RESUMEN
This study reports a case of a 49-year-old woman having B-cell acute lymphoblastic leukemia with glycophorin A, a representative erythroid marker, expression. According to the WHO criteria for mixed phenotype acute leukemia (MPAL), erythroid lineage is not defined, and to the best of our knowledge, only one other case with erythroid/B-cell biphenotypic acute leukemia has been reported previously. To establish the disease entity and clarify the pathophysiology of erythroid/lymphoid MPAL, additional cases need to be analyzed.
Asunto(s)
Leucemia Bifenotípica Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Enfermedad Aguda , Linfocitos B , Femenino , Glicoforinas , Humanos , Inmunofenotipificación , Persona de Mediana EdadRESUMEN
Nephrotic syndrome (NS) rarely occurs in post-hematopoietic stem cell transplantation (HSCT) recipients but represents the renal manifestation of graft-versus-host disease (GVHD). Membranous nephropathy (MN) accounts for almost two thirds of post-HSCT NS and is caused by immune complex deposition. Renal thrombotic microangiopathy (TMA) without fulfillment of clinical criteria for TMA has been underreported because of reduced opportunity for histological examination. However, renal TMA has recently been reported in association with GVHD and humoral immunological reactions. Although both MN and TMA after HSCT are associated with GVHD and immunological abnormalities, these diseases are exceptionally coexistent in renal biopsy specimens. We herein describe a case of post-HSCT NS, histologically showing overlapped lesions of TMA and MN. Renal biopsy specimen after presentation of NS revealed early stage MN and TMA with evidence of chronicity. TMA was thought to have preceded MN, and renal biopsy at the phase of pre-nephrotic proteinuria might reveal earlier histological changes of isolated renal TMA. Detection of subclinical renal TMA earlier by spontaneous renal biopsy can help prevent progression of renal injury or overlapping of other renal pathologies. We also demonstrated Th2 predominant intraglomerular infiltration of lymphocytes by immunohistochemistry.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/complicaciones , Síndrome Nefrótico/diagnóstico por imagen , Microangiopatías Trombóticas/diagnóstico por imagen , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/diagnóstico por imagen , Glomerulonefritis Membranosa/inmunología , Glomerulonefritis Membranosa/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunohistoquímica , Riñón/diagnóstico por imagen , Riñón/inmunología , Riñón/patología , Masculino , Persona de Mediana Edad , Síndrome Nefrótico/complicaciones , Síndrome Nefrótico/inmunología , Síndrome Nefrótico/patología , Células Th2/inmunología , Microangiopatías Trombóticas/complicaciones , Microangiopatías Trombóticas/inmunología , Microangiopatías Trombóticas/patologíaAsunto(s)
Antirreumáticos/efectos adversos , Cromonas/efectos adversos , Inmunosupresores/efectos adversos , Trastornos Linfoproliferativos/inducido químicamente , Metotrexato/efectos adversos , Sulfonamidas/efectos adversos , Anciano , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Cromonas/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Recurrencia , Sulfonamidas/uso terapéuticoRESUMEN
The deleted in colorectal carcinoma (DCC) gene at 18q21 encodes a netrin-1 receptor, a tumor suppressor that prevents cell growth. While allele loss or decreased expression of DCC has been associated with the progression of solid tumors and hematologic malignancies, including leukemias and malignant lymphomas, its involvement has not been evaluated in multiple myeloma (MM), a plasma cell malignancy characterized by complex and heterogenous molecular abnormalities. We here show that 10 of 11 human myeloma-derived cell lines (HMCLs) expressed non-translated aberrant DCC transcriptional variants, in which exon 2 fuses with intron 1 instead of exon 1 (mt.DCC). Among them, two co-expressed wild type transcripts (wt.DCC), while eight co-expressed the splicing variant (sv.DCC) lacking exon 1. The remaining HMCL expressed only sv.DCC. In addition, analyses revealed that there were two types of mt.DCC that differed in their fusion of intron 1 with exon 2. In patient-derived samples from 30 MM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients, wt.DCC was expressed in 53% of MM, but not in MGUS, while 23% of MM and 75% of MGUS expressed only sv.DCC. Considering that 25% of MGUS, 57% of MM, and 91% HMCLs expressed mt.DCC, our results suggest that the acquisition of mt.DCC might be a secondary genetic change in plasma cell dyscrasia.
Asunto(s)
Genes Supresores de Tumor , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Mieloma Múltiple/genética , Receptores de Superficie Celular/genética , Proteínas Supresoras de Tumor/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Biomarcadores de Tumor/metabolismo , Caspasas/metabolismo , Línea Celular Tumoral , Cromosomas Humanos Par 18/genética , Receptor DCC , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Regulación hacia Abajo , Exones , Humanos , Intrones , Pérdida de Heterocigocidad , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores de Superficie Celular/metabolismo , Proteína Smad4/metabolismo , Sindecano-1/genética , Factor de Transcripción 4 , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Bone marrow (BM) microenvironment (BMME) constitutes the sanctuary for leukemic cells. In this study, we investigated the molecular mechanisms for BMME-mediated drug resistance and BM lodgment in chronic myelogenous leukemia (CML). Gene-expression profile as well as signal pathway and protein analyses revealed that galectin-3 (Gal-3), a member of the ß-gal-binding galectin family of proteins, was specifically induced by coculture with HS-5 cells, a BM stroma cell-derived cell line, in all five CML cell lines examined. It was also found that primary CML cells expressed high levels of Gal-3 in BM. Enforced expression of Gal-3 activated Akt and Erk, induced accumulation of Mcl-1, and promoted in vitro cell proliferation, multidrug resistance to tyrosine kinase inhibitors for Bcr-Abl and genotoxic agents as a result of impaired apoptosis induction, and chemotactic cell migration to HS-5-derived soluble factors in CML cell lines independently of Bcr-Abl tyrosine kinase. The conditioned medium from Gal-3-overexpressing CML cells promoted in vitro cell proliferation of CML cells and HS-5 cells more than did the conditioned medium from parental cells. Moreover, the in vivo study in a mice transplantation model showed that Gal-3 overexpression promoted the long-term BM lodgment of CML cells. These results demonstrate that leukemia microenvironment-specific Gal-3 expression supports molecular signaling pathways for disease maintenance in BM and resistance to therapy in CML. They also suggest that Gal-3 may be a candidate therapeutic target to help overcome BMME-mediated therapeutic resistance.
Asunto(s)
Galectina 3/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Animales , Médula Ósea/patología , Línea Celular Tumoral , Proliferación Celular , Medios de Cultivo Condicionados , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/fisiología , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Modelos Biológicos , Trasplante de Neoplasias , Transducción de Señal , Trasplante Heterólogo , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologíaRESUMEN
PP2A activator FTY720 has been shown to possess the anti-leukemic activity for chronic myelogenous leukemia (CML), however, the cell killing mechanism underlying its anti-leukemic activity has remained to be verified. We investigated the precise mechanisms underlying the apoptosis induction by FTY720, especially focusing on the roles of BH3-only proteins, and the therapeutic potency of FTY720 for CML. Enforced expression of either BCL2 or the dominant-negative protein of FADD (FADD.DN) partly protected CML cells from apoptosis by FTY720, indicating the involvement of both cell extrinsic and intrinsic apoptosis pathways. FTY720 activates pro-apoptotic BH3-only proteins: BIM, which is essential for apoptosis by BCR-ABL1 tyrosine kinase inhibitors (TKIs), and BID, which accelerates the extrinsic apoptosis pathway. Gene knockdown of either BIM or BID partly protected K562 cells from apoptosis by FTY720, but the extent of cell protection was not as much as that by overexpression of either BCL2 or FADD.DN. Moreover, knockdown of both BIM and BID did not provide additional protection compared with knockdown of only BIM or BID, indicating that BIM and BID complement each other in apoptosis by FTY720, especially when either is functionally impaired. FTY720 can overcome TKI resistance caused by ABL kinase domain mutations, dysfunction of BIM resulting from gene deletion polymorphism, and galectin-3 overexpression. In addition, ABT-263, a BH3-mimetic, significantly augmented cell death induction by FTY720 both in TKI-sensitive and -resistant leukemic cells. These results provide the rationale that FTY720, with its unique effects on BIM and BID, could lead to new therapeutic strategies for CML.
Asunto(s)
Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/genética , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Proteínas de la Membrana/genética , Glicoles de Propileno/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/genética , Esfingosina/análogos & derivados , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/antagonistas & inhibidores , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Proteína 11 Similar a Bcl2 , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Proteína de Dominio de Muerte Asociada a Fas/genética , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Clorhidrato de Fingolimod , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/metabolismo , Mutación , Cultivo Primario de Células , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Esfingosina/farmacología , Proteína Letal Asociada a bcl/genética , Proteína Letal Asociada a bcl/metabolismoRESUMEN
High-dose chemotherapy (HDT) supported by autologous stem cell transplantation (ASCT) has long been one of the standards of care for younger patients with multiple myeloma (MM). Cyclophosphamide (CY) plus granulocyte colony-stimulating factor (G-CSF) has been the conventional preparation for hematopoietic progenitor cell (HPC) mobilization, although the optimal dosage of CY in this setting has not yet been clearly defined. This study investigated the efficacy and safety of low-dose (LD-)CY (1.5 g/m(2)) plus G-CSF for conditioning for HPC apheresis harvest (HPC-A) in 18 MM patients, and compared it with a regimen consisting of intermediate-dose (ID)-CY (4 g/m(2)) plus G-CSF for 13 MM patients. Eleven patients in the former and six in the latter were treated with bortezomib (BTZ) during the induction therapy. Both regimens were comparably effective in terms of CD34(+) cell yields, while adverse events, such as leukopenia, thrombocytopenia, and febrile neutropenia, occurred significantly less frequently in the LD-CY cohort. All patients in LD-CY cohort started and completed their apheresis on day 7 or 8, whereas for the ID-CY cohort the day of first apheresis varied widely from day 8 to 15. These findings indicate that the LD-CY regimen is as effective as ID-CY for HPC mobilization, while the former is clearly more practicable and convenient than the ID-CY regimen for patients with MM.
Asunto(s)
Ciclofosfamida/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas/citología , Mieloma Múltiple/terapia , Adulto , Anciano , Antígenos CD34/metabolismo , Eliminación de Componentes Sanguíneos , Ácidos Borónicos/administración & dosificación , Bortezomib , Esquema de Medicación , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Plasmacitoma/terapia , Pirazinas/administración & dosificación , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo , Resultado del TratamientoRESUMEN
OBJECTIVE: The incorporation of rituximab in immunochemotherapy has improved treatment outcomes for diffuse large B-cell lymphoma, but the prognosis for some diffuse large B-cell lymphomas remains dismal. Identification of adverse prognostic subgroups is essential for the choice of appropriate therapeutic strategy. METHODS: We retrospectively investigated the impact of so-called 'double-hit' cytogenetic abnormalities, i.e. cytogenetic abnormalities involving c-MYC co-existing with other poor prognostic cytogenetic abnormalities involving BCL2, BCL6 or BACH2, on treatment outcomes for 93 consecutive diffuse large B-cell lymphoma patients. RESULTS: According to the revised international prognostic index, no patients were cytogenetically diagnosed with double-hit lymphomas in the 'very good' risk group or in the 'good' risk group, while 5 of 33 patients had double-hit lymphomas in the 'poor' risk group. All the double-hit lymphoma patients possessed both nodal and extranodal involvement. The overall complete response rate was 89.3%, overall survival 87.1% and progression-free survival 75.8% over 2 years (median observation period: 644 days). The complete response rates were 93.2% for the non-double-hit lymphoma patients and 40.0% for the double-hit lymphoma patients. Significantly longer progression-free survival and overall survival were observed for the 'very good' and the 'good' risk patients than for the 'poor' risk patients. Moreover, the progression-free survival of double-hit lymphoma was significantly shorter than that of the non-double-hit lymphoma 'poor' risk patients (P = 0.016). In addition, the overall survival of the double-hit lymphoma patients also tended to be shorter than that of the non-double-hit lymphoma 'poor' risk group. CONCLUSIONS: The diagnosis of double-hit lymphoma can help discriminate a subgroup of highly aggressive diffuse large B-cell lymphomas and indicate the need for the development of novel therapeutic strategies for double-hit lymphoma.
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Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Adulto , Anciano , Antineoplásicos/uso terapéutico , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Aberraciones Cromosómicas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Genes myc/genética , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Estudios Retrospectivos , Rituximab , Resultado del TratamientoRESUMEN
We herein report the rare case of a 72-year-old female who presented with paraneoplastic pemphigus (PNP) and bronchiolitis obliterans (BO) associated with follicular lymphoma (FL), who was successfully treated with obinutuzumab (GA101; G) and bendamustine (B). The patient had severe erosive stomatitis and bilateral conjunctival hyperemia that persisted for more than 6 months. A huge mass was found in the abdominal cavity, and a biopsy revealed grade 1 FL (stage IV). Based on a lip biopsy result, the patient was diagnosed with PNP associated FL. The patient received bendamustine and obinutuzumab (BG) chemotherapy and FL and PNP responded very well, but BO was additionally associated during the course of BG. BO progressed without exacerbation as BG therapy progressed to a 2 year maintenance therapy with G, and combination of azithromycin, inhaled bronchodilator therapy, and corticosteroid. She was followed up at the outpatient department with no pulmonary function decline or FL and PNP recurrence. Our case suggests that BG could be a promising treatment option for PNP and BO.
Asunto(s)
Bronquiolitis Obliterante , Linfoma Folicular , Síndromes Paraneoplásicos , Pénfigo , Anciano , Anticuerpos Monoclonales Humanizados , Clorhidrato de Bendamustina/uso terapéutico , Bronquiolitis Obliterante/complicaciones , Bronquiolitis Obliterante/tratamiento farmacológico , Femenino , Humanos , Linfoma Folicular/complicaciones , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamiento farmacológico , Síndromes Paraneoplásicos/complicaciones , Síndromes Paraneoplásicos/etiología , Pénfigo/complicaciones , Pénfigo/tratamiento farmacológicoRESUMEN
We describe a case of coronavirus disease 2019 (COVID-19) in a patient with mixed cellularity classical Hodgkin lymphoma (cHL) undergoing brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) therapy. A 43-year-old man presented to our hospital with a complaint of fever, for which he was diagnosed with COVID-19 after a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and antiviral therapy with favipiravir and ciclesonide was started subsequently. The fever persisted for the first few days of treatment, but his respiratory status was stable, and he became asymptomatic and afebrile on day 9. Although the PCR tests remained positive, he met the updated discharge criteria of the World Health Organization (WHO) on day 12. However, his fever recurred, and his condition worsened on day 16. A chest X-ray showed a new opacity. It is likely that favipiravir and ciclesonide treatment probably did not completely eliminate the virus in the patient, and therefore the infection persisted. We added remdesivir from day 21, and the improvement was remarkable. He was discharged on day 29 after two consecutive PCR test results were negative. PCR tests are not mandatory for the updated WHO discharge criteria. However, even after antiviral therapy, COVID-19 patients with hematologic malignancies may have prolonged active infection with impaired viral excretion. Depending on the background disease and comorbidities, there may be some patient populations for whom it is not appropriate to simply comply with the current discharge criteria. Therefore, more emphasis may be needed on PCR examinations.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , COVID-19/complicaciones , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/tratamiento farmacológico , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Adulto , Alanina/análogos & derivados , Alanina/uso terapéutico , Amidas/uso terapéutico , Brentuximab Vedotina/uso terapéutico , COVID-19/diagnóstico , Prueba de Ácido Nucleico para COVID-19 , Dacarbazina/uso terapéutico , Progresión de la Enfermedad , Doxorrubicina/uso terapéutico , Humanos , Masculino , Pregnenodionas/uso terapéutico , Pirazinas/uso terapéutico , Factores de Tiempo , Vinblastina/uso terapéuticoAsunto(s)
Antineoplásicos/administración & dosificación , Ácidos Borónicos/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/administración & dosificación , Administración Intravenosa , Anciano , Anciano de 80 o más Años , Bortezomib , Dexametasona/administración & dosificación , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Mieloma Múltiple/patologíaRESUMEN
This multicenter phase II study (UMIN000008145) aims to investigate the efficacy and safety of six cycles of combination therapy (RBD) comprising rituximab, bendamustine, and dexamethasone (DEX) for relapsed or refractory (RR) indolent B-cell non-Hodgkin lymphoma (B-NHL) and mantle cell lymphoma (MCL). Although the initial study protocol comprised 20 mg/body DEX on days 1 and 2, and 10 mg/body on days 3-5 [high-dose (HD-) DEX group], the dose of DEX was later decreased to 8 mg/body on days 1 and 2 [low-dose (LD-) DEX group] due to frequent cytomegalovirus (CMV) antigenemia and recurrent retinitis. We enrolled 33 patients, and LD-DEX and HD-DEX were administered in 15 and 18 patients, respectively. The overall response and the 3-year progression-free survival rates were 88% and 75.5%, respectively. The leading adverse event was myelosuppression. Incidence of grade 3-4 leukocytopenia, neutropenia, and lymphocytopenia was 55%, 67%, and 91%, respectively. The most frequent nonhematological adverse events were CMV antigenemia and rash (33% and 30%, respectively). Incidence of CMV antigenemia over 10/100,000 white blood cells was significantly lower with LD-DEX than that with HD-DEX (P = 0.0127). In conclusion, RBD showed significant effectiveness for RR indolent B-NHL and MCL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Terapia Recuperativa/métodos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Infecciones por Citomegalovirus/etiología , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Esquema de Medicación , Femenino , Humanos , Leucopenia/etiología , Linfoma de Células B/complicaciones , Linfoma de Células del Manto/complicaciones , Masculino , Persona de Mediana Edad , Neutropenia/etiología , Rituximab/administración & dosificación , Terapia Recuperativa/efectos adversos , Adulto JovenRESUMEN
Diffuse large B-cell lymphoma (DLBCL), which is the most prevalent disease subtype of non-Hodgkin lymphoma, is highly heterogeneous in terms of cytogenetic and molecular features. This study retrospectively investigated the clinical impact of G-banding-defined chromosomal abnormality on treatment outcomes of DLBCL in the era of rituximab-containing immunochemotherapy. Of 181 patients who were diagnosed with DLBCL and treated with R-CHOP or an R-CHOP-like regimen between January 2006 and April 2014, metaphase spreads were evaluable for G-banding in 120. In these 120 patients, 40 were found to harbor a single chromosomal aberration type; 63 showed chromosomal abnormality variations (CAVs), which are defined by the presence of different types of chromosomal abnormalities in G-banding, including 19 with two CAVs and 44 with ≥3 CAVs; and 17 had normal karyotypes. No specific chromosomal break point or numerical abnormality was associated with overall survival (OS) or progression-free survival (PFS), but the presence of ≥3 CAVs was significantly associated with inferior OS rates (hazard ratio (HR): 2.222, 95% confidence interval (CI): 1.056-4.677, P = 0.031) and tended to be associated with shorter PFS (HR: 1.796, 95% CI: 0.965-3.344, P = 0.061). In addition, ≥3 CAVs more frequently accumulated in high-risk patients, as defined by several conventional prognostic indices, such as the revised International Prognostic Index. In conclusion, our results suggest that the emergence of more CAVs, especially ≥3, based on chromosomal instability underlies the development of high-risk disease features and a poor prognosis in DLBCL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bandeo Cromosómico/métodos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/farmacología , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Femenino , Humanos , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/farmacología , Prednisona/uso terapéutico , Pronóstico , Estudios Retrospectivos , Rituximab , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/farmacología , Vincristina/uso terapéuticoRESUMEN
Disease-specific cytogenetic abnormalities involving BCL2 gene rearrangement frequently co-exist with other cytogenetic abnormalities, contributing to disease progression in follicular lymphoma (FL). In the present study, we retrospectively investigated the prognostic impact of BCL2-unrelated cytogenetic abnormalities in FL. Of 139 consecutively diagnosed patients with FL at two independent institutes, metaphase spreads of tumor cells were obtained for use in G-banding analysis in 77 patients. The recurrent additional cytogenetic abnormalities included chromosome gains +5 (n = 8), +7 (n = 16), +12 (n = 10), and +X (n = 12), and losses -8 (n = 7), -13 (n = 12) -15 (n = 7), and 6q- (n = 7). While -15 was associated with shorter progression-free survival (PFS) in all 77 analyzed patients with evaluable G-banding results (p = 0.04), this negative impact was not evident in 42 patients treated using an R-CHOP-like regimen as first-line treatment. By contrast, 6q- was predictive for shorter PFS in patients who were initially treated with R-CHOP-like regimens without maintenance therapy (p < 0.01), while this negative impact was not evident in all 77 patients with evaluable G-banding results. These results suggest the presence of a molecular region in chromosome 6q that is responsible for the shorter PFS following R-CHOP-like chemotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aberraciones Cromosómicas , Bandeo Cromosómico/métodos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/genética , Rituximab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Cariotipo , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Estudios RetrospectivosRESUMEN
We herein report a rare case of Burkitt lymphoma (BL) preceded by autoimmune hemolytic anemia (AIHA) caused by autoantibodies against D antigen. After a partial response to AIHA with prednisolone (PSL) treatment for 7 months, the patient developed BL with a t(8;22)(q24;q11.2) chromosomal translocation. Intensive immunochemotherapy, including rituximab, led to a complete response (CR) of BL; however, anti-D antibody remained detectable in the plasma and antibody-dissociated solution from erythrocytes, thus continuous therapy with PSL was necessary even after achievement of the CR. BL with AIHA is extremely rare, with only one previously reported case in the literature.
Asunto(s)
Anemia Hemolítica Autoinmune/diagnóstico por imagen , Linfoma de Burkitt/sangre , Globulina Inmune rho(D)/sangre , Anciano , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Linfoma de Burkitt/complicaciones , Femenino , Humanos , Prednisolona/uso terapéuticoRESUMEN
This report concerns a 62-year-old man with primary cutaneous diffuse large B-cell lymphoma (PCLBCL), leg type that developed during methotrexate (MTX) treatment for rheumatoid arthritis (RA). Several tumors were observed on the left lower leg. A histological analysis showed diffuse proliferation of large neoplastic B-cells that were immunophenotypically CD10-/MUM1+/BCL6-/BCL2+ and cytogenetically had IgH/c-MYC translocation without translocation involving BCL6 or IgH/BCL2. No evidence of Epstein-Barr virus (EBV) infection was found. The discontinuation of MTX resulted in a 20-month disease-free period. No previous cases of PCLBCL, leg type associated with RA or MTX therapy have been reported. The phenotypes of our patient were partly different from those of typical PCLBCL, leg type or RA/MTX-associated lymphoma.
Asunto(s)
Artritis Reumatoide/complicaciones , Linfoma de Células B/etiología , Metotrexato/efectos adversos , Anciano , Artritis Reumatoide/tratamiento farmacológico , Linfocitos B , Humanos , Pierna/patología , Linfoma de Células B/genética , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patología , Translocación GenéticaRESUMEN
Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles.
Asunto(s)
Proteínas Quinasas Dependientes de 3-Fosfoinosítido/genética , Carcinogénesis/genética , Mieloma Múltiple/genética , Transducción de Señal/genética , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/antagonistas & inhibidores , Proteínas Quinasas Dependientes de 3-Fosfoinosítido/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Mieloma Múltiple/patologíaRESUMEN
Galectin-3 is induced in chronic myelogenous leukemia (CML) cells by co-culture with bone marrow stromal cells, making paracrine growth promotion of CML cells in conditioned medium (CM) from galectin-3 overexpressing CML cells more potent. We used gel filtration chromatography to demonstrate that the bovine SERPINA1-fetal bovine serum albumin (BSA) complex was specifically suppressed in CM from galectin-3 overexpressing cells. The SERPINA1-BSA complex as well as human plasma SERPINA1 inhibited the growth of CML cells, while exogenous galectin-3 partly offset this effect. These findings suggest that galectin-3 overexpression promotes paracrine growth of CML cells by interfering with the action of the growth inhibitory SERPINA1-albumin complex.
Asunto(s)
Proliferación Celular , Galectina 3/metabolismo , Albúmina Sérica/metabolismo , alfa 1-Antitripsina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Bovinos , Línea Celular , Línea Celular Tumoral , Técnicas de Cocultivo , Medios de Cultivo Condicionados/farmacología , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Electroforesis en Gel de Poliacrilamida , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Galectina 3/genética , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Albúmina Sérica/química , Albúmina Sérica/farmacología , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/metabolismo , Albúmina Sérica Bovina/farmacología , Microambiente Tumoral/efectos de los fármacos , alfa 1-Antitripsina/química , alfa 1-Antitripsina/farmacologíaRESUMEN
The pathogenetic roles of 8q24 amplified segments in leukemic cells with double minute chromosomes remain to be verified. Through comprehensive molecular analyses of 8q24 amplicons in leukemic cells from an acute myelogenous leukemia (AML) patient and AML-derived cell line HL60 cells, we identified two novel fusion genes between NSMCE2 and long noncoding RNAs (lncRNAs), namely, PVT1-NSMCE2 and BF104016-NSMCE2. Our study suggests that 8q24 amplicons are associated with the emergence of aberrant chimeric genes between NSMCE2 and oncogenic lncRNAs, and also implicate that the chimeric genes involving lncRNAs potentially possess as-yet-unknown oncogenic functional roles.
Asunto(s)
Cromosomas Humanos Par 8/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia Mieloide Aguda/genética , Ligasas/genética , ARN Largo no Codificante/genética , Cariotipo Anormal , Anciano , Femenino , Amplificación de Genes , Células HL-60 , Humanos , CariotipificaciónRESUMEN
Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of non-Hodgkin lymphoma characterized by aggressive symptoms and various abnormal laboratory test results. One of the rare immunologic abnormalities in AITL is exuberant polyclonal plasmacytosis, but its clinical significance has not been evaluated. This report concerns three AITL cases with exuberant polyclonal plasmacytosis and investigates its clinical impact by comparison with 12 patients without plasmacytosis. Our study found that the performance status (PS) of the former was significantly worse and their serum immunoglobulin levels were significantly higher. All other parameters, including B symptoms, various prognostic scores, blood cell counts other than plasmacyte, and serum levels of lactate dehydrogenase, C-reactive protein and soluble interleukin-2 receptor, showed no significant differences. More importantly, although the diagnosis of AITL with plasmacytosis was not straightforward in our series, outcomes of treatment with conventional chemotherapy or immunosuppressive therapy with cyclosporine A were favorable. To conclude, AITL should be considered a candidate underlying disease of exuberant polyclonal plasmacytosis. Provided a correct diagnosis is made early and is followed by adequate treatment, the prognosis for AITL with plasmacytosis may not be worse than that for those without plasmacytosis despite the severe exhaustion at first presentation.