RESUMEN
Gastrointestinal stromal tumors (GISTs) originating from the interstitial cells of Cajal are mesenchymal tumors of the gastrointestinal tract and have been found to harbor c-KIT mutations and KIT (CD117) expression since 1998. Later, PDGFRA mutations, SDH alterations, and other drive mutations were identified in GISTs. In addition, more and more protein markers such as DOG1, PKCθ were found to be expressed in GISTs which might help clinicians diagnose CD117-negative GISTs. Therefore, we plan to comprehensively review the molecular markers and genetics of GISTs and provide clinicians useful information in diagnostic and therapeutic strategies of GISTs. Twenty years after the discovery of KIT in GISTs, the diagnosis of GISTs became much more accurate by using immunohistochemical (IHC) panel (CD117/DOG1) and molecular analysis (KIT/PDGFRA), both of which constitute the gold standard of diagnosis in GISTs. The accurately molecular diagnosis of GISTs guides clinicians to precision medicine and provides optimal treatment for the patients with GISTs. Successful treatment in GISTs prolongs the survival of GIST patients and causes GISTs to become a chronic disease. In the future, the development of effective treatment for GISTs resistant to imatinib/sunitinib/regorafenib and KIT/PDGFRA-WT GISTs will be the challenge for GISTs.
RESUMEN
BACKGROUND: Gastrointestinal stromal tumors (GISTs) are caused by the constitutive activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Imatinib selectively inhibits KIT and PDGFR, leading to disease control for 80%-90% of patients with metastatic GIST. Imatinib resistance can occur within a median of 2-3 years due to secondary mutations in KIT. According to preclinical studies, both imatinib and sunitinib are ineffective against exon 17 mutations. However, the treatment efficacy of regorafenib for patients with GIST with exon 17 mutations is still unknown. PATIENTS AND METHODS: Documented patients with GIST with exon 17 mutations were enrolled in this study. Patients received 160 mg of oral regorafenib daily on days 1-21 of a 28-day cycle. The primary end point of this trial was the clinical benefit rate (CBR; i.e., complete or partial response [PR], as well as stable disease [SD]) at 16 weeks. The secondary end points of this study included progression free survival (PFS), overall survival, and safety. RESULTS: Between June 2014 to May 2016, 18 patients were enrolled (15 of which were eligible for response evaluation). The CBR at 16 weeks was 93.3% (14 of 15; 6 PR and 8 SD). The median PFS was 22.1 months. The most common grade 3 toxicities were hand-and-foot skin reactions (10 of 18; 55.6%), followed by hypertension (5 of 18; 27.8%). CONCLUSION: Regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17. A phase III trial of regorafenib versus placebo is warranted. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov in November 2015, number NCT02606097.Key message: This phase II trial was conducted to assess the efficacy and safety of regorafenib in patients with GIST with exon 17 mutations. The results provide strong evidence that regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17.
Asunto(s)
Antineoplásicos/uso terapéutico , Exones , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Mutación , Compuestos de Fenilurea/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Piridinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Femenino , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Retratamiento , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors originating in the gastrointestinal tract. With the introduction of molecular-targeted therapy for GISTs which has yielded remarkable outcomes, these tumors have become a model of multidisciplinary oncological treatment. Although Western clinical guidelines are available for GISTs, such as those published by the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO), the clinical situations in Asian countries are different from those in Western countries in terms of diagnostic methods, surgical approach, and availability of new targeted agents. Accordingly, we have reviewed current versions of several GIST guidelines published by Asian countries (Japan, Korea, China, and Taiwan) and the NCCN and ESMO and discussed the areas of dissensus. We here present the first version of the Asian GIST consensus guidelines that were prepared through a series of meetings involving multidisciplinary experts in the four countries. These guidelines provide an optimal approach to the diagnosis and management of GIST patients in Asian countries.
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Manejo de la Enfermedad , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/terapia , Terapia Molecular Dirigida , Pueblo Asiatico/genética , China , Consenso , Tumores del Estroma Gastrointestinal/patología , Guías como Asunto , Humanos , República de Corea , TaiwánRESUMEN
A 4-year-old boy presented with enteroviral infection complicated with atypical hemolytic uremic syndrome (aHUS). Enterovirus RNA was detected by reverse transcription polymerase chain reaction (RT-PCR) of both blood and kidney biopsy specimens. A survey of the complement system did not reveal a specific complement defect. Supportive therapy with blood components transfusion, plasma therapy, and immunosuppressants was administered, however, renal function did not recover. The results of this report demonstrate that the enterovirus is the cause of aHUS.
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Infecciones por Enterovirus/complicaciones , Síndrome Hemolítico-Urémico/etiología , Preescolar , Síndrome Hemolítico-Urémico/terapia , Humanos , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The effect of NRAS mutations on the pathological features and clinical outcomes in patients with cutaneous melanoma was compared with that of tumors containing BRAF(V600E) mutations and tumors wild type for both (WT). Clinical outcome data were obtained from a prospective cohort of 249 patients. Mutations involving NRAS and BRAF(V600E) were detected by PCR and were sequence verified. Cox proportional hazards regression was performed to relate NRAS and BRAF mutations to clinical outcome. Seventy-five percentage of NRAS mutations occurred in tumors >1 mm thick (BRAF(V600E) 40%, WT 34%); 75% of NRAS mutations had >1 mitosis/mm(2) (BRAF(V600E) 40%, WT 55%). When compared to WT, multivariate analysis of melanoma-specific survival (MSS) identified NRAS mutations as an adverse prognostic factor [hazard ratio (HR) 2.96; P = 0.04] but not BRAF(V600E) mutations (HR 1.73; P = 0.23). NRAS mutations were associated with thicker tumors and higher rates of mitosis when compared to BRAF(V600E) and WT melanoma and independently of this, with shorter MSS.
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Melanoma/genética , Melanoma/patología , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Proliferación Celular , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Melanoma/complicaciones , Melanoma/terapia , Persona de Mediana Edad , Mitosis , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/terapia , Quemadura Solar/complicaciones , Resultado del Tratamiento , Adulto JovenRESUMEN
Here we presented a 60-year-old Taiwanese man with advanced gastrointestinal stromal tumor. Disease progression was noted during imatinib treatment. Surgical resection was done and mutation analysis of KIT gene in all the resected tumors revealed deletion mutations of codons 558-565 in exon 11, whereas a missense mutation was also identified at codon 822 in exon 17 in one resected tumor. Patient's disease was refractory to escalating dose of imatinib and dasatinb. Surprisingly, combination of imatinib with pegylated liposomal doxorubicin produced a substantial response and resulted in a 5-month progression free period for this imatinib-resistant gastrointestinal stromal tumor.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Terapia Recuperativa , Benzamidas , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Resistencia a Antineoplásicos , Tumores del Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Polietilenglicoles/administración & dosificación , Proteínas Proto-Oncogénicas c-kit/genética , Pirimidinas/administración & dosificaciónRESUMEN
BACKGROUND: Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are uraemic toxins that have similar protein binding, dialytic clearance and proinflammatory features. However, only a few prospective studies have evaluated possible associations between these two retained solutes and renal disease progression in chronic kidney disease (CKD) patients. METHODS: This prospective observational study evaluated independent associations between serum total IS and PCS with renal progression in a selected cohort of patients having different stages of CKD. Baseline PCS and IS were correlated with renal progression [defined as decrements in estimated glomerular filtration rate (eGFR) > 50% from baseline or progression to end-stage renal disease (ESRD)] and death during a follow-up period of 24 months. RESULTS: Of 268 patients, 35 (13.1%) had renal progression and 14 (5.2%) died after a mean follow-up of 21 ± 3 months. Univariate Cox regression analysis followed by multivariate analysis showed that high-serum PCS levels were associated with renal progression and all-cause mortality independent of age, gender, diabetes status, albumin levels, serum IS, serum creatinine, Ca × P product, intact parathyroid hormone, haemoglobin or high-sensitivity C-reactive protein level. Serum IS was only associated with renal progression; however, the predictive power of serum IS was weakened when serum PCS was also present in the analytical model. CONCLUSIONS: In addition to traditional and uraemia-related risk factors such as renal function, serum IS and PCS levels may help in predicting the risk of renal progression in patients having different stages of CKD.
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Cresoles/sangre , Indicán/sangre , Fallo Renal Crónico/sangre , Ésteres del Ácido Sulfúrico/sangre , Uremia/sangre , Anciano , Biomarcadores/metabolismo , Estudios de Cohortes , Creatinina/sangre , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Pruebas de Función Renal , Masculino , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Epithelial neuroendocrine tumors (NETs) have been the subject of much debate regarding their optimal classification. Although multiple systems of nomenclature, grading, and staging have been proposed, none has achieved universal acceptance. To help define the underlying common features of these classification systems and to identify the minimal pathology data that should be reported to ensure consistent clinical management and reproducibility of data from therapeutic trials, a multidisciplinary team of physicians interested in NETs was assembled. At a group meeting, the participants discussed a series of "yes" or "no" questions related to the pathology of NETs and the minimal data to be included in the reports. After discussion, anonymous votes were taken, using the Delphic principle that 80% agreement on a vote of either yes or no would define a consensus. Questions that failed to achieve a consensus were rephrased once or twice and discussed, and additional votes were taken. Of 108 questions, 91 were answerable either yes or no by more than 80% of the participants. There was agreement about the importance of proliferation rate for tumor grading, the landmarks to use for staging, the prognostic factors assessable by routine histology that should be reported, the potential for tumors to progress biologically with metastasis, and the current status of advanced immunohistochemical and molecular testing for treatment-related biomarkers. The lack of utility of a variety of immunohistochemical stains and pathologic findings was also agreed upon. A consensus could not be reached for the remaining 17 questions, which included both minor points related to extent of disease assessment and some major areas such as terminology, routine immunohistochemical staining for general neuroendocrine markers, use of Ki67 staining to assess proliferation, and the relationship of tumor grade to degree of differentiation. On the basis of the results of the Delphic voting, a minimum pathology data set was developed. Although there remains disagreement among experts about the specific classification system that should be used, there is agreement about the fundamental pathology data that should be reported. Examination of the areas of disagreement reveals significant opportunities for collaborative study to resolve unanswered questions.
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Lista de Verificación/normas , Técnica Delphi , Estadificación de Neoplasias/normas , Tumores Neuroendocrinos/patología , Biomarcadores de Tumor/análisis , Diferenciación Celular , Proliferación Celular , Conferencias de Consenso como Asunto , Técnicas Genéticas/normas , Humanos , Inmunohistoquímica/normas , Tumores Neuroendocrinos/química , Tumores Neuroendocrinos/clasificación , Tumores Neuroendocrinos/secundario , Guías de Práctica Clínica como Asunto , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Terminología como AsuntoRESUMEN
BACKGROUND/PURPOSE: Human KIT protooncogene is the cellular homolog of v-kit from the Hardy-Zuckerman 4 feline sarcoma virus, and encodes a 145-kDa type III tyrosine kinase growth factor receptor that is often mutated in gastrointestinal stromal tumors (GIST). Standardized mutation analysis is not available in many countries; therefore, we aimed to determine if the presence of KIT mutation in GIST can be predicted by the immunoprofile of the tumor cells. METHODS: One hundred and forty-nine GIST were subjected to mutation analysis for KIT and immunohistochemical analysis for the expression of CD117, CD34, alpha-smooth muscle actin (SMA), and S100 protein. Mutation and immunohistochemistry data were correlated. RESULTS: KIT mutation rates were higher in certain immunoprofile subsets of GIST than in GIST in general. Compared with the overall mutation rate of KIT (70%), all GIST with CD117+ and S100+ had > 80% probability of harboring mutated KIT, and the subset with additional CD34+ and SMA- had a mutation rate of 88%. The overall KIT mutation rate in CD117- GIST was 31%. However, the probability of KIT mutation in CD117- GIST with CD34+SMA+S100-, CD34-SMA-S100+, and CD34+SMA-S100+ was 100%, 100%, and 67%, respectively. Compared with the overall mutation rate (8.7%) of exon 9, GISTs with CD34+SMA+ had > or = 20% probability of harboring an exon 9 mutation, and all GISTs in the small intestine had a probability of 19%. CONCLUSION: When mutation analysis is not available, immunoprofiles based on CD117, CD34, SMA, and S100 can be used to predict the presence of KIT mutation, but it is less useful for the prediction of exon 9 mutation in GISTs.
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Biomarcadores de Tumor/análisis , Tumores del Estroma Gastrointestinal/genética , Mutación/genética , Proteínas Proto-Oncogénicas c-kit/genética , Actinas/genética , Actinas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD34/análisis , Femenino , Predicción , Tumores del Estroma Gastrointestinal/metabolismo , Tumores del Estroma Gastrointestinal/patología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Proteínas S100/análisis , Análisis de Secuencia de ADNRESUMEN
We report an 18-gestational-week fetus with oligohydramnios, orofacial clefting, bilateral multicystic kidneys and the Dandy-Walker malformation. Characteristic craniofacial features include a turricephalic prominent forehead, hypertelorism, low-set ears, a flat nasal bridge, mid-face hypoplasia, bilateral cleft lip and palate, and a thick nuchal fold. Array-comparative genomic hybridization (CGH) analysis demonstrated a 12Mb deletion of 6p24.1-->pter.
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Deleción Cromosómica , Cromosomas Humanos Par 6 , Labio Leporino/genética , Fisura del Paladar/genética , Síndrome de Dandy-Walker/genética , Feto/anomalías , Riñón Displástico Multiquístico/genética , Hibridación Genómica Comparativa , Cara/anomalías , Femenino , Edad Gestacional , Humanos , Embarazo , Segundo Trimestre del Embarazo , Cráneo/anomalíasRESUMEN
This study was aimed to test whether PIK3CA, BRAF and RAS are mutated in nasopharyngeal carcinomas (NPCs) and, if so, to further determine whether such mutations affect patients' survival. For this purpose, a total of 73 NPCs were subjected to mutational analyses for PIK3CA (exons 4, 7, 9, and 20), BRAF (codon 600), and RAS (codons 12, 13 and 61). Clinicopathological characteristics were correlated to the mutation data. Survival rates were compared with the log-rank test. The result showed that the mutation rate of PIK3CA in NPC (n = 73) was 9.6%, whereas both BRAF (n = 65) and RAS (n = 45) were wild type in every specimen with adequate DNA for analysis. PIK3CA mutation was slightly influenced by sex (P = 0.0418, Fisher's exact test), but had no significant relationship to other clinicopathological characteristics. Disease-specific survival was not significantly affected by PIK3CA mutations (P = 0.8825, log-rank test), albeit it was slightly better in younger patients (< or = 35 vs. >35 years of age) (P = 0.0477). These findings show that mutated PI3K may be involved in the NPC tumorigenesis but does not affect patient's prognosis, suggesting that PI3K is a potential target in NPC for targeted therapeutics using specific kinase inhibitors.
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Neoplasias Nasofaríngeas/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Fosfatidilinositol 3-Quinasa Clase I , Análisis Mutacional de ADN , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/enzimologíaRESUMEN
Most gastrointestinal stromal tumors (GISTs) are associated with activating kinase mutation in KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene, and imatinib has revolutionized the care of advanced GISTs. However, most patients gradually developed resistance to imatinib. We intend to identify the secondary kinase mutations in imatinib-resistant GISTs and to study the relationship between secondary kinase mutations and the clinical response to imatinib. Twelve advanced GIST patients, who have developed resistance to imatinib were included in this study. Paraffin-embedded pretreatment GIST specimens and progression lesions of the tumors after resistance to imatinib were analyzed for kinase mutations in exons 9, 11, 13, and 17 of KIT gene and exons of 10, 12, 14, and 18 of PDGFRA gene. Primary KIT mutations have been found in all but one of the primary tumors including one case harboring de novo double KIT exon 11 mutations. Secondary kinase mutations in KIT and PDGFRA were found in seven and 1 of 12 patients, respectively. Two patients harbored more than one secondary KIT mutations in different progression sites, and there are four types of clonal or polyclonal evolution being observed. The secondary PDGFRA exon 14 mutation H687Y is a novel mutation that has never been reported before. Acquired secondary kinase mutations are the most important cause of secondary imatinib resistance in advanced GISTs. The identification of secondary kinase mutations is important in the development of new therapeutic strategies.
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Antineoplásicos/uso terapéutico , Tumores del Estroma Gastrointestinal/genética , Mutación , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Pirimidinas/uso terapéutico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Anciano , Anciano de 80 o más Años , Benzamidas , Resistencia a Antineoplásicos , Femenino , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/mortalidad , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana EdadAsunto(s)
Anomalías Múltiples/diagnóstico por imagen , Cromosomas Humanos Par 13 , Holoprosencefalia/diagnóstico por imagen , Nariz/anomalías , Trisomía , Aborto Terapéutico , Adulto , Femenino , Humanos , Nariz/diagnóstico por imagen , Embarazo , Segundo Trimestre del Embarazo , Ultrasonografía PrenatalRESUMEN
BACKGROUND: Prognostic factors that could select breast cancer patients with poor survival, and influence clinical trials of targeted therapy, are needed. However, the reported observations regarding the impact of PI3KCA mutation on breast cancers are controversial. METHODS: We analyzed exons 4, 7, 9, and 20 of PI3KCA on a series of 158 patients. Clinicopathological characteristics were correlated with the mutation data. RESULTS: Among 152 patients who were available for follow-up (median follow-up time, 6.57 years), 26% had PIK3CA mutations, more than half of which occurred in exon 20. The five-year survival rate of patients with exon 20 mutations (46%) was significantly lower than that of patients without (75%) (p = 0.0054). Multivariate analysis showed that PIK3CA exon 20 mutations and nodal involvement were independent risk factors for overall survival. The relative risk of death in patients with PIK3CA exon 20 mutations was 2.881 (95% CI, 1.406-5.900; p = 0.0038). CONCLUSIONS: PIK3CA mutations are common in invasive ductal carcinomas of the breast. Our result suggests that PIK3CA exon 20 mutation is an independent risk factor for poor prognosis in breast cancer patients, indicating that differences in patient numbers with PIK3CA exon 20 mutations in study and control arms should be avoided in clinical trials of PI3K inhibitors.
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Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Fosfatidilinositol 3-Quinasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/mortalidad , Fosfatidilinositol 3-Quinasa Clase I , Exones , Femenino , Humanos , Persona de Mediana Edad , Mutación , Pronóstico , Factores de Riesgo , Análisis de SupervivenciaAsunto(s)
Anomalías Múltiples/diagnóstico , Enfermedades en Gemelos/diagnóstico , Deformidades Congénitas de las Extremidades/diagnóstico , Defectos del Tubo Neural/diagnóstico , Adulto , Amniocentesis , Femenino , Edad Gestacional , Humanos , Cariotipificación , Deformidades Congénitas de las Extremidades/complicaciones , Masculino , Defectos del Tubo Neural/complicaciones , Embarazo , Síndrome , Ultrasonografía PrenatalRESUMEN
PURPOSE: To investigate the prognostic value of epidermal growth factor receptor (EGFR) mutations in a series of Taiwanese patients with primary resected lung adenocarcinomas never treated with epidermal growth factor receptor tyrosine kinase (TK) inhibitor. PATIENTS AND METHODS: A total of 27 of 35 patients whose EGFR mutational status in exons 18, 19, and 21 of the TK domain had been previously determined using nested polymerase chain reaction (PCR) were included in this retrospective study. All 27 patients underwent potentially curative pulmonary resection. Clinicopathological information was obtained from patient records and pathology reports. Disease-free survival (DFS) and overall survival (OS) of patients were estimated with the Kaplan-Meier method, and Cox regression model was used for multivariate analysis. RESULTS: Heterozygous EGFR mutations were detected in 15 of 27 patients (55.5%). There was no significant difference in DFS between patients with wild-type EGFR (median, 16.87 months) and mutant EGFR (median, 18.13 months; P = 0.83). No significant difference in OS was also noted between the wild-type and mutant groups (P = 0.45, median follow-up 22.6 months). Cox regression model and multivariate analysis of survival difference by age, stage, histology, and adjuvant treatment did not reach statistical significance. CONCLUSION: EGFR mutations do not have significant prognostic value in primary resected non-small cell lung cancer (NSCLC), and further well-designed large prospective studies are warranted to determine the prognostic value of EGFR mutations in NSCLC.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del TratamientoRESUMEN
The mechanism governing cell quiescence remains to be elucidated, albeit some tumor suppressor genes are known to be involved in this process. If more genes belonging to this regulatory circuit are identified, we will have a better understanding on cell quiescence. For this purpose, the present study was designed to clone genes preferentially expressed in cell quiescence. Using the method of differential display, we cloned ras-recision gene (rrg), also known as lysyl oxidase gene (lox), from BALB/c 3T3T cells, which were rendered quiescent by serum deprivation. Northern blot analysis showed that the induction of rrg/lox gene could be detected as early as 12 h following serum deprivation and it was dramatically elevated from 24 hours on after serum starvation. Induction of rrg/lox was also observed in cells rendered quiescent by contact inhibition, indicating that rrg/lox is induced by cell quiescence in general rather than specific to serum deprivation. Because rrg/lox gene products are known to be involved in extracellular matrix maturation, and function as tumor suppressors against ras oncogene, our finding suggests that quiescence-associated cell physiology is partly mediated by induction of rrg/lox.
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Senescencia Celular/fisiología , Proteínas de la Matriz Extracelular/fisiología , Regulación de la Expresión Génica/fisiología , Proteína-Lisina 6-Oxidasa/fisiología , Adipocitos/citología , Adipocitos/fisiología , Animales , Células 3T3 BALB , Diferenciación Celular/fisiología , Senescencia Celular/genética , Clonación Molecular , Matriz Extracelular/fisiología , Proteínas de la Matriz Extracelular/genética , Genes Supresores de Tumor/fisiología , Ratones , Ratones Endogámicos BALB C , Proteína-Lisina 6-Oxidasa/genéticaAsunto(s)
Anomalías Múltiples/diagnóstico , Deleción Cromosómica , Cromosomas Humanos Par 8 , Diagnóstico Prenatal , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/genética , Aborto Terapéutico , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Embarazo , Segundo Trimestre del Embarazo , UltrasonografíaRESUMEN
BACKGROUND: Anaplastic thyroid carcinoma (ATC), a rare and highly malignant tumor, has long been thought to arise from well-differentiated carcinoma (WDC) such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC). The purpose of this study was to test this notion by examining whether and, if so, how often ATC harbors the oncogenes that are commonly associated with WDC, such as RAS in FTC and BRAF in PTC. METHODS: We analyzed the mutation hotspots of BRAF (codon 600) and N-, K-, and H-RAS (codons 12, 13, and 61) in 16 ATCs. We also examined two genes, PIK3CA (exons 9 and 20) and TP53 (exons 5-9), both of which have been reported in ATCs. RESULTS: The results showed that approximately 31% (5 of 16) of ATCs harbored N-RAS mutation, 6% (1 of 16) had mutated BRAF, and approximately 56% (9 of 16) had mutated TP53. As to the three ATCs that had coexisted PTCs, mutated BRAF was detected in all PTC components but only in one ATC, while mutated PIK3CA was found in only one PTC component but not in the ATC. CONCLUSION: A number of ATCs arise from WDCs, more often from RAS-mutant tumors than from BRAF-mutant tumors, implying that particular attention should be paid to the WDC harboring RAS mutation.