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Aim: This study aimed to evaluate the usefulness of the serum creatinine/cystatin C (Cr/CysC) ratio as a prognostic factor after pancreatic surgery in patients with pancreatic cancer. Methods: We retrospectively analyzed the data of 88 patients with pancreatic ductal carcinoma who underwent pancreatic surgery from January 2017 to December 2020. CysC measured from frozen serum samples and circulating Cr levels were used to calculate the Cr/CysC ratio. The cutoff value of the Cr/CysC ratio was determined using receiver operating characteristic curves. Cox proportional hazards model analysis and survival curves were applied to identify the prognostic factors. Results: The optimal cutoff value of the Cr/CysC ratio for predicting mortality after surgery was 1.05. This study included 20 (22.7%) and 68 (77.3%) patients with high and low Cr/CysC ratios, respectively. The low Cr/CysC ratio was significantly associated with female sex (p = 0.020) and higher levels of C-reactive protein (p = 0.020). The postoperative length of stay was significantly longer in patients with low Cr/CysC rates (p = 0.044). Patients with low Cr/CysC ratio showed poorer prognosis in relapse-free survival (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.54-4.20; p = 0.002) and overall survival (HR = 2.52, 95% CI: 1.04-6.10, p = 0.041), respectively, which were significantly worse than in those with high Cr/CysC ratios (p = 0.003 and 0.049, respectively). Conclusion: The Cr/CysC ratio could be a useful screening tool for predicting the prognosis of patients with pancreatic ductal carcinoma undergoing pancreatic surgery.
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BACKGROUND: The ratio of creatinine and cystatin C estimated glomerular filtration rates (eGFRcre/eGFRcys) is significantly positively correlated with sarcopenia. However, there are no published reports on the relationship between eGFRcre/eGFRcys and long-term prognosis in patients after hepatic resection for hepatocellular carcinoma (HCC). METHODS: A total of 157 patients who had undergone curative hepatic resection for HCC were retrospectively reviewed. Cystatin C levels were measured in serum samples that had been frozen after collection at surgery. We aimed to investigate the significance of cystatin C in prognostic value following hepatic resection for HCC. RESULTS: The best cut-off eGFRcre/eGFRcys value for overall survival after hepatic resection for HCC was 1.0025. High eGFRcre/eGFRcys was significantly associated with poor liver function, low skeletal muscle mass, large tumor size, large ascitic volume, worse overall and recurrence-free survival. The eGFRcre/eGFRcys was significantly related to severe recurrence patterns (multiple liver recurrences, distant metastasis). CONCLUSIONS: Preoperative eGFRcre/eGFRcys can predict overall and recurrence-free survival in HCC patients undergoing hepatic resection. The eGFRcre/eGFRcys is a simple and reliable surrogate marker that indicates eligibility for hepatic resection for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores , Carcinoma Hepatocelular/cirugía , Creatinina , Cistatina C , Tasa de Filtración Glomerular/fisiología , Humanos , Neoplasias Hepáticas/cirugía , Estudios RetrospectivosRESUMEN
OBJECTIVES: The objective of this study was to assess the performance and recognition of transfusion practice at the bedside by nurses in our hospital, where a barcode-based electronic identification system (EIS) has been used since 2002. BACKGROUND: More than half of the steps in the transfusion chain are dependent on nurses' awareness and skills. METHODS: Our transfusion policy at the bedside includes two-person checking of the patient and two-person signing of the label at the time of collecting blood samples for pre-transfusion testing and two-person blood administration, which generally involved a doctor-nurse pair but sometimes involved two nurses. Anonymous, paper-based questionnaires were sent in January 2018 to 1051 nurses who were working in Juntendo University Hospital, Tokyo, Japan. The questionnaire consisted of three parts: (a) background of respondents, (b) performance of collection of blood samples for pre-transfusion testing and (c) performance of pre-transfusion check procedures at the bedside using an EIS based on a total of 20 questions. RESULTS: There was a good response rate of individual nurses (1006/1051, 96%). Most nurses (>90%) performed two-person checking of the patient and two-person signing of the label at the time of collecting blood samples. Most nurses (>90%) performed two-person blood administration involving a doctor-nurse pair and electronic pre-transfusion check using an EIS before blood administration. CONCLUSIONS: The survey revealed that most nurses complied with our transfusion policy at the bedside, but some nurses did not. Further education/training and continuous support by the transfusion service may be needed for all nurses.
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Transfusión Sanguínea , Procesamiento Automatizado de Datos , Registros Electrónicos de Salud , Conocimientos, Actitudes y Práctica en Salud , Enfermeras y Enfermeros , Encuestas y Cuestionarios , Femenino , Humanos , Japón , MasculinoRESUMEN
PURPOSE: To propose a new strategy to prevent communication errors caused by unread radiology reports. MATERIALS AND METHODS: Medical emergencies were prefixed with triple stars on radiology reports, and the attending physician was contacted by telephone. Semi-emergencies (medical issues needing addressing within 2 weeks) were prefixed with double stars. Two weeks later, the duty radiologist would search the double-starred reports, and reviewed relevant patient charts to confirm that the information had been appropriately understood and acted upon. If not, the duty radiologist contacted the referral physician by telephone. One year after implementing this strategy, we retrospectively evaluated 1-year worth of data for all the reports of CT, MRI, nuclear medicine and ultrasonography (April 2018 to March 2019). RESULTS: Three hundred and twenty-one reports were double starred (0.52% of 62,143 reports, 1.32 reports/day), and transmission of relevant information was incomplete in 23 cases (7.17%). Causes of incomplete transmission were (1) reports not being opened (n = 17), (2) relevant information on reports being overlooked (n = 5), and (3) the wrong report being opened (n = 1). Sixty-five reports contained triple stars (0.10%, 0.27 reports/day). CONCLUSION: The proposed strategy may be effective in preventing communication errors in radiology reports with important findings requiring semi-emergency clinical action.
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Comunicación , Errores Diagnósticos/prevención & control , Mejoramiento de la Calidad , Servicio de Radiología en Hospital/normas , Sistemas de Información Radiológica/normas , Radiología/normas , Humanos , Japón , Derivación y Consulta , Estudios Retrospectivos , TeléfonoRESUMEN
We herein report the results of the New TARGET study 2nd-line, which collected data on patients with chronic-phase (CP) chronic myeloid leukemia (CML) who received a 2nd-line tyrosine kinase inhibitor (TKI) because of resistance and/or to a 1st-line TKI. A total of 98 patients were enrolled intolerance between April 2010 and March 2013, and 82 patients were analyzed. The median age was 54 years (range 22-88 years). Seventy-six patients (93%) received imatinib as the 1st-line TKI. Forty-five (55%) and 37 (45%) patients began nilotinib and dasatinib treatments at entry, respectively. First-line TKI treatment achieved complete hematological response in 79 patients (96%) and complete cytogenetic response (CCyR) in 49 patients (60%), respectively. Nine patients (11%) had BCR-ABL1 kinase domain point mutations at enrollment. The estimated 3-year progression-free-survival rate after enrollment was 98.7% (95% CI 91.1-99.8%). Overall, the probabilities of achieving CCyR and a major molecular response were 89.3% (95% CI 81.4-94.8%) and 87.2% (95% CI 78.1-93.8%), respectively. There were no new safety issues. This study demonstrated that CML-CP patients in Japan who are resistant and/or intolerant to a 1st-line TKI can achieve an extremely good outcome by 2nd-line TKI treatment.
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Dasatinib/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Japón , Leucemia Mieloide de Fase Crónica/genética , Masculino , Persona de Mediana Edad , Mutación Puntual , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Acute myeloid leukemia (AML) with granulocytic sarcoma (GS) is characterized by poor prognosis; however, its underlying mechanism is unclear. Bone marrow samples from 64 AML patients (9 with GS and 55 without GS) together with AML cell lines PL21, THP1, HL60, Kasumi-1, and KG-1 were used to elucidate the pathology of AML with GS. RNA-Seq analyses were performed on samples from seven AML patients with or without GS. Gene set enrichment analyses revealed significantly upregulated candidates on the cell surface of the GS group. Expression of the adhesion integrin α7 (ITGA7) was significantly higher in the GS group, as seen by RT-qPCR (p = 0.00188) and immunohistochemistry of bone marrow formalin-fixed, paraffin-embedded (FFPE) specimens. Flow cytometry revealed enhanced proliferation of PL21 and THP1 cells containing surface ITGA7 in the presence of laminin 211 and stimulated ERK phosphorylation; this effect was abrogated following ITGA7 knockdown or ERK inhibition. Overall, high ITGA7 expression was associated with poor patient survival (p = 0.0477). In summary, ITGA7 is highly expressed in AML with GS, and its ligand (laminin 211) stimulates cell proliferation through ERK signaling. This is the first study demonstrating the role of integrin α7 and extracellular matrix interactions in AML cell proliferation and extramedullary disease development.
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OBJECTIVE: Myelodysplastic syndromes (MDS), caused by various genetic mutations in hematopoietic stem cells, are associated with highly variable outcomes. Poly (ADP-ribose) polymerase-1 (PARP1) plays an important role in DNA damage repair and contributes to the progression of several types of cancer. Here, we investigated the impact of PARP1 V762A polymorphism on the susceptibility to and prognosis of MDS. METHODS: Samples collected from 105 MDS patients and 202 race-matched healthy controls were subjected to polymerase chain reaction-restriction fragment length polymorphism for genotyping. RESULTS: The allele and genotype frequencies of PARP1 V762A did not differ between MDS patients and the control group. However, MDS patients with the PARP1 V762A non-AA genotype, which is associated with high gene activity, had shorter overall survival rates (P = .01) than those with the AA genotype. Multivariate analysis of overall survival also revealed PARP1 V762A non-AA genotype as a poor prognostic factor (P = .02). When patients were analyzed according to treatment history, the PARP1 V762A non-AA genotype was only associated with poor survival in patients who had received treatment (P = .02). CONCLUSION: PARP1 V762A polymorphism may be an independent prognostic factor for MDS, and a predictive biomarker for MDS treatment.
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Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Poli(ADP-Ribosa) Polimerasa-1/genética , Polimorfismo Genético , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Sustitución de Aminoácidos , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Oportunidad Relativa , Pronóstico , Adulto JovenRESUMEN
A 69-year-old man with palpitations and decreased blood pressure was referred. Echocardiography showed a mass in the right atrium and cardiac septum. The serum IgG4 level was 1,450 mg/dL. A biopsy of the cardiac mass showed fibrosis with inflammatory cells and increased IgG4-positive plasma cells and lymphocytes. Flow cytometry and polymerase chain reaction of the immunoglobulin heavy chain did not demonstrate monoclonality. He was diagnosed with IgG4-related disease (IgG4-RD). IgG4-RD with a cardiac mass is rare and it is difficult to distinguish it from malignant lymphoma by a pathological examination alone. We therefore performed a biopsy and analyzed the clonality in order to make an accurate diagnosis of IgG4-RD.
