RESUMEN
BACKGROUND: The efficacy of conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been controversial as post-remission therapies for adult Philadelphia chromosome-negative acute lymphoblastic leukemia patients. METHODS: We retrospectively analyzed 96 adolescent and adult cases of Philadelphia chromosome-negative acute lymphoblastic leukemia to evaluate whether allo-HSCT should be performed after first complete remission (1CR). RESULTS: In total, 34 patients received chemotherapy followed by allo-HSCT (HSCT group) and 62 received chemotherapy alone (chemotherapy group). No significant differences in the event-free survival (EFS) or overall survival were observed between the two groups. In the chemotherapy group, use of pediatric regimens was significantly associated with favorable EFS, while high white blood cell (WBC) count and CD20 positivity were associated with poor outcome. In patients who received pediatric regimens, subsequent allo-HSCT did not influence EFS. In patients who received conventional chemotherapy (adult regimen), subsequent allo-HSCT did not improve EFS. High WBC count and CD20 positivity were also significantly associated with poor EFS in patients who received adult regimens. Patients with low WBC count and absence of CD20 who received adult regimens did not benefit from allo-HSCT. CONCLUSIONS: Allo-HSCT may not be required in the pediatric regimen-eligible patients; however, pediatric regimen-ineligible patients with either CD20 positivity or high WBC count should receive allo-HSCT after achieving 1CR. This study was registered at http://www.umin.ac.jp/ctr/ as #C000016287.
Asunto(s)
Antígenos CD20/análisis , Recuento de Leucocitos , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy derived from precursors of plasmacytoid dendritic cells. The majority of patients initially respond to multi-agent chemotherapy, though most relapse within a year and the prognosis is very poor. We report a 67-year-old man with erythema on the right chest and a nasopharyngeal mass. Histological examination revealed a mass of tumor cells expressing CD4, CD56, and CD123, but neither CD3 nor CD20. He was diagnosed with BPDCN. Bone marrow involvement was not seen at diagnosis. He achieved complete remission (CR) with CHOP-like chemotherapy. After 1 year, he relapsed with a cutaneous tumor on the head, a nasopharyngeal tumor, and massive bone marrow involvement. Relapsed BPDCN is generally resistant to chemotherapy and the prognosis is dismal. However, he was successfully treated with biweekly CHOP therapy and achieved a second CR lasting 16 months.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/patología , Neoplasias Hematológicas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Ciclofosfamida/uso terapéutico , Células Dendríticas/patología , Doxorrubicina/uso terapéutico , Neoplasias Hematológicas/diagnóstico , Humanos , Masculino , Recurrencia Local de Neoplasia/diagnóstico , Prednisolona/uso terapéutico , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Vincristina/uso terapéuticoRESUMEN
Primary gastrointestinal follicular lymphoma (FL) has an indolent clinical presentation and many of cases are diagnosed incidentally during routine endoscopic examinations. Herein, we present 3 cases with FL of the small intestine developed massive intestinal hemorrhage that necessitated blood transfusion. In all three patients, upper and lower endoscopic examinations failed to detect the bleeding sites. Eventually, video capsule endoscopies identified ulcerative lesions in the jejunum and biopsies using single- or double-balloon endoscopy confirmed the FL diagnosis in our three cases. The respective clinical stages according to the Lugano system were I, II-1 and II-1. PET-CT did not play a significant role in identifying the gastrointestinal lesions. Two patients received rituximab monotherapy and achieved a complete response. The other remains under observation after termination of antiplatelet drug therapy. Generally, the macroscopic appearance of multiple whitish nodules and the absence of symptoms represent the typical clinical picture of gastrointestinal FL. However, this study demonstrates that patients with ulcerative lesions may be at risk for massive bleeding. Further discussion is required to determine the optimal indications for total endoscopic examination of the small intestine.
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Neoplasias Duodenales/tratamiento farmacológico , Neoplasias Duodenales/patología , Hemorragia Gastrointestinal/etiología , Neoplasias del Yeyuno/tratamiento farmacológico , Neoplasias del Yeyuno/patología , Linfoma Folicular/tratamiento farmacológico , Anciano , Antineoplásicos/uso terapéutico , Neoplasias Duodenales/complicaciones , Femenino , Humanos , Neoplasias del Yeyuno/complicaciones , Linfoma Folicular/complicaciones , Masculino , Persona de Mediana Edad , Inducción de Remisión , Rituximab/uso terapéuticoRESUMEN
Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. Although ABL1-specific tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML, the TKI efficacy depends on the individual patient. In this work, we found that the patients with different nilotinib responses can be classified by using the estimated parameters of our simple dynamical model with two common laboratory findings. Furthermore, our proposed method identified patients who failed to achieve a treatment goal with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéuticoRESUMEN
Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II-expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II-expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I-MHC-II+ tumors but not on MHC-I-MHC-II- tumors, in a cytotoxic CD4+ T-cell-dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II-expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II-expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.
Asunto(s)
Enfermedad de Hodgkin , Animales , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Antígenos de Histocompatibilidad Clase II , Enfermedad de Hodgkin/tratamiento farmacológico , Ratones , Receptor de Muerte Celular Programada 1 , Microambiente TumoralRESUMEN
For patients who have chronic myeloid leukemia (CML), one of the primary treatment options is administration of nilotinib 300 mg twice daily (BID). In previous studies which compared outcomes associated with nilotinib or imatinib treatment, nilotinib achieved a higher rate of deep molecular response (MR). We conducted a phase II, open-label, multicenter study to investigate an intrapatient nilotinib dose-escalation strategy for patients with newly diagnosed chronic-phase (CP) CML based on early MR4.5 achievement. The primary study endpoint was achievement of MR4.5 by 24 months following the initiation of nilotinib 300 mg BID. Fifty-three patients were enrolled, 51 received nilotinib, and 37 completed the treatment. An increase in the nilotinib dose (to 400 mg BID) was allowed when patients satisfied our criteria for no optimal response at any time point. The median (range) dose intensity was 600 (207-736) mg/day. Of 46 evaluable patients, 18 achieved an optimal response and 28 did not. Of the latter, nine patients underwent dose escalation to 400 mg BID, and none achieved MR4.5 . The remaining 19 patients could not undergo dose escalation, 12 (63%) because of adverse events (AEs), and 7 (37%) for non-AE related reasons. Four of these patients achieved MR4.5 . The MR4.5 rate by 24 months was 45.7%. The progression-free, overall and event-free survival were each 97.6%. No new safety concerns were observed. Our findings support the use of continuous nilotinib at a dose of 300 mg BID for newly diagnosed patients with CML-CP.
Asunto(s)
Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Pirimidinas/normas , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados no Aleatorios como Asunto , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: LR11 (also called SorLA or SORL1) is a type I membrane protein, originally identified as a biomarker for atherosclerosis and Alzheimer's disease. We recently found that LR11 was specifically expressed in Diffuse Large B-cell lymphoma (DLBCL) cells, and high serum sLR11 concentrations in retrospective cohort indicated inferior survival. In this study, we prospectively validated the clinical impact of serum sLR11 in 97 patients with newly-diagnosed, untreated DLBCL. RESULTS: Serum sLR11 concentrations were increased in DLBCL patients compared to normal controls (mean±SD: 21.2±27.6 vs. 8.8±1.8ng/ml, P<0.0001), and significantly reduced at remission (mean±SD: 17.4±16.4 vs. 10.9±4.5ng/ml, P=0.02). Increased serum sLR11 concentrations were affected by tumor burden and bone marrow invasion. The 2-y OS and PFS were significantly lower in patients with high sLR11 concentrations (≤18.1ng/ml vs. >18.1ng/ml; 2-y OS: 89.0% vs. 56.4%, P<0.0001; 2-y PFS: 85.8% vs. 56.9%, P<0.0001). CONCLUSIONS: Serum sLR11 is a tumor-derived biomarker for predicting the survival of newly diagnosed patients with DLBCL.
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Proteínas Relacionadas con Receptor de LDL/sangre , Proteínas Relacionadas con Receptor de LDL/química , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/diagnóstico , Proteínas de Transporte de Membrana/sangre , Proteínas de Transporte de Membrana/química , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/química , Médula Ósea/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Solubilidad , Análisis de Supervivencia , Carga Tumoral , Adulto JovenRESUMEN
Histiocytic sarcoma (HS) is an extremely rare malignant neoplasm that often exhibits an aggressive clinical presentation. In this report, we describe the case of a 38-year-old female with advanced-stage HS who was found to have a subcutaneous tumor in the left calf and enlarged lymph nodes in the left inguinal and internal iliac regions. The subcutaneous tumor and inguinal nodes were resected operatively. Immunohistochemistry of the surgical specimens showed that the malignant cells stained positive for CD163, CD68, and related markers; a diagnosis of HS was established. Following the administration of induction chemotherapy consisting of dose-escalated CHOP plus etoposide, the remaining internal iliac tumors disappeared. At that point, high-dose chemotherapy with autologous stem cell transplantation was performed as consolidation treatment. The patient remains alive with no evidence of disease for 30 months post-treatment. This report provides valuable insight into the treatment of advanced HS.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Sarcoma Histiocítico/terapia , Adulto , Biopsia , Quimioterapia de Consolidación , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Etopósido/administración & dosificación , Femenino , Fluorodesoxiglucosa F18 , Sarcoma Histiocítico/diagnóstico , Humanos , Quimioterapia de Inducción , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Prednisona/uso terapéutico , Piel/patología , Trasplante Autólogo , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
OBJECTIVE: Fus is the gene for a member of the FET family of RNA-binding proteins often involved in chromosomal translocations to generate oncogenic fusion genes in human cancers. Fus participates in multiple cellular functions, including RNA processing and transport, transcriptional regulation, and genome integrity. However, its role in hematopoiesis remains obscure. In this study, we examined its role in the self-renewal of hematopoietic stem cells (HSCs). MATERIALS AND METHODS: HSCs in Fus(-/-) fetal livers were analyzed for proliferative capacity in vitro and long-term repopulating capacity in recipient mice. Radiation sensitivity of Fus(-/-) HSCs was evaluated in recipient mice repopulated by Fus(-/-) fetal liver cells. RESULTS: Fus(-/-) fetal livers developed normally, except for a mild reduction in numbers of hematopoietic stem and progenitor cells compared to wild-type. The proliferation and differentiation of Fus(-/-) hematopoietic progenitors were normal in vitro. However, the number of colony-forming cells present in long-term cocultures of Fus(-/-) hematopoietic progenitors and stromal cells was significantly reduced. Fus(-/-) HSCs had an impaired long-term repopulating capacity and failed to repopulate in tertiary recipient mice. Fus(-/-) HSCs were highly susceptible to radiation both in vitro and in vivo and showed retardation of radiation-induced DNA damage repair. CONCLUSION: Our findings define Fus as a novel regulator of self-renewal and radioprotection of HSCs and also implicate it in stress-resistance and maintenance of the genomic integrity of HSCs.
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Diferenciación Celular/fisiología , Proliferación Celular , Feto/metabolismo , Células Madre Hematopoyéticas/metabolismo , Hígado/metabolismo , Proteína FUS de Unión a ARN/metabolismo , Animales , Diferenciación Celular/efectos de la radiación , Daño del ADN/genética , Daño del ADN/efectos de la radiación , Reparación del ADN/genética , Reparación del ADN/efectos de la radiación , Feto/citología , Rayos gamma/efectos adversos , Humanos , Hígado/citología , Ratones , Ratones Noqueados , Proto-Oncogenes Mas , Proteína FUS de Unión a ARN/genética , Tolerancia a Radiación/genética , Tolerancia a Radiación/fisiología , Tolerancia a Radiación/efectos de la radiaciónRESUMEN
A 56-year-old Japanese man was admitted to our hospital due to a fever of unknown origin. He had had a history of extranodal natural killer (NK)/T-cell lymphoma, nasal type, and had been in complete remission for 7 years until June 2003, when he developed high fever, eyelid swelling, and muscular weakness. Serum creatine kinase levels were elevated. Histopathological examination of skin and muscle biopsy specimens revealed subcutaneous infiltration of lymphoid cells positive for CD3, CD56, and Epstein-Barr virus-encoded small nuclear RNA-1. We report this unique case of Epstein-Barr virus-associated lymphoma mimicking dermatomyositis.