RESUMEN
The 3' untranslated region (3'UTR) of the hepatitis C virus (HCV) RNA genome, which contains a highly conserved 3' region named the 3'X-tail, plays an essential role in RNA replication and promotes viral IRES-dependent translation. Although our previous work has found a cis-acting element for genome encapsidation within 3'X, there is limited information on the involvement of the 3'UTR in particle formation. In this study, proteomic analyses identified host cell proteins that bind to the 3'UTR containing the 3'X region but not to the sequence lacking the 3'X. Further characterization showed that RNA-binding proteins, ribosomal protein L17 (RPL17), and Y-box binding protein 1 (YBX1) facilitate the efficient production of infectious HCV particles in the virus infection cells. Using small interfering RNA (siRNA)-mediated gene silencing in four assays that distinguish between the various stages of the HCV life cycle, RPL17 and YBX1 were found to be most important for particle assembly in the trans-packaging assay with replication-defective subgenomic RNA. In vitro assays showed that RPL17 and YBX1 bind to the 3'UTR RNA and deletion of the 3'X region attenuates their interaction. Knockdown of RPL17 or YBX1 resulted in reducing the amount of HCV RNA co-precipitating with the viral Core protein by RNA immunoprecipitation and increasing the relative distance in space between Core and double-stranded RNA by confocal imaging, suggesting that RPL17 and YBX1 potentially affect HCV RNA-Core interaction, leading to efficient nucleocapsid assembly. These host factors provide new clues to understanding the molecular mechanisms that regulate HCV particle formation. IMPORTANCE: Although basic research on the HCV life cycle has progressed significantly over the past two decades, our understanding of the molecular mechanisms that regulate the process of particle formation, in particular encapsidation of the genome or nucleocapsid assembly, has been limited. We present here, for the first time, that two RNA-binding proteins, RPL17 and YBX1, bind to the 3'X in the 3'UTR of the HCV genome, which potentially acts as a packaging signal, and facilitates the viral particle assembly. Our study revealed that RPL17 and YBX1 exert a positive effect on the interaction between HCV RNA and Core protein, suggesting that the presence of both host factors modulate an RNA structure or conformation suitable for packaging the viral genome. These findings help us to elucidate not only the regulatory mechanism of the particle assembly of HCV but also the function of host RNA-binding proteins during viral infection.
Asunto(s)
Regiones no Traducidas 3' , Genoma Viral , Hepacivirus , ARN Viral , Proteínas Ribosómicas , Ensamble de Virus , Proteína 1 de Unión a la Caja Y , Regiones no Traducidas 3'/genética , Hepacivirus/genética , Hepacivirus/fisiología , Hepacivirus/metabolismo , Humanos , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genética , Proteína 1 de Unión a la Caja Y/metabolismo , Proteína 1 de Unión a la Caja Y/genética , Ensamble de Virus/genética , ARN Viral/metabolismo , ARN Viral/genética , Replicación Viral , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteómica/métodosRESUMEN
Hepatitis B virus (HBV) is a human hepatotropic pathogen causing hepatocellular carcinoma. We recently obtained HBV-susceptible immortalized human hepatocyte NKNT-3 by exogenously expressing NTCP and its derived cell clones, #28.3.8 and #28.3.25.13 exhibiting different levels of HBV susceptibility. In the present study, we showed that HBV infection activated the ATM-Chk2 signaling pathway in #28.3.25.13 cells but not in #28.3.8 cells. Both the cell culture supernatant and extracellular vesicles (EVs) derived from HBV-infected #28.3.25.13 cells also activated the ATM-Chk2 signaling pathway in naïve #28.3.25.13 cells. Interestingly, EVs derived from HBV-infected #28.3.25.13 cells included higher level of mitochondrial DNA (mtDNA) than those from HBV-infected #28.3.8 cells. Based on our results, we propose the novel model that EVs mediate the activation of ATM-Chk2 signaling pathway by the intercellular transfer of mtDNA in HBV-infected human hepatocyte.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Quinasa de Punto de Control 2/metabolismo , ADN Mitocondrial/genética , Vesículas Extracelulares/metabolismo , Hepatitis B/patología , Hepatocitos/patología , Replicación Viral , Proteínas de la Ataxia Telangiectasia Mutada/genética , Quinasa de Punto de Control 2/genética , ADN Mitocondrial/metabolismo , Células Hep G2 , Hepatitis B/genética , Hepatitis B/metabolismo , Hepatitis B/microbiología , Virus de la Hepatitis B/fisiología , Hepatocitos/metabolismo , Hepatocitos/microbiología , HumanosRESUMEN
Current histopathological diagnosis methods cannot distinguish the two types of thyroid carcinoma: clinically significant carcinomas with a potential risk of recurrence, metastasis, and cancer death, and clinically insignificant carcinomas with a slow growth rate. Both thyroid tumors are diagnosed as "carcinoma" in current pathology practice. The clinician usually recommends surgery to the patient and the patient often accepts it because of cancer terminology. The treatment for these clinically insignificant carcinomas does not benefit the patient and negatively impacts society. The author proposed risk stratification of thyroid tumors using the growth rate (Ki-67 labeling index), which accurately differentiates four prognostically relevant risk groups based on the Ki-67 labeling index, ≥30%, ≥10 and <30%, >5 and <10%, and ≤5%. Indolent thyroid tumors with an excellent prognosis have the following four features: young age, early-stage (T1-2 M0), curatively treated, and low proliferation index (Ki-67 labeling index of ≤5%), and are unlikely to recur, metastasize, or cause cancer death. Accurate identification of these indolent tumors helps clinicians select more conservative treatments to avoid unnecessary aggressive (total thyroidectomy followed by radio-active iodine) treatments. Clinicians can alleviate the fears of patients by confirming these four features, including the low proliferation rate, in a pathology report immediately after surgery when patients are most concerned.
Asunto(s)
Cáncer Papilar Tiroideo/patología , Glándula Tiroides/patología , Neoplasias de la Tiroides/patología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Cáncer Papilar Tiroideo/cirugía , Glándula Tiroides/cirugía , Neoplasias de la Tiroides/cirugía , TiroidectomíaRESUMEN
Glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) is a rate-limiting enzyme catalyzing triglyceride synthesis. Recently, we demonstrated that the anti-viral drug ribavirin (RBV) reduces GPAM expression by downregulating CCAAT/enhancer-binding protein α (C/EBPα). However, the precise mechanisms of GPAM suppression have remained unclear. Here, we found that RBV suppressed GPAM expression by downregulating not only C/EBPα, but also sterol regulatory element-binding protein-1c (SREBP-1c). We also found that cis-elements regulated by C/EBPα and SREBP-1c functioned as distal and proximal enhancers, respectively, to express hepatocyte- and adipocytes-specific GPAM variants. These results imply that RBV disrupts formation of the enhancer machineries on the GPAM genome by downregulating both transcription factors. Our findings may contribute to the development of treatments for fatty liver diseases caused by aberrant triglyceride synthesis.
Asunto(s)
Antivirales/farmacología , Regulación hacia Abajo/efectos de los fármacos , Regiones Promotoras Genéticas/efectos de los fármacos , Ribavirina/farmacología , Antimetabolitos/farmacología , Proteína alfa Potenciadora de Unión a CCAAT/genética , Línea Celular , Glicerol-3-Fosfato O-Aciltransferasa , Humanos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genéticaRESUMEN
The most characteristic feature of the hepatitis C virus (HCV) genome in patients with chronic hepatitis C is its remarkable variability and diversity. To better understand this feature, we performed genetic analysis of HCV replicons recovered from two human hepatoma HuH-7-derived cell lines after 1, 3, 5, 7, and 9 years in culture: The cell lines 50-1 and sO harbored HCV 1B-1 and O strain-derived HCV replicons established in 2002 and 2003, respectively. The results revealed that genetic variations in both replicons accumulated in a time-dependent manner at a constant rate despite the maintenance of moderate diversity (less than 1.8% difference) between the clones and that the mutation rate in the 50-1 and sO replicons was 2.5 and 2.9 × 10-3 base substitutions/site/year, respectively. We found that the genetic distance of both replicons increased from 7.9% to 10.5% after 9 years in culture. In addition, we observed that the guanine + cytosine (GC) content of both replicon RNAs increased in a time-dependent manner, as observed in our previous studies. Finally, we demonstrated that the high sensitivity of both replicons to direct-acting antivirals was maintained even after 9 years in culture. Our results suggest that long-term cultured HCV replicon-harboring cells are a useful model for understanding the variability and diversity of the HCV genome and the drug sensitivity of HCV in patients with chronic hepatitis C.
Asunto(s)
Variación Genética/genética , Hepacivirus/genética , Replicación Viral/genética , Carcinoma Hepatocelular/virología , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Genes Reporteros/genética , Genoma Viral/genética , Genotipo , Hepatitis C Crónica/virología , Humanos , Neoplasias Hepáticas/virología , ARN Viral/genética , Replicón/genéticaRESUMEN
Research on the primary thyroid lymphoma (PTL) diagnosis is limited, with only a few large sample size studies, reported from Asian countries. The aim of the present study was to clarify the current prevalence and challenges in PTL diagnosis, and recommended ancillary studies for PTL in non-Western countries. PTL (n = 153) cases were retrieved from 10 institutions in non-Western countries and analyzed. Ultrasound examination (UE) and fine needle aspiration cytology (FNAC) were used as main preoperative diagnostic tools in all participating institutions. Flow cytometry (FCM) was performed in the 5 institutions (50%). Lobectomy was the most common histological procedure to confirm the PTL diagnosis. All institutions routinely performed immuno-histochemical analysis. PTL was 0.54% of malignant thyroid tumor cases, with mucosa-associated lymphoid tissue lymphoma (MALTL) and diffuse large B-cell lymphoma (DLBCL) being 54.9% and 38.6%, respectively. Kuma Hospital, where the frequency of MALTL was highest (83.7%), routinely performed FCM using the materials obtained by FNAC. UE and FNAC sensitivities were 62.5% and 57.8%, respectively. In both UE and FNAC, sensitivity of MALTL was lower than of DLBCL. The study elucidated that the prevalence of PTL in non-Western countries was lower than previously reported. We propose that FCM should be more actively used to improve the preoperative diagnosis of MALTL. Our data predicted that the MALTL proportion will increase with improved diagnostic tools, while observation of PTL-suspected nodules without histological examination remains a viable option.
Asunto(s)
Linfoma/epidemiología , Neoplasias de la Tiroides/epidemiología , Biopsia con Aguja Fina , China/epidemiología , Humanos , Inmunohistoquímica , India/epidemiología , Japón/epidemiología , Linfoma/diagnóstico , Linfoma/patología , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/epidemiología , Linfoma de Células B de la Zona Marginal/patología , Linfoma Folicular/diagnóstico , Linfoma Folicular/epidemiología , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/epidemiología , Linfoma de Células B Grandes Difuso/patología , Prevalencia , República de Corea/epidemiología , Serbia/epidemiología , Taiwán/epidemiología , Tailandia/epidemiología , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patología , Tiroidectomía , Turquía/epidemiología , UltrasonografíaRESUMEN
Recently, we demonstrated that the anti-viral drug ribavirin (RBV) had the ability to suppress lipogenesis through down-regulation of retinoid X receptor α (RXRα) under the control of the intracellular GTP-level and AMP-activated protein kinase-related kinases, especially microtubule affinity regulating kinase 4 (MARK4). RXRα-overexpression attenuated but did not abolish lipogenesis suppression by RBV, implying that additional factor(s) were involved in this suppressive effect. In the present study, we found that the protein level, but not the mRNA level, of CCAAT/enhancer-binding protein α (C/EBPα) was down-regulated by RBV in hepatic cells. Treatment with proteasome inhibitor attenuated RBV-induced down-regulation of C/EBPα, suggesting that RBV promoted degradation of C/EBPα protein via the ubiquitin-proteasome pathway. Depletion of intracellular GTP through inosine monophosphate dehydrogenase inhibition by RBV led to down-regulation of C/EBPα. In contrast, down-regulation of C/EBPα by RBV was independent of RXRα and MARK4. Knockdown of C/EBPα reduced the intracellular neutral lipid levels and the expression of genes related to the triglyceride (TG) synthesis pathway, especially glycerol-3-phosphate acyltransferase, mitochondrial (GPAM), which encodes the first rate-limiting TG enzyme. Overexpression of C/EBPα yielded the opposite results. We also observed that RBV decreased GPAM expression. Moreover, overexpression of GPAM attenuated RBV-induced reduction in the intracellular neutral lipid levels. These data suggest that down-regulation of C/EBPα by RBV leads to the reduction in GPAM expression, which contributes to the suppression of lipogenesis. Our findings about the mechanism of RBV action in lipogenesis suppression will provide new insights for therapy against the active lipogenesis involved in hepatic steatosis and hepatocellular carcinomas.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Hepatocitos/metabolismo , Lipogénesis/efectos de los fármacos , Ribavirina/farmacología , Triglicéridos/biosíntesis , Proteínas Potenciadoras de Unión a CCAAT/genética , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen , Hepatocitos/citología , Humanos , Lipogénesis/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptor alfa X Retinoide , Triglicéridos/genéticaRESUMEN
Hepatitis B virus (HBV) infection, which increases the risk of cirrhosis and hepatocellular carcinoma and requires lifelong treatment, has become a major global health problem. However, host factors essential to the HBV life cycle are still unclear, and the development of new drugs is needed. Cells derived from the human hepatoma cell line HepG2 and engineered to overexpress sodium taurocholate cotransporting polypeptide (NTCP: a receptor for HBV), termed HepG2/NTCP cells, are widely used as the cell-based HBV infection and replication systems for HBV research. We recently found that human hepatoma cell line Li23-derived cells overexpressing NTCP (A8 cells subcloned from Li23â¯cells), whose gene expression profile was distinct from that of HepG2/NTCP cells, were also sensitive to HBV infection. However, the HBV susceptibility of A8 cells was around 1/100 that of HepG2/NTCP cells. Since we considered that plural cell assay systems will be needed for the objective evaluation of anti-HBV reagents, as we previously demonstrated in hepatitis C virus research, we here attempted to develop a new Li23 cell-derived assay system equivalent to that using HepG2/NTCP cells. By repeated subcloning of A8 cells, we successfully established a new cell line (A8.15.78.10) exhibiting high HBV susceptibility equal to that of HepG2/NTCP cells. Characterization of A8.15.78.10â¯cells revealed that the increase of HBV susceptibility was correlated with increases in the protein and glycosylation levels of NTCP, and with decreased expression of STING, a factor contributing to innate immunity. Finally, we performed a comparative evaluation of HBV entry inhibitors (cyclosporin A and rosiglitazone) by an HBV/secNL reporter assay using A8.15.78.10â¯cells or HepG2/NTCP cells. The results confirmed that cyclosporin A exhibited anti-HBV activity in both cell lines, as previously reported. However, we found that rosiglitazone did not show the anti-HBV activity in A8.15.78.10â¯cells, although it worked in HepG2/NTCP cells as previously reported. This suggested that the difference in anti-HBV activity between cyclosporin A and rosiglitazone was due to the different types of cells used for the assay. In conclusion, plural assay systems using different types of cells are required for the objective and impartial evaluation of anti-HBV reagents.
Asunto(s)
Carcinoma Hepatocelular/virología , Virus de la Hepatitis B/fisiología , Hepatitis B/virología , Neoplasias Hepáticas/virología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Ciclosporina/farmacología , Células Hep G2 , Virus de la Hepatitis B/efectos de los fármacos , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Rosiglitazona/farmacología , Simportadores/genética , Simportadores/metabolismo , Internalización del Virus/efectos de los fármacosRESUMEN
OBJECTIVE: To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS: This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort nâ¯=â¯1196, and Japan cohort nâ¯=â¯495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS: During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (Pâ¯=â¯0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, Pâ¯=â¯0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, Pâ¯=â¯0.805), overall survival (HR not estimated, Pâ¯=â¯0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, Pâ¯=â¯0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, Pâ¯=â¯0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, Pâ¯=â¯0.021), but was not associated with overall survival (HR not estimated, Pâ¯=â¯0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9â¯years, and all cases were salvaged. CONCLUSION: Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.
Asunto(s)
Carcinoma Endometrioide/epidemiología , Carcinoma Endometrioide/terapia , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/terapia , Neoplasias Primarias Secundarias/epidemiología , Tratamientos Conservadores del Órgano/estadística & datos numéricos , Ovario/fisiología , Adulto , Estudios de Cohortes , Supervivencia sin Enfermedad , Neoplasias Endometriales/cirugía , Femenino , Humanos , Histerectomía/métodos , Histerectomía/estadística & datos numéricos , Japón/epidemiología , Clasificación del Tumor , Estudios Retrospectivos , Estados Unidos/epidemiologíaRESUMEN
The myelodysplastic syndromes (MDS) are clonal haematopoietic disorders that develop de novo and also secondary to chemotherapy and/or radiation therapy. We previously demonstrated that the risk of MDS is increased among atomic bomb survivors with significant correlation to radiation dose; however, the clinical characteristics of these survivors have not been well analysed. In this study, we investigated chromosomal abnormalities of MDS among survivors. The frequency of abnormal karyotypes was significantly higher, with more very poor risk karyotypes, according to the revised International Prognostic Scoring System, among those exposed close to the hypocentre compared with unexposed cases. However, abnormal karyotype frequency did not reflect the prognosis of exposed cases with respect to distance from the hypocentre. In addition, there was no difference in prognosis between exposed and unexposed cases. Among proximally exposed cases (<1·5 km from the hypocentre), chromosomal translocations and inversions were more frequent, and the frequency of structural alterations in chromosomes 3, 8, and 11 was significantly increased compared with unexposed cases. These results suggest that chromosomal alterations in MDS among survivors have different features compared with those in de novo or therapy-related MDS. Detailed molecular study is warranted.
Asunto(s)
Aberraciones Cromosómicas , Víctimas de Desastres , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/genética , Armas Nucleares , Sobrevivientes , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células Sanguíneas , Médula Ósea/patología , Análisis Citogenético , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Evaluación del Resultado de la Atención al Paciente , Sistema de Registros , Análisis de SupervivenciaRESUMEN
Hepatitis B virus (HBV) causes hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. These diseases are closely associated with persistent HBV infection. To prevent the progression of hepatic diseases, it is thus important to suppress persistent HBV infection. Daunorubicin (DNR), a topoisomerase II (Top II) poison, is a clinically used anticancer agent with a wide spectrum of activity against malignancies. DNR was recently reported to cause DNA damage-dependent interferon (IFN)-ß induction through exogenous cyclic GMP-AMP synthetase (cGAS) and subsequently to suppress Ebola virus replication. In the present study, we demonstrated that DNR caused the inhibition of cell proliferation, but not cell death, through the DNA damage response in immortalized human hepatocyte NKNT-3/NTCP cells. Interestingly, DNR triggered the endogenous cGAS-dependent innate immune response and subsequently suppressed viral production of HBV in NKNT-3/NTCP cells. Top II poisons may be anti-HBV drug candidates.
Asunto(s)
Daunorrubicina/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Nucleotidiltransferasas/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Células Hep G2 , Virus de la Hepatitis B/fisiología , Hepatocitos/inmunología , Hepatocitos/metabolismo , Hepatocitos/virología , Humanos , Nucleotidiltransferasas/genética , Inhibidores de Topoisomerasa II/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
PURPOSE: To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance. METHODS: This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization. RESULTS: Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01). CONCLUSION: Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system.
Asunto(s)
Carcinosarcoma/secundario , Neoplasias Uterinas/patología , Carcinosarcoma/mortalidad , Carcinosarcoma/cirugía , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Proyectos Piloto , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Neoplasias Uterinas/mortalidad , Neoplasias Uterinas/cirugíaRESUMEN
OBJECTIVE: The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS). METHODS: This was a secondary analysis of a prior multicenter retrospective study that examined women with stage I-IV UCS who underwent primary hysterectomy. Archived histopathology slides were reviewed and LVSI was scored as follows: LVSI with a carcinomatous component alone (LVSI-carcinoma; n = 375, 76.8%) or LVSI containing a sarcomatous component with or without a carcinomatous component (LVSI-sarcoma; n = 113, 23.2%). Qualitative metrics of LVSI were correlated to clinicopathological factors and survival outcome. RESULTS: Tumors in the LVSI-sarcoma group were more likely to have sarcoma dominance (82.1 vs. 26.4%) heterologous sarcomatous component (51.3 vs. 37.9%), low-grade carcinoma (42.5 vs. 22.4%), and large tumor size (81.0 vs. 70.2%) in the primary tumor site compared with tumors in the LVSI-carcinoma group (all p < 0.05). On multivariate analysis, LVSI-sarcoma was independently associated with decreased progression-free survival (5-year rates: 34.9 vs. 40.8%, adjusted hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.36-2.50, p < 0.001), and cause-specific survival (5-year rates: 41.8 vs. 55.9%, adjusted HR 1.95, 95% CI 1.39-2.75, p < 0.001) compared with LVSI-carcinoma. Postoperative radiotherapy for women with LVSI-sarcoma had a higher reduction rate of recurrence/progression of disease (54% reduction, p = 0.04) compared with postoperative radiotherapy for women with LVSI-carcinoma (26% reduction, p = 0.08). CONCLUSION: In UCS, the presence of a sarcomatous component in LVSI is particularly prevalent when a tumor has sarcoma dominance. Our study suggests that LVSI containing a sarcomatous component may be a predictor of decreased survival for women with UCS.
Asunto(s)
Vasos Sanguíneos/patología , Carcinosarcoma/patología , Carcinosarcoma/terapia , Vasos Linfáticos/patología , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapia , Quimioterapia Adyuvante , Progresión de la Enfermedad , Femenino , Humanos , Histerectomía , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Supervivencia sin Progresión , Radioterapia Adyuvante , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
OBJECTIVE: To identify risk factors for venous thromboembolism (VTE) and to examine the association of VTE and survival in women with uterine carcinosarcoma. METHODS: This multicenter retrospective study examined 906 women who underwent primary surgical treatment for stage I-IV uterine carcinosarcoma. Time-dependent analyses were performed for cumulative incidence of VTE after surgery on multivariate models. RESULTS: There were 72 (7.9%) women who developed VTE after surgery with 1-, 2-, and 5-year cumulative incidences being 5.1%, 7.3%, and 10.2%, respectively. On multivariate analysis, older age (hazard ratio [HR] per year 1.03, P=0.012), non-Asian race (HR 6.28, P<0.001), large body habitus (HR per kg/m2 1.04, P=0.014), residual disease at surgery (HR 3.04, P=0.003), tumor size ≥5cm (HR 2.73, P=0.003), and stage IV disease (HR 2.12, P=0.025) were independently associated with increased risk of developing VTE. A risk pattern analysis identified that obese Non-Asian women with large tumors (13.7% of population) had the highest incidence of VTE (2-year cumulative rate, 26.1%) whereas Asian women with no residual disease (47.1% of population) had the lowest (2-year cumulative rate, 1.6%) (P<0.001). Presence of carcinoma/sarcoma in metastatic sites was significantly associated with increased risk of VTE compared to carcinoma alone (2-year rates, 31.2% versus 8.4%, P=0.049). VTE was independently associated with decreased progression-free survival on multivariate models (5-year rates, 24.9% versus 47.2%, HR 1.46, 95%CI 1.05-2.04, P=0.026). CONCLUSION: Our study suggests that VTE represents a surrogate marker of aggressive tumor behavior and diminished patient condition in uterine carcinosarcoma; obese Non-Asian women with large tumors carry a disproportionally high risk of VTE, suggesting that long-term prophylaxis may benefit this population.
Asunto(s)
Carcinosarcoma/cirugía , Complicaciones Posoperatorias/etiología , Neoplasias Uterinas/cirugía , Tromboembolia Venosa/etiología , Anciano , Carcinosarcoma/mortalidad , Carcinosarcoma/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasia Residual , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/patología , Estudios Retrospectivos , Factores de Riesgo , Carga Tumoral , Neoplasias Uterinas/mortalidad , Neoplasias Uterinas/patología , Tromboembolia Venosa/mortalidadRESUMEN
BACKGROUND AND OBJECTIVES: To examine survival of women with stage IV uterine carcinosarcoma (UCS) who received neoadjuvant chemotherapy followed by hysterectomy. METHODS: This is a nested case-control study within a retrospective cohort of 1192 UCS cases. Women who received neoadjuvant chemotherapy followed by hysterectomy based-surgery for stage IV UCS (n = 26) were compared to those who had primary hysterectomy-based surgery without neoadjuvant chemotherapy for stage IV UCS (n = 120). Progression-free survival (PFS) and cause-specific survival (CSS) were examined. RESULTS: The most common regimen for neoadjuvant chemotherapy was carboplatin/paclitaxel (53.8%). Median number of neoadjuvant chemotherapy cycles was 4. PFS was similar between the neoadjuvant chemotherapy group and the primary surgery group (unadjusted-hazard ratio [HR] 1.19, 95% confidence interval [CI] 0.75-1.89, P = 0.45). Similarly, CSS was comparable between the two groups (unadjusted-HR 1.13, 95%CI 0.68-1.90, P = 0.64). When the types of neoadjuvant chemotherapy regimens were compared, women who received a carboplatin/paclitaxel regimen had better survival outcomes compared to those who received other regimens: PFS, unadjusted-HR 0.38, 95%CI 0.15-0.93, P = 0.027; and CSS, unadjusted-HR 0.21, 95%CI 0.07-0.61, P = 0.002. CONCLUSION: Our study found that there is no statistically significant difference in survival between women with stage IV UCS who are tolerated neoadjuvant chemotherapy and those who undergo primary surgery.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinosarcoma/tratamiento farmacológico , Carcinosarcoma/mortalidad , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/mortalidad , Carboplatino/administración & dosificación , Carcinosarcoma/patología , Carcinosarcoma/cirugía , Estudios de Casos y Controles , Quimioterapia Adyuvante , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Estudios Retrospectivos , Neoplasias Uterinas/patología , Neoplasias Uterinas/cirugíaRESUMEN
OBJECTIVE: To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. METHODS: This is a multicenter retrospective study examining stage I-IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. RESULTS: Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P<0.001) and had a past history of malignancy (100% versus 12.7%, P<0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P=0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P=0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P=0.48) and disease-specific survival (64.0% versus 59.1%, P=0.39). After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P=0.60) and disease-specific survival (adjusted-hazard ratio 0.68, 95% confidence interval 0.36 to 1.29, P=0.24). CONCLUSION: Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma.
Asunto(s)
Carcinosarcoma/inducido químicamente , Antagonistas de Estrógenos/efectos adversos , Tamoxifeno/efectos adversos , Neoplasias Uterinas/inducido químicamente , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Carcinosarcoma/mortalidad , Carcinosarcoma/patología , Carcinosarcoma/terapia , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias Uterinas/mortalidad , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapiaRESUMEN
BACKGROUND: To examine recurrence patterns in women with stage I uterine carcinosarcoma (UCS) stratified by adjuvant therapy pattern. METHODS: We examined 443 cases of stage I UCS derived from a retrospective cohort of 1192 UCS cases from 26 institutions. Adjuvant therapy patterns after primary hysterectomy-based surgery were correlated to recurrence patterns. RESULTS: The most common adjuvant therapy was chemotherapy alone (41.5%) followed by chemotherapy/radiotherapy (15.8%) and radiotherapy alone (8.4%). Distant-recurrence was the most common recurrence pattern (5-year cumulative rate, 28.1%) followed by local-recurrence (13.3%). On multivariate analysis, chemotherapy but not radiotherapy remained an independent prognostic factor for decreased risk of local-recurrence (5-year cumulative rates 8.7% versus 19.8%, adjusted-hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25-0.83, P=0.01) and distant-recurrence (21.2% versus 38.0%, adjusted-HR 0.41, 95%CI 0.27-0.62, P<0.001). The chemotherapy/radiotherapy group had a lower 5-year cumulative local-recurrence rate compared to the chemotherapy alone group but it did not reach statistical significance (5.1% versus 10.1%, adjusted-HR 0.46, 95%CI 0.13-1.58, P=0.22). Radiotherapy significantly decreased local-recurrence when tumors had high-grade carcinoma, sarcoma component dominance, and deep myometrial tumor invasion (all, P<0.05); and combining radiotherapy with chemotherapy was significantly associated with decreased local-recurrence compared to chemotherapy alone in the presence of multiple risk factors (5-year cumulative rates, 2.5% versus 21.8%, HR 0.12, 95%CI 0.02-0.90; P=0.013) but not in none/single factor (P=0.36). CONCLUSION: Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Braquiterapia/métodos , Carcinosarcoma/terapia , Histerectomía , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Uterinas/terapia , Carcinosarcoma/patología , Quimioradioterapia Adyuvante/métodos , Quimioterapia Adyuvante/métodos , Estudios de Cohortes , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante/métodos , Estudios Retrospectivos , Neoplasias Uterinas/patologíaRESUMEN
OBJECTIVE: To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. METHODS: We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. RESULTS: There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P<0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P=0.02). When stratified by disease-free interval, women with a disease-free interval ≥6months who received a taxane/platinum doublet had a higher 2-year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P=0.002); conversely, in women with a disease-free interval <6months, 2-year SAR rates were similar between the two groups (20.5% versus 18.4%, HR 0.80, 95% CI 0.33 to 1.90, P=0.61). Among women who received a taxane/platinum doublet as adjuvant chemotherapy, re-treatment with taxane/platinum doublet as salvage chemotherapy remained beneficial (2-year SAR rate, 62.1% versus 39.7%, HR 0.40, 95% CI 0.18 to 0.86, P=0.019). CONCLUSION: Our study suggests that taxane/platinum doublet may be a more effective chemotherapy regimen compared to other regimens among women with recurrent uterine carcinosarcoma, especially for those who had a disease-free interval of ≥6months.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinosarcoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Uterinas/tratamiento farmacológico , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Carcinosarcoma/mortalidad , Estudios de Cohortes , Femenino , Humanos , Japón/epidemiología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Compuestos Organoplatinos/administración & dosificación , Estudios Retrospectivos , Terapia Recuperativa , Taxoides/administración & dosificación , Estados Unidos/epidemiología , Neoplasias Uterinas/mortalidadRESUMEN
Di- and trimethylation of lysine 27 on histone H3 (H3K27me2/3) is an important gene repression mechanism. H3K27me2/3-specific demethylase, Jmjd3, was expressed in the inner nuclear layer during late retinal development. In contrast, H3K27 methyltransferase, Ezh2, was highly expressed in the embryonic retina but its expression decreased rapidly after birth. Jmjd3 loss of function in the developing retina resulted in failed differentiation of PKC-positive bipolar cell subsets (rod-ON-BP) and reduced transcription factor Bhlhb4 expression, which is critical for the differentiation of rod-ON-BP cells. Overexpression of Bhlhb4, but not of other BP cell-related genes, such as transcription factors Neurod and Chx10, in Jmjd3-knockdown retina rescued loss of PKC-positive BP cells. Populations of other retinal cell subsets were not significantly affected. In addition, proliferation activity and apoptotic cell number during retinal development were not affected by the loss of Jmjd3. Levels of histone H3 trimethyl Lys27 (H3K27me3) in the Bhlhb4 locus were lower in Islet-1-positive BP cells and amacrine cells than in the Islet-1-negative cell fraction. The Islet-1-negative cell fraction consisted mainly of photoreceptors, suggestive of lineage-specific demethylation of H3K27me3 in the Bhlhb4 locus. We propose that lineage-specific H3K27me3 demethylation of critical gene loci by spatiotemporal-specific Jmjd3 expression is required for appropriate maturation of retinal cells.
Asunto(s)
Diferenciación Celular/genética , Regulación de la Expresión Génica/genética , Histonas/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Células Bipolares de la Retina/fisiología , Anticuerpos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Bromodesoxiuridina , Diferenciación Celular/fisiología , Inmunoprecipitación de Cromatina , Cartilla de ADN/genética , Electroporación , Citometría de Flujo , Humanos , Hibridación in Situ , Metilación , Reacción en Cadena en Tiempo Real de la Polimerasa , Células Bipolares de la Retina/citologíaRESUMEN
Sry-related HMG box (Sox) proteins, Sox11 and Sox4 are members of the SoxC subtype. We found that Sox11 was strongly expressed in early retinal progenitor cells and that Sox4 expression began around birth, when expression of Sox11 subsided. To analyze the roles of Sox11 and Sox4 in retinal development, we perturbed their expression patterns in retinal explant cultures. Overexpression of Sox11 and Sox4 in retinal progenitors resulted in similar phenotypes: an increased number of cone cells and dramatically decreased numbers of rod cells and Müller glia. Birth-date analysis showed that cone cells were produced at a later developmental stage than that in which cone genesis normally occurs. Sox11-knockout retinas showed delayed onset and progress of differentiation of subsets of retinal cells during the embryonic period. After birth, retinal differentiation took place relatively normally, probably because of the redundant activity of Sox4, which starts to be expressed around birth. Overexpression and loss-of-function analysis failed to provide any evidence that Sox11 and Sox4 directly regulate the transcription of genes crucial to the differentiation of subsets of retinal cells. However, histone H3 acetylation of some early proneural genes was reduced in knockout retina. Thus, Sox11 may create an epigenetic state that helps to establish the competency to differentiate. Taking our findings together, we propose that the sequential expression of Sox11 and Sox4 during retinogenesis leads to the fine adjustment of retinal differentiation by helping to establish the competency of retinal progenitors.