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Neoplasias Cardíacas/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Anciano , Arritmias Cardíacas/etiología , Biopsia , Diagnóstico Diferencial , Ecocardiografía , Atrios Cardíacos , Neoplasias Cardíacas/complicaciones , Neoplasias Cardíacas/diagnóstico por imagen , Neoplasias Cardíacas/patología , Humanos , Enfermedad Relacionada con Inmunoglobulina G4/complicaciones , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico por imagen , Enfermedad Relacionada con Inmunoglobulina G4/patología , Masculino , Tomografía Computarizada por Rayos XRESUMEN
90Y-ibritumomab tiuxetan (90Y-IT) is widely used, but the factors responsible for its optimal treatment effects are unknown. We enrolled 34 patients with relapsed indolent lymphoma treated with 90Y-IT monotherapy at Gunma University Hospital between 2003 and 2014 in the present study. Clinical data including computed tomography and 18-Fluoro-deoxyglucose positron emission tomography were retrospectively analyzed. The overall response rate and complete response rate were 91% and 82%, respectively. The median progression-free survival (PFS) and overall survival were 32 months and not reached, respectively. In univariate analysis, tumor long-axis diameter ≤ 2.5 cm, maximum standardized uptake value (SUVmax) ≤ 6.5, localized disease, normal levels of serum soluble interleukin-2 receptor, and the number of involved nodal sites ≤ 3 immediately prior to 90Y-IT were associated with median PFS greater than 6 years. However, in multivariate analysis, only tumor long-axis diameter ≤ 2.5 cm and SUVmax ≤ 6.5 affected PFS [hazard ratio (HR) 0.130, P = 0.0021 and HR 0.283, P = 0.0311, respectively]. Patients with only one prior regimen needed less granulocyte colony-stimulating factor and platelet transfusion. Thus, 90Y-IT treatment should be considered for patients with indolent lymphoma in first relapse who have tumor long-axis diameter ≤ 2.5 cm and SUVmax ≤ 6.5.
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Anticuerpos Monoclonales/uso terapéutico , Linfoma no Hodgkin/radioterapia , Diagnóstico por Imagen , Linfoma no Hodgkin/diagnóstico por imagen , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/patología , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Tomografía Computarizada por Rayos X , Radioisótopos de Itrio/uso terapéuticoRESUMEN
The chromosomal abnormalities associated with follicular lymphoma (FL) prognosis are not fully elucidated. Here, we evaluated the pattern of chromosomal abnormalities in FL, and clarified the correlations between the cytogenetic features and clinical outcome. Cytogenetic analysis was performed using standard methods of Giemsa-banding at diagnosis for 201 FL patients admitted to our hospitals between 2001 and 2013. The identified chromosomal abnormalities were: t(14;18)(q32;q21) (59·2%), +X (17·9%), del(6)(q)/-6 (16·9%), +7 (14·4%), abnormality of 1q12-21/1q (12·9%), del(13)(q)/-13 (11·9%), abnormality of 3q27 (10·4%), abnormality of 10q22-24 (10·0%), +12/dup(12)(q) (10·0%), abnormality of 1p21-22/1p (9·0%), +18 (9·0%), del(17)(p)/-17 (5·0%), and a complex karyotype (54·7%). Patients with trisomy 21 had a significantly shorter progression-free survival (P = 0·00171) and overall survival (OS) (P < 0·001) than those without trisomy 21; additionally, patients with trisomy 21 in the rituximab-treated cohort also had a significantly shorter OS (P = 0·000428). Multivariate analysis identified trisomy 21 as an independent risk factor in our cohorts with or without t(14;18) (P = 0·015). In conclusion, the presence of trisomy 21 was an independent risk factor for in FL. Chromosomal analysis of FL patients at diagnosis can provide useful information about their expected survival.
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Cromosomas Humanos Par 21/genética , Linfoma Folicular/genética , Linfoma Folicular/microbiología , Trisomía , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma Folicular/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Factores de Riesgo , Rituximab/administración & dosificación , Tasa de SupervivenciaRESUMEN
Recent studies have shown that tumors of relapsed acute myeloid leukemia (AML) present additional genetic mutations compared to the primary tumors. The base excision repair (BER) pathway corrects oxidatively damaged mutagenic bases and plays an important role in maintaining genetic stability. The purpose of the present study was to investigate the relationship between BER functional polymorphisms and AML relapse. We focused on five major polymorphisms: OGG1 S326C, MUTYH Q324H, APE1 D148E, XRCC1 R194W, and XRCC1 R399Q. Ninety-four adults with AML who achieved first complete remission were recruited. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The OGG1 S326C CC genotype (associated with lower OGG1 activity) was observed more frequently in patients with AML relapse [28.9 vs. 8.9%, odds ratio (OR) = 4.10, 95% confidence interval (CI) = 1.35-12.70, P = 0.01]. Patients with the CC genotype exhibited shorter relapse-free survival (RFS). Moreover, the TCGA database suggested that low OGG1 expression in AML cells is associated with a higher frequency of mutations. The present findings suggest that the OGG1 S326C polymorphism increased the probability of AML relapse and may be useful as a prognostic factor for AML relapse risk.
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ADN Glicosilasas/genética , Reparación del ADN/genética , Reparación del ADN/fisiología , Estudios de Asociación Genética , Genotipo , Leucemia Mieloide Aguda/genética , Mutación , Polimorfismo Genético , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Daño del ADN , Supervivencia sin Enfermedad , Femenino , Expresión Génica , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Especies Reactivas de Oxígeno , Recurrencia , Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
Recent studies have revealed the clinical and biological features of stage I follicular lymphoma (FL), but information about patients with stage I FL who underwent total resection after tissue biopsy is limited. Among 305 FL patients diagnosed between 2001 and 2013, clinical stage I disease was observed in 36 patients. Of these, 18 patients underwent total resection after diagnostic tissue biopsy. We used 18F-fluorodeoxyglucose positron emission CT for staging assessment in 13 of 18 patients (72.2%). The median age was 56.5 years. Six patients (33.3%) were male. The soluble interleukin-2 receptor alpha concentration was significantly lower than in patients with residual disease. Among these 18 patients, 7 patients (38.9%) were treated with a "watch-and-wait" (WW) policy, 7 (38.9%) were treated with involved-field irradiation, and 4 (22.2%) received systemic chemotherapy. Patients with resected disease were treated with significantly different strategies from those with residual disease (p = 0.0026). Five patients experienced relapse during follow-up (median follow-up: 48.2 months). All relapses were distant from the primary site, irrespective of treatment strategy. Among all stage I patients, disease resection was not a significant factor for survival (p = 0.9294). Collectively, the choice of treatment strategy was significantly influenced by patient status. Resection status was not significantly associated with survival after several treatment strategies.
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Glucosa-6-Fosfato/análogos & derivados , Linfoma Folicular , Tomografía de Emisión de Positrones , Anciano , Supervivencia sin Enfermedad , Femenino , Glucosa-6-Fosfato/administración & dosificación , Humanos , Linfoma Folicular/diagnóstico por imagen , Linfoma Folicular/mortalidad , Linfoma Folicular/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasia Residual , Tasa de SupervivenciaRESUMEN
Programmed death-1 (PD-1, PDCD1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CTLA4) play central roles in immune checkpoint pathways. Single nucleotide polymorphisms (SNPs) of PDCD1 and CTLA4 have been reported to be associated with susceptibility to some autoimmune diseases. However, the potential association between SNPs in these immune checkpoint genes and risk of chronic immune thrombocytopenia (cITP) remain controversial and obscure. The aims of this study were to clarify the influence of PDCD1 and CTLA4 SNPs on the risk of developing cITP and its clinical features. We obtained genomic DNA from 119 patients with cITP and 223 healthy controls; their genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Patients with cITP had a significantly higher frequency of the PDCD1 +7209 TT genotype compared with healthy controls. The CTLA4 -1577 GG genotype and CT60 GG genotype showed higher frequencies of platelet count <5 × 109 /l at diagnosis, minimum platelet count <5 × 109 /l, and bleeding symptoms. Moreover, the PDCD1 -606 AA genotype and +63379 TT genotype were significantly associated with a lower number of patients who achieved a complete response to prednisolone treatment. Our results suggest that the immune checkpoint polymorphisms may affect the susceptibility to the clinical features of cITP, and treatment response of the affected patients.
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Antígeno CTLA-4/genética , Polimorfismo de Nucleótido Simple/genética , Receptor de Muerte Celular Programada 1/genética , Púrpura Trombocitopénica Idiopática/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Enfermedad Crónica , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Factores de Riesgo , Adulto JovenRESUMEN
We describe a rare case of chronic active Epstein-Barr virus (CAEBV) infection, with infiltration of the skeletal muscle. A 19-year-old woman with swollen cervical lymph nodes and a fever was referred to our hospital. Swelling of the trapezium muscle and elevation of creatinine kinase level were observed. Biopsy results of the brachialis muscle revealed infiltration of Epstein-Barr virus (EBV)-encoded RNA-positive CD8 T lymphocytes. The EBV virus load in the peripheral blood was high, and EBV monoclonality was determined by Southern blot analysis. Owing to the rarity of CAEBV with skeletal muscle infiltration, this case alerts physicians to the potential diagnostic pitfalls of CAEBV.
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Linfocitos T CD8-positivos/virología , Infecciones por Virus de Epstein-Barr/patología , Músculo Esquelético/patología , Enfermedad Crónica , Femenino , Herpesvirus Humano 4 , Humanos , Miositis/patología , Miositis/virología , Adulto JovenRESUMEN
Single nucleotide polymorphisms (SNPs) in interleukin 17 (IL17A) and IL-23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. We investigated the influence of IL17A and IL23R SNPs on the risk of developing multiple myeloma (MM) and its clinical features. We obtained genomic DNA from 120 patients with MM and 201 healthy controls and detected IL17A -197 G/A (rs2275913) and IL23R H3Q (rs1884444) genotypes using the polymerase chain reaction-restriction fragment length polymorphism method. There were no significant differences in the genotype and allele frequencies of IL17A -197 G/A and IL23R H3Q between the controls and patients with MM. Compared with the GG and GA genotypes, the IL17A AA genotype was significantly associated with lower hemoglobin levels. The IL23R HH genotype was significantly associated with higher frequency of bone lesions and plasmacytoma than the HQ and QQ genotypes. We observed significant differences in overall survival (OS) between patients treated with thalidomide and/or bortezomib and those treated conventionally. Therefore, we also examined the effect of IL17A and IL23R polymorphisms on the clinical variables and OS in patients treated with thalidomide and/or bortezomib. We observed that the IL23R HH genotype was significantly associated with poor survival compared with the QH and HH genotypes in these patients. Our findings indicate that IL17A -197 G/A and IL23R H3Q are not associated with susceptibility to MM. However, IL-17 and IL-23R polymorphisms may affect severity, bone lesions, and extra-medullary disease in patients with MM. Moreover, IL23R polymorphisms may contribute to poor prognosis in patients with MM treated with thalidomide and/or bortezomib.
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Interleucina-17/genética , Mieloma Múltiple/genética , Receptores de Interleucina/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Polimorfismo de Nucleótido Simple , Pronóstico , Análisis de SupervivenciaRESUMEN
Extramedullary myeloma (EMM) occurs when myeloma develops outside the bone marrow; it often develops after chemotherapy and is associated with the acquisition of chemo-resistance and a fatal course. The mechanisms underlying extramedullary spread have not yet been fully elucidated. MALAT1 is a highly abundantly and ubiquitously expressed long non-coding RNA that plays important roles in cancer metastasis. The aims of this study were to clarify the association of MALAT1 with EMM and to elucidate the underlying mechanism of EMM formation under chemotherapeutic pressure. MALAT1 expression was significantly higher in multiple myeloma (MM) than in monoclonal gammopathy of undetermined significance. Furthermore, MALAT1 expression was markedly higher in EMM compared with that in corresponding intramedullary myeloma cells. A higher MALAT1 level was associated with shorter overall and progression-free survival. MALAT1 expression level was positively correlated with expression of HSP90AA1, HSP90AB1 and HSP90B1 but not with TP53 expression. MALAT1 was significantly upregulated by bortezomib and doxorubicin. Considering the known functions of MALAT1, our results suggest that it acts as a stress response gene that is upregulated by chemotherapy, thereby linking chemotherapy to EMM formation. Elucidating the biological implication of long non-coding RNA contributes to deeper understanding concerning the pathogenesis and investigation of novel therapeutic targets for MM.
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Biomarcadores de Tumor/genética , Mieloma Múltiple/patología , ARN Largo no Codificante/genética , Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Bortezomib/farmacología , Progresión de la Enfermedad , Doxorrubicina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Gammopatía Monoclonal de Relevancia Indeterminada/metabolismo , Mieloma Múltiple/genética , Pronóstico , ARN Largo no Codificante/biosíntesis , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Estrés Fisiológico/genética , Análisis de Supervivencia , Células Tumorales CultivadasRESUMEN
B-cell lymphoma 6 (BCL6) attenuates DNA damage response (DDR) through gene repression and facilitates tolerance to genomic instability during immunoglobulin affinity maturation in germinal center (GC) B cells. Although BCL6 expression is repressed through normal differentiation of GC B cells into plasma cells, a recent study showed the ectopic expression of BCL6 in primary multiple myeloma (MM) cells. However, the functional roles of BCL6 in MM cells are largely unknown. Here, we report that overexpression of BCL6 in a MM cell line, KMS12PE, induced transcriptional repression of ataxia telangiectasia mutated (ATM), a DDR signaling kinase, which was associated with a reduction in γH2AX formation after DNA damage. In contrast, transcription of known targets of BCL6 in GC B cells was not affected, suggesting a cell type-specific function of BCL6. To further investigate the effects of BCL6 overexpression on the MM cell line, we undertook mRNA sequence analysis and found an upregulation in the genomic mutator activation-induced cytidine deaminase (AID) with alteration in the gene expression profile, which is suggestive of de-differentiation from plasma cells. Moreover, interleukin-6 exposure to KMS12PE led to upregulation of BCL6 and AID, downregulation of ATM, and attenuation of DDR, which were consistent with the effects of BCL6 overexpression in this MM cell line. Taken together, these results indicated that overexpression of BCL6 alters gene expression profile and confers decreased DDR in MM cells. This phenotypic change could be reproduced by interleukin-6 stimulation, suggesting an important role of external stimuli in inducing genomic instability, which is a hallmark of MM cells.
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Daño del ADN , Perfilación de la Expresión Génica/métodos , Mieloma Múltiple/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Análisis de Secuencia de ARN/métodos , Regulación hacia Arriba , Proteínas de la Ataxia Telangiectasia Mutada/genética , Línea Celular Tumoral , Citidina Desaminasa/genética , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Inestabilidad Genómica , Humanos , FenotipoRESUMEN
Autoimmune hemophilia-like disease (hemorrhaphilia) due to anti-factor XIII (FXIII) antibodies (AH13) is a very rare, life-threatening bleeding disorder. A 77-year-old woman developed macrohematuria and a right renal pelvic hematoma. The coagulation times were not prolonged, but FXIII activity and antigen levels were severely and moderately reduced to 9 and 29% of normal values, respectively. Accordingly, the FXIII-specific activity turned out to be low. FXIII inhibitor and anti-FXIII-A subunit autoantibodies were detected by a 1:1 crossmixing test and immunoblot and immunochromatographic assays. She was therefore diagnosed with "definite AH13" and treated with plasma-derived FXIII concentrates to arrest the hemorrhage. In addition to a highly compressed inferior vena cava by a huge renal pelvic hematoma, deep vein thrombosis (DVT) and pulmonary thromboembolism (PE) were identified by systemic computed tomography. The patient was immediately started on anticoagulation therapy with low-dose heparin. Emboli disappeared quickly, probably because under-crosslinked thrombi caused by severe FXIII deficiency are vulnerable to fibrinolysis. After about 1.5 years, anti-FXIII-A subunit autoantibodies still remained despite the use of rituximab, steroid pulse therapy, oral prednisolone, and oral cyclophosphamide treatments. In conclusion, an extremely rare AH13 case complicated by DVT and PE was successfully managed by balancing anticoagulation therapy with hemostatic therapy.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/terapia , Deficiencia del Factor XIII/complicaciones , Deficiencia del Factor XIII/terapia , Factor XIII/antagonistas & inhibidores , Factor XIII/inmunología , Embolia Pulmonar/complicaciones , Anciano , Anticoagulantes/uso terapéutico , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Ciclofosfamida/uso terapéutico , Factor XIII/uso terapéutico , Deficiencia del Factor XIII/inmunología , Femenino , Hematoma/complicaciones , Hematoma/diagnóstico por imagen , Heparina/uso terapéutico , Humanos , Enfermedades Renales/complicaciones , Enfermedades Renales/diagnóstico por imagen , Rituximab/uso terapéutico , Trombosis de la Vena/complicacionesRESUMEN
The incidence of chronic lymphocytic leukemia (CLL) is low in Japan. The clinical course ranges from very indolent to rapidly progressive. Recently, several reports have indicated that mutation of the splicing factor 3b, subunit 1 (SF3B1) gene in CLL is predictive of a poor prognosis. Here, we investigated the SF3B1 mutational status of Japanese CLL patients and clarified the association between SF3B1 mutational status and prognostic factors. One hundred and two patients that were referred to our institutions between 1999 and 2013 were enrolled. Mutation analysis of SF3B1 (n = 87) and of the immunoglobulin heavy chain gene (IGHV) (n = 102) was performed at diagnosis. FISH analysis of del(11)(q22) was performed for 17 patients. Seven patients have SF3B1 mutation (8.0 %: K700E, 5/7; G742D, 1/7 and Y623C, 1/7). The median survival times for patients with mutated and non-mutated SF3B1 were 53 and 130 months, respectively. Overall survival of the mutated SF3B1 group was significantly lower than that of the non-mutated group (p = 0.0187). No relationship was observed between IGHV mutational status and SF3B1 mutation. There was no patient with SF3B1 mutation in the IGHV1-69 population (0/2). In conclusion, mutation of SF3B1 at diagnosis in Japanese CLL patients is predictive of a poor prognosis.
Asunto(s)
Cadenas Pesadas de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Fosfoproteínas/genética , Factores de Empalme de ARN/genética , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Progresión de la Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , PronósticoRESUMEN
An 80-year-old man, presenting with gait disturbance and memory loss, had findings of normal pressure hydrocephalus. Primary leptomeningeal lymphoma (PLML) was diagnosed based on cytology and flow cytometry of cerebrospinal fluid obtained by examination. Gadolinium-enhanced MRI showed enhancement of the brain and spinal cord but FDG-PET/CT revealed no lymph node swelling. With intrathecal chemotherapy, meningeal lesions disappeared and the gait disturbance and memory loss improved. However, the disease recurred three months later, manifesting as left facial nerve palsy, but the symptoms disappeared in response to intrathecal chemotherapy and systemic rituximab administration. Although a tumor lesion in the spinal canal was suggested by MRI examination, the patient has maintained a good clinical course for four years with intrathecal chemotherapy every three months. PLML is a very rare disease and its diagnosis is difficult. Repeated intrathecal chemotherapy appeared to be effective against PLML in this case.