RESUMEN
PURPOSE: Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS: In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. RESULTS: Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 µg h/mL, 2.52 µg h/mL, and 2.66 µg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION: Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.
Asunto(s)
Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Quinolinas , Adolescente , Adulto , Niño , Preescolar , Humanos , Lactante , Compuestos de Anilina/efectos adversos , Antineoplásicos/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Nitrilos/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Mutation analysis and cytogenetic testing in clear cell renal cell carcinoma (ccRCC) is not yet implemented in a routine diagnostics of ccRCC. MATERIAL AND METHODS: We characterized the chromosomal alterations in 83 ccRCC tumors from Polish patients using whole genome SNP genotyping assay. Moreover, the utility of next generation sequencing of cell free DNA (cfDNA) in patients plasma as a potential tool for non-invasive cytogenetic analysis was tested. Additionally, tumor specific somatic mutations in PBRM1, BAP1 and KDM5C were determined. RESULTS: We confirmed a correlation between deletions at 9p and higher tumor size, and deletion of chromosome 20 and the survival time. In Fuhrman grade 1, only aberrations of 3p and 8p deletion, gain of 5q and 13q and gains of chromosome 7 and 16 were present. The number of aberrations increased with Fuhrman grade, all chromosomes displayed cytogenetic changes in G3 and G4. ccRCC specific chromosome aberrations were observed in cfDNA, although discrepancies were found between cfDNA and tumor samples. In total 12 common and 94 rare variants were detected in PBRM1, BAP1 and KDM5C, with four potentially pathogenic variants. We observed markedly lower mutation load in PBRM1. CONCLUSIONS: Cytogenetic analysis of cfDNA may allow more accurate diagnosis of tumor aberrations and therefore the correlation between the chromosome aberrations in cfDNA and clinical outcome should be studied in larger cohorts. The functional studies on in BAP1, KDM5C, PBRM1 mutations in large, independent sample set would be necessary for the assessment of their prognostic and diagnostic potential.
Asunto(s)
Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Aberraciones Cromosómicas , ADN Tumoral Circulante , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Proteínas de Unión al ADN , Femenino , Histona Demetilasas/genética , Humanos , Biopsia Líquida , Masculino , Mutación , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Proteínas Nucleares/genética , Polonia/epidemiología , Polimorfismo de Nucleótido Simple , Pronóstico , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
Objetivo: confirmar la aplicabilidad clínica de la ley exponencial de ayuda diagnóstica específicamente en arritmias y evaluar la concordancia diagnóstica del mismo con respecto al Gold Estándar, por medio del cálculo de la sensibilidad, especificidad y el coeficiente Kappa. Metodología: se realizó un estudio de 40 Holter, 10 corresponden a sujetos normales y 30 diagnosticados con diferentes tipos de arritmias. Se realizó una simulación teórica de todas las frecuencias cardiacas de mínimo 21 horas a partir de los valores máximos y mínimos de frecuencias registrados, para construir el atractor de la dinámica cardiaca. Seguidamente se calculó la dimensión fractal del atractor y se cuantificó la ocupación espacial de cada uno ellos en el espacio generalizado de Box-counting. Finalmente, se aplicaron los parámetros matemáticos que diferencian dinámicas cardiacas normales de enfermas y agudas, así como en evolución hacia la enfermedad. Resultados: los casos con arritmias diagnosticados matemáticamente con dinámica aguda fueron seis, se encontraron 24 casos entre los rangos de 73 y 200 de ocupación de la rejilla Kp, que corresponden a casos de evolución hacia agudización de la dinámica. El diagnóstico físico-matemático, después de ser comparado con el Gold Estándar, presentó una sensibilidad y especificidad del 100% y un coeficiente Kappa de uno. Conclusiones: la aplicación de esta metodología al estudio de la dinámica cardiaca caótica, evidencia su utilidad como herramienta de ayuda diagnóstica para la predicción y prevención de eventos arrítmicos agudos que pueden implicar situaciones con riesgo vital.
Objective: To confirm the clinical applicability of the diagnostic methodology based on the power law of cardiac dynamic systems, specifically for detecting arrhythmias, evaluating its concordance with respect to the Gold Standard, by means of the sensitivity, specificity, and Kappa coefficient. Methods: Forty Holter were studied, of which 10 corresponded to normal subjects and 30 to patients diagnosed with different types of arrhythmias. A theoretical simulation of all cardiac frequencies (of at least 21 hours) was performed from the maximum and minimum frequency values registered, to build the cardiac dynamics attractor and its fractal dimension was calculated; the spatial occupation of each one of them was quantified in the generalized Box-Counting space. Finally, the mathematical parameters to differentiate normality of acute cardiac disease and of the evolution toward disease were applied. Results: There were six cases with mathematically-diagnosed acute arrhythmias, 24 cases were between 73 and 200 occupied ranges for the Kp grid that correspond to cases of evolution toward disease. This physical-mathematical diagnosis was compared with the Gold Standard and yielded a sensitivity and specificity of 100% and a Kappa coefficient of 1. Conclusions: The application of this method to the study of chaotic cardiac dynamics evidences its usefulness as a tool of diagnostic aid for the prediction of acute arrhythmic events which may imply situations of vital risk.
Objetivo: confirmar a aplicabilidade clínica da lei exponencial de ajuda diagnóstica especificamente em arritmias e avaliar a concordância diagnóstica do mesmo com respeito ao Gold Estándar, por meio do cálculo da sensibilidade, especificidade e o coeficiente Kappa. Metodologia: se realizou um estudo de 40 Holter, 10 correspondem a sujeitos normais e 30 diagnosticados com diferentes tipos de arritmias. Se realizou una simulação teórica de todas as frequências cardíacas de mínimo 21 horas a partir dos valores máximos e mínimos de frequências registrados, para construir o atractor da dinâmica cardíaca. Seguidamente se calculou a dimensão fractal do atractor e se quantificou a ocupação espacial de cada um deles no espaço generalizado de Box-counting. Finalmente, se aplicaram os parâmetros matemáticos que diferenciam dinâmicas cardíacas normais de doentes e agudas, assim como em evolução para a doença. Resultados: os casos com arritmias diagnosticados matematicamente com dinâmica aguda foram seis, se encontraram 24 casos entre as faixas de 73 e 200 de ocupação da grade Kp, que correspondem a casos de evolução para o agravamento da dinâmica. O diagnóstico físico-matemático, depois de ser comparado com o Gold Estándar, apresentou uma sensibilidade e especificidade de 100% e um coeficiente Kappa de um. Conclusões: a aplicação desta metodologia ao estudo da dinâmica cardíaca caótica, evidência sua utilidade como ferramenta de ajuda diagnóstica para a predição e prevenção de eventos arrítmicos agudos que possam implicar situações com risco vital.
Asunto(s)
Humanos , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares , Física , Arritmias Cardíacas , Electrocardiografía Ambulatoria , Diagnóstico , MatemáticaRESUMEN
The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.
Asunto(s)
Inestabilidad Cromosómica , Cromosomas Humanos Par 8/genética , Neoplasias del Colon/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Línea Celular Tumoral , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Metástasis de la Neoplasia/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína 1 Similar al Factor de Transcripción 7/genética , Proteína 1 Similar al Factor de Transcripción 7/metabolismo , Transcripción Genética , Vía de Señalización WntRESUMEN
BACKGROUND: Vitamin B6 is present in various forms (vitamers) in the diet that need to be metabolized to pyridoxal phosphate (PLP), the active cofactor form of vitamin B6. In literature, the liver has been reported to be the major site for this conversion, whereas the exact role of the intestine remains to be elucidated. OBJECTIVE: To gain insight into the role of the intestine in human vitamin B6 metabolism. MATERIALS AND METHODS: Expression of the enzymes pyridoxal kinase (PK), pyridox(am)ine phosphate oxidase (PNPO) and PLP-phosphatase was determined in Caco-2 cells and in lysates of human intestine. Vitamin B6 uptake, conversion and excretion were studied in polarized Caco-2 cell monolayers. B6 vitamer concentrations (pyridoxine (PN), pyridoxal (PL), PLP, pyridoxamine (PM), pyridoxamine phosphate (PMP)) and pyridoxic acid (PA) were quantified by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) using stable isotope-labeled internal standards. RESULTS: The enzymatic system involved in vitamin B6 metabolism (PK, PNPO and PLP-phosphatase) is fully expressed in Caco-2 cells as well as in human intestine. We show uptake of PN, PM and PL by Caco-2 cells, conversion of PN and PM into PL and excretion of all three unphosphorylated B6 vitamers. CONCLUSION: We demonstrate, in a Caco-2 cell model, that the intestine plays a substantial role in human vitamin B6 metabolism.
Asunto(s)
Mucosa Intestinal/metabolismo , Vitamina B 6/metabolismo , Western Blotting , Células CACO-2 , Células Hep G2 , Humanos , Técnicas In Vitro , Piridoxal/metabolismo , Piridoxal Quinasa/metabolismo , Piridoxamina/análogos & derivados , Piridoxamina/metabolismo , Ácido Piridóxico/metabolismo , Piridoxina/metabolismