RESUMO
Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal expansion of CD1a+ CD207+ myeloid dendritic cells. The features of LCH are mainly described in children and remain poorly defined in adults; therefore, we conducted a nationwide survey to collect clinical data from 148 adult patients with LCH. The median age at diagnosis was 46.5 (range: 20-87) years with male predominance (60.8%). Among the 86 patients with detailed treatment information, 40 (46.5%) had single system LCH, whereas 46 (53.5%) had multisystem LCH. Moreover, 19 patients (22.1%) had an additional malignancy. BRAF V600E in plasma cell-free DNA was associated with a low overall survival (OS) rate and the risk of the pituitary gland and central nervous system involvement. At a median follow-up of 55 months from diagnosis, six patients (7.0%) had died, and the four patients with LCH-related death did not respond to initial chemotherapy. The OS probability at 5 years post-diagnosis was 90.6% (95% confidence interval: 79.8-95.8). Multivariate analysis showed that patients aged ≥60 years at diagnosis had a relatively poor prognosis. The probability of event-free survival at 5 years was 52.1% (95% confidence interval: 36.6-65.5), with 57 patients requiring chemotherapy. In this study, we first revealed the high rate of relapse after chemotherapy and mortality of poor responders in adults as well as children. Therefore, prospective therapeutic studies of adults with LCH using targeted therapies are needed to improve outcomes in adults with LCH.
Assuntos
Histiocitose de Células de Langerhans , Neoplasias , Criança , Humanos , Masculino , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/terapia , Intervalo Livre de Progressão , MutaçãoRESUMO
Persistent primitive olfactory artery (POA) is a relatively rare variation of the proximal anterior cerebral artery (ACA) that generally follows an extreme anteroinferior course and takes a hairpin turn before continuing to the A2 segment of the ACA. There are other extremely rare variations, such as (1) that continuing to the ethmoidal artery without a hairpin turn, (2) that continuing to both ethmoidal artery and distal ACA with a hairpin turn, and (3) that continuing to the accessory middle cerebral artery with a hairpin turn. We herein report a case of persistent POA without a hairpin turn continuing to the A3 segment of the ACA. We propose calling this new type of persistent POA Type 5.
Assuntos
Artéria Cerebral Anterior/anormalidades , Infarto Cerebral/diagnóstico , Idoso , Artéria Cerebral Anterior/diagnóstico por imagem , Angiografia Cerebral , Humanos , Achados Incidentais , Angiografia por Ressonância Magnética , MasculinoRESUMO
The posterior inferior cerebellar artery (PICA) rarely arises from the cavernous segment of the internal carotid artery (ICA) and is called persistent trigeminal artery variant. The PICA also can arise from the cervical segment of the ICA, and it enters the posterior fossa via the hypoglossal canal, where it is called persistent hypoglossal artery variant. Using magnetic resonance angiography (MRA), we diagnosed a 79-year-old man with a PICA arising from the ascending pharyngeal artery and passing through the medial side of the jugular foremen pars vascularis. Only six cases of this variation have been reported previously in the English language literature. To identify this variation on MRA, the careful observation of source images is useful. Recognizing this variation is important in order to avoid ischemic cerebellar complications during neck surgery and endovascular therapy.
Assuntos
Variação Anatômica , Artéria Carótida Externa/anormalidades , Forâmen Jugular/irrigação sanguínea , Artéria Cerebral Posterior/anormalidades , Vertigem/diagnóstico , Idoso , Artéria Carótida Externa/diagnóstico por imagem , Humanos , Angiografia por Ressonância Magnética , Masculino , Artéria Cerebral Posterior/diagnóstico por imagem , Vertigem/etiologiaRESUMO
There are four types of fetal anastomosis between the carotid and vertebrobasilar arteries at 5 weeks gestation; from caudal to cranial position, these involve the proatlantal intersegmental, hypoglossal, otic, and trigeminal arteries. Excluding otic artery, these arteries may persist rarely. Persistent trigeminal artery (PTA) is the most common carotid-vertebrobasilar anastomosis, and the medial type (intrasellar) PTA is quite rare, accounting for approximately 10% of all PTA cases. An aneurysm is occasionally found at the origin of the PTA. Rarely, an aneurysm arises at the trunk of the PTA. Using magnetic resonance angiography, we identified a case of medial type PTA with an unruptured saccular aneurysm at its trunk.
Assuntos
Aneurisma da Aorta Torácica/complicações , Artéria Basilar/anormalidades , Artérias Carótidas/anormalidades , Aneurisma Intracraniano/diagnóstico , Artéria Cerebral Posterior/anormalidades , Idoso , Artéria Basilar/diagnóstico por imagem , Artérias Carótidas/diagnóstico por imagem , Feminino , Humanos , Aneurisma Intracraniano/complicações , Angiografia por Ressonância Magnética , Artéria Cerebral Posterior/diagnóstico por imagemRESUMO
We described four patients with diffuse large B-cell lymphoma (DLBCL) carrying t(9;14)(p13;q32) that places the PAX5 adjacent to the immunoglobulin heavy chain (IGH) gene. Ages ranged between 63 and 80, and three were female. One developed a nodal disease, and the other three involved extranodal organs. The lymphoma cells were CD10- /BCL6- /MUM1+ in three and CD10+ /BCL6+ /MUM1+ in one. BCL2 was weak or negative. All had t(9;14)(p13;q32), and three had additional 14q32/IGH translocations or +der(14)t(9;14)(p13;q32). Fluorescence in situ hybridization using the PAX5 break-apart probe showed that the locus was disrupted between the 5' and 3' probes or within the 5' probe. Immunohistochemistry (IHC) using a monoclonal antibody against PAX5 showed strong nuclear positivity in all four patients. Cell block IHC of a CD30+ DLBCL cell line, KIS-1, which carried the t(9;14)(p13;q32) and PAX5-IGH fusion gene, reproduced the CD10- /BCL6- /MUM1+ immunophenotype, low-level BCL2, and strong nuclear PAX5. Uniform nuclear positivity of MUM1 in all four cases and KIS-1 cells suggest that these lymphomas arose at a late stage of B-cell differentiation, where expression of PAX5 physiologically becomes downregulated. It is therefore possible that high-level PAX5 resulting from t(9;14)(p13;q32) at this stage of differentiation perturbs the plasma cell differentiation program initiated by PAX5 repression, thereby contributing to the development of a fraction of DLBCL.
Assuntos
Núcleo Celular/metabolismo , Cadeias Pesadas de Imunoglobulinas/genética , Imuno-Histoquímica/métodos , Fatores Reguladores de Interferon/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Fator de Transcrição PAX5/metabolismo , Translocação Genética , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 9/genética , Feminino , Humanos , Fatores Reguladores de Interferon/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX5/genética , PrognósticoRESUMO
The pharmacokinetic and metabolite profiles of mizagliflozin, a novel selective sodium glucose co-transporter 1 inhibitor designed to act only in the intestine, were investigated in rats. Mizagliflozin administrated intravenously (0.3 mg/kg) and orally (3 mg/kg) declined with a short half-life (0.23 and 1.14 h, respectively). The absolute bioavailability was only 0.02%. Following intravenous administration of [14 C]mizagliflozin (0.3 mg/kg), radioactivity in plasma was also rapidly declined. Up to 24 h after oral administration of [14 C]mizagliflozin (1 mg/kg), radioactivity was recovered in the faeces (98.4%) and in the urine (0.8%). No remarkable accumulation of radioactivity in tissues was observed using tissue dissection technique and whole body autoradiography. Orally dosed [14 C]mizagliflozin was mostly metabolised to its aglycone, KP232, in the intestine. In the plasma, KP232 and its glucuronide were predominant. KP232 glucuronide was also prominent in the bile and was recovered as KP232 in the faeces possibly because of the deconjugation by gut microflora. Mizagliflozin was observed neither in the urine nor the faeces. These findings suggest that orally administered mizagliflozin is poorly absorbed, contributing to low systemic exposure; if absorbed, mizagliflozin is rapidly cleared from circulation.
Assuntos
Absorção Fisiológica , Radioisótopos de Carbono/farmacocinética , Inibidores Enzimáticos/farmacocinética , Glucosídeos/farmacocinética , Pirazóis/farmacocinética , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Administração Oral , Animais , Bile/metabolismo , Radioisótopos de Carbono/administração & dosagem , Fezes , Glucosídeos/administração & dosagem , Glucosídeos/sangue , Glucosídeos/química , Masculino , Metaboloma , Pirazóis/administração & dosagem , Pirazóis/sangue , Pirazóis/química , Ratos Sprague-Dawley , Transportador 1 de Glucose-Sódio/metabolismo , Distribuição TecidualRESUMO
The impact of HLA mismatch in hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) has not been fully examined. We analyzed a total of 1130 cases to examine the effects of HLA allele mismatch in unrelated bone marrow transplantation (BMT) with RIC in the Japan Marrow Donor Program registry cohort. Compared with HLA 8/8-allele match (n = 720, 8/8 match), both 1 (n = 295, 7/8 match) and 2 allele mismatches (n = 115, 6/8 match) were associated with significant reduction of overall survival (OS) (hazard ratio [HR], 1.34; P = .0024 and HR, 1.33; P = .035 for 7/8 and 6/8 match, respectively). The incidence of grades 2 to 4 acute graft-versus-host disease (aGVHD) increased with increasing number of mismatched alleles (HR, 1.36 and HR, 2.08 for 7/8 and 6/8 match, respectively). Nonrelapse mortality showed a similar tendency to aGVHD (HR, 1.35 for 7/8 and HR, 1.63 for 6/8). One-allele mismatches at the HLA-A or -B and HLA-C loci were significantly associated with inferior OS compared with 8/8 match (HR, 1.64 for A or B mismatch and HR, 1.41 for C mismatch), whereas HLA-DRB1 allele mismatch was not (HR, 1.16; P = .30). However, the effect of HLA-A or -B and -C mismatch on OS was not observed in those who received RIC BMT since 2010, in contrast to recipients before 2010. These results suggested that in unrelated RIC BMT, 1-allele mismatch is associated with poorer outcome, and the impact of HLA mismatch may differ depending on the HLA locus, although these HLA mismatch effects may be different in recent cases.
Assuntos
Transplante de Medula Óssea , Antígenos HLA/imunologia , Histocompatibilidade , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Aloenxertos , Bussulfano/administração & dosagem , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Humanos , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Doadores Vivos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Neutrófilos , Estudos Retrospectivos , Risco , Irradiação Corporal Total , Adulto JovemRESUMO
We describe the establishment and characterization of a cell line, AM-HLH, obtained from a patient with Epstein-Barr virus-positive (EBV+ ) nodular sclerosis-type Hodgkin lymphoma (HL). The cells were positive for CD2 and CD30 and negative for CD15. The immunoglobulin heavy- and κ light-chain genes were rearranged. The karyotype was of the triploid range. Southern blotting using the EBV terminal repeat probe detected 3 hybridizing bands that were identical to those of the parental HL material. The cells expressed EBV-encoded RNAs as well as latent genes (EBNA1, EBNA2, LMP1, and LMP2A) and lytic genes (BZLF1 and BALF2). Fluorescence in situ hybridization (FISH) with the cosmid pJB8 clone containing a fragment of EBV DNA as a probe revealed multiple hybridization signals at a marker chromosome. Additional FISH using whole chromosome painting and centromere probes in combination with multicolor FISH determined that multiple EBV copies were clustered within the chromosome 20 materials of the marker chromosome. Culture supernatants of AM-HLH contained IL-10 as measured by the bead-based immunoassay. It is possible that an integrated EBV genome and cellular genes on chromosome 20 were coamplified, leading to the enhanced expression of genes involved in cell growth control. The AM-HLH cell line will be useful to clarify the role of cytokines in the development of EBV+ HL.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Genoma Viral , Herpesvirus Humano 4/genética , Doença de Hodgkin/etiologia , Doença de Hodgkin/patologia , Integração Viral , Idoso , Biomarcadores , Linhagem Celular Tumoral , Bandeamento Cromossômico , Interações Hospedeiro-Patógeno , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hibridização in Situ Fluorescente , Masculino , FenótipoRESUMO
Among 42 consecutive patients with malignant lymphoma who underwent high-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (AHSCT), 5 developed hemolytic anemia with fragmented red blood cells (HA-FrRBCs) on days 87-125 (median 107) of AHSCT. Nadir Hb levels ranged between 5.0 and 6.4 g/dL with 2.2-5.6% FrRBCs. All patients developed grade ≥3 hypoxia and heart failure, and 4 developed grade ≥3 hypertension. The ejection fraction of the left ventricle assessed by echocardiography was significantly reduced in 3 patients. Peak creatinine levels were >4 times above the baseline and estimated glomerular filtration rates were reduced to <30 mL/min/1.73 m2. One patient received plasma exchange, while the remaining 4 responded to treatment with diuretics and cardiovascular agents. Hematological parameters normalized within a median duration of 91 days after the development of HA-FrRBCs. Renal and cardiac functions gradually improved, even though renal function did not return to the baseline. HA-FrRBCs associated with cardiac and renal impairments may represent a thrombotic microangiopathy syndrome and are a delayed complication of HDC/AHSCT. The close monitoring of laboratory abnormalities and persistent treatment with cardiovascular agents and diuretics are the mainstay for the management of this condition.
Assuntos
Anemia Hemolítica/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Eritrócitos/metabolismo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfoma/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Creatinina/sangue , Intervalo Livre de Doença , Ecocardiografia , Eritrócitos/citologia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Hemoglobinas/análise , Humanos , Linfoma/mortalidade , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/etiologia , Transplante Autólogo , Resultado do TratamentoRESUMO
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) may include the lymphoid blast crisis of chronic myeloid leukemia (CML-BC). We applied fluorescence in situ hybridization (FISH) of the BCR-ABL fusion gene to peripheral blood and/or bone marrow smears to determine whether the fusion was restricted to mononuclear cell nuclei or if segmented cell nuclei representing mature neutrophils also carried the fusion (Seg-FISH). Among 20 patients with Ph+ ALL without a prior diagnosis of CML, 9 were Seg-FISH+ and 11 were Seg-FISH-. Seg-FISH+ cases were characterized by a higher rate of p210-type BCR-ABL transcripts, higher white cell and blast counts, and a higher rate of myeloid and T-lymphoid antigen expression than Seg-FISH- cases, in addition to 'major route' cytogenetic abnormalities associated with CML-BC. Eighteen patients were treated with tyrosine kinase inhibitors (TKIs) either alone or in combination with multiagent chemotherapy, and 7 underwent allogeneic hematopoietic stem cell transplantation. Progression-free and overall survivals were greater in the Seg-FISH+ group than in the Seg-FISH- group. These results suggest that the Seg-FISH+ group represents lymphoid CML-BC that occurs de novo, while the Seg-FISH- represents Ph+ ALL in the strict sense, and the two groups are associated with survival when treated with TKIs or TKI-combined therapy.
Assuntos
Hibridização in Situ Fluorescente , Cromossomo Filadélfia , Núcleo Celular , Proteínas de Fusão bcr-abl/sangue , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMO
BACKGROUND: Although the number of patients aged 80 years or older with aggressive B-cell non-Hodgkin lymphoma (B-NHL) has increased in the clinical setting, management has been challenging due to lower tolerability. The aim of the present study was to evaluate the efficacy and safety of reduced-dose chemotherapy for very elderly patients. METHODS: We retrospectively analyzed the clinical outcomes of patients aged ≥80 years old with diffuse large B-cell lymphoma (n = 58) or grade 3 follicular lymphoma (n = 3). RESULTS: Patient ages ranged from 80 to 93 years old, with a median of 83 years old. Twenty-four patients were treated with CHOP or THP-COP, the dosages of which were variably reduced, in combination with rituximab (R-vCHOP), while another 24 patients were treated with R-miniCHOP. Twelve R-vCHOP and 16 R-miniCHOP patients completed the chemotherapy cycles. The estimated 2-year progression-free and overall survival rates in the R-vCHOP and R-miniCHOP groups were 53 and 39 % (P = 0.92) and 53 and 48 % (P = 0.95), respectively. Performance status ≥2, lactate dehydrogenase level >normal, serum albumin ≤3.5 g/dL, C-reactive protein ≥2.0 mg/dL, age-adjusted International Prognostic Score 2/3, and withdrawal from the chemotherapy cycle were associated with poor survival. The frequency of chemotherapy-related hospitalization during the second or later cycles was significantly less in the R-miniCHOP group. CONCLUSIONS: The efficacies of R-vCHOP and R-miniCHOP were similar in patients aged ≥80 years old with aggressive B-NHL. The reduced frequency of hospitalization observed for R-miniCHOP treatment is beneficial for very elderly patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Doxorrubicina/análogos & derivados , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteína C-Reativa/metabolismo , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Hospitalização , Humanos , L-Lactato Desidrogenase/sangue , Linfoma Difuso de Grandes Células B/sangue , Masculino , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Retrospectivos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Albumina Sérica/metabolismo , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Suspensão de TratamentoRESUMO
BCL6 translocations are common in B-cell lymphomas and frequently have chromosomal breaks in immunoglobulin heavy chain (IgH) switch regions, suggesting that they occur during class-switch recombination. We analyze 120 BCL6 translocation breakpoints clustered in a 2156-bp segment of BCL6 intron 1, including 62 breakpoints (52%) joined to IgH, 12 (10%) joined to Ig light chains, and 46 (38%) joined to non-Ig partners. The BCL6 breaks in Ig-BCL6 translocations prefer known activation-induced cytosine deaminase (AID) hotspots such as WGCW and WRC (W = A/T, R = A/G), whereas BCL6 breaks in non-Ig rearrangements occur at CpG/CGC sites in addition to WGCW. Unlike previously identified CpG breaks in pro-B/pre-B-cell translocations, the BCL6 breaks do not show evidence of recombination activating gene or terminal deoxynucleotidyl transferase activity. Both WGCW/WRC and CpG/CGC breaks at BCL6 are most likely initiated by AID in germinal center B-cells, and their differential use suggests subtle mechanistic differences between Ig-BCL6 and non-Ig-BCL6 rearrangements.
Assuntos
Quebra Cromossômica , Citidina Desaminase/genética , Proteínas de Ligação a DNA/genética , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma de Células B/genética , Translocação Genética/genética , Citidina Desaminase/metabolismo , Rearranjo Gênico do Linfócito B/genética , Centro Germinativo/patologia , Humanos , Linfoma de Células B/patologia , Células Precursoras de Linfócitos B/enzimologia , Células Precursoras de Linfócitos B/patologia , Proteínas Proto-Oncogênicas c-bcl-6Assuntos
Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 22/genética , Infecções por Vírus Epstein-Barr/genética , Translocação Genética , Cariótipo Anormal , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/química , Linfócitos B/virologia , Cromossomos Humanos Par 19/ultraestrutura , Cromossomos Humanos Par 22/ultraestrutura , Cisplatino/administração & dosagem , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Humanos , Linfoma Difuso de Grandes Células B/virologia , Masculino , Metilprednisolona/administração & dosagem , Prednisona/administração & dosagem , RNA Neoplásico/análise , RNA Viral/análise , Rituximab/administração & dosagem , Vincristina/administração & dosagemRESUMO
UNLABELLED: This study aimed to determine the population pharmacokinetics of doxapram in low-birth-weight (LBW) infants. A total of 92 serum concentration measurements that were obtained from 34 Japanese neonates were analyzed using nonlinear mixed-effect modeling (NONMEM). Estimates generated by NONMEM indicated that clearance of doxapram (CL; L/kg/h) was affected by postmenstrual age (PMA; weeks), body weight (BW; g), and aspartate aminotransferase (AST; IU/L). In addition, the volume of distribution (Vd; L/kg) was affected by gestational age (GA; weeks). The final pharmacokinetic model was as follows: CL = BW / PMA × 0.0453 × serum AST(-0.373); Vd = 2.54 (if GA >28 weeks) and Vd = 2.54 × 2.11 (if GA ≤28 weeks). The interindividual variabilities in CL and Vd were 39.9 and 83.0 %, respectively, and the residual variability was 20.9 %. To clarify the reasons for large interindividual variations, the enzymes involved in the metabolic pathway of doxapram were also determined. We found that doxapram was metabolized by CYP3A4/5. CONCLUSION: We report the population pharmacokinetics of doxapram in neonates and the involvement of CYP3A4/5 in its metabolism. The final model of population pharmacokinetics may be useful for formulating a safe and effective dosage regimen and for predicting serum doxapram concentrations in neonates.
Assuntos
Apneia/metabolismo , Estimulantes do Sistema Nervoso Central/farmacocinética , Doxapram/farmacocinética , Recém-Nascido de Baixo Peso , Apneia/tratamento farmacológico , Povo Asiático , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450 , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Japão , Masculino , Espectrometria de Massas , Modelos BiológicosRESUMO
We characterized 5 B-cell tumors carrying t(14;19)(q32;q13) that creates the IGH::BCL3 fusion gene. The patients' ages ranged between 55 and 88 years. Two patients presented with progression or recurrence of B-cell chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma (SLL), two with diffuse large B-cell lymphoma (DLBCL) of non-germinal center B-like phenotype, and the remaining one with composite angioimmunoblastic T-cell lymphoma and Epstein-Barr virus-positive DLBCL. The presence of t(14;19)(q32;q13) was confirmed by fluorescence in situ hybridization (FISH), showing colocalization of 3' IGH and 3' BCL3 probes on der(14)t(14;19) and 5' BCL3 and 5' IGH probes on der(19)t(14;19). One B-CLL case had t(2;14)(p13;q32)/IGH::BCL11A, and 2 DLBCL cases had t(8;14)(q24;q32) or t(8;11;14)(q24;q11;q32), both of which generated IGH::MYC by FISH, and showed nuclear expression of MYC and BCL3 by immunohistochemistry. The IGH::BCL3 fusion gene was amplified by long-distance polymerase chain reaction in 2 B-CLL/SLL cases and the breakpoints occurred immediately 5' of BCL3 exon 1 and within the switch region associated with IGHA1. The 5 cases shared IGHV preferentially used in B-CLL cells, but the genes were unmutated in 2 B-CLL/SLL cases and significantly mutated in the remaining 3. B-cell tumors with t(14;19)(q32;q13) can be divided into B-CLL/SLL and DLBCL groups, and the anatomy of IGH::BCL3 in the latter may be different from that of the former.
Assuntos
Infecções por Vírus Epstein-Barr , Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Hibridização in Situ Fluorescente , Translocação Genética , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4 , Linfoma Difuso de Grandes Células B/genética , Cromossomos Humanos Par 14/genéticaRESUMO
We describe two types of IGH::BCL2 breakpoints involving the 5' region of BCL2 (5' BCL2). One was ins(14;18)(q32;q21q21) observed in 2 follicular lymphoma (FL) cases, in which IGH was cleaved at 3' of IGHD and 5' of IGHJ and BCL2 was cleaved at 5' BCL2 and downstream regions, and a 281- or 201-kilobase pair fragment containing the BCL2 protein-coding sequences was invertedly inserted into IGH. In another type observed in 2 FL and 2 chronic lymphocytic leukemia (CLL) cases, breakage and reunion occurred within the switch region associated with IGHM (Sµ) and 5' BCL2, creating IGH Sµ::5' BCL2 fusion sequences on der(18)t(14;18)(q32;q21). The former is considered to be mediated by VDJ-recombination, while the latter by the class switch recombination process. There were no particular features in FL or CLL cases with IGH::5' BCL2 breakpoints compared with those with t(14;18)(q32;q21)/IGH::BCL2 involving the 3' breakpoint cluster regions.