunosuppressive drug therapy with antithymocyte globulin and cyclosporine. During follow-up, magnetic resonance imaging revealed high signals at right thalamus and right pons by diffusion-weighted image. He was diagnosed with repeated cerebral infarctions of right thalamus and right pons. We successfully managed cerebral infarctions by frequent transfusions, edaravone administration, keeping the trough of serum cyclosporine (CsA) concentration around lower limit. This is the first report of successful management of acquired aplastic anemia with repeated cerebral infarctions.
Asunto(s)
Anemia Aplásica/complicaciones , Anemia Aplásica/tratamiento farmacológico , Infarto Cerebral/etiología , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Anciano , Anemia Aplásica/patología , Anemia Aplásica/fisiopatología , Animales , Infarto Cerebral/patología , Humanos , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , MasculinoRESUMEN
A 71-year-old man presented with progressive dysuria. Several imaging examinations indicated possibility of prostate tumor, therefore he underwent prostate biopsy. This resulted in a diagnosis of granulocytic sarcoma of the prostate. Since bone marrow appeared normal on aspiration biopsy, he was treated with local irradiation. Prostate swelling then markedly diminished and his symptoms disappeared. However, four months later he progressed to AML. He then received systemic chemotherapy and achieved complete remission. We discuss the management of granulocytic sarcoma when findings do not indicate overt leukemia at the time of diagnosis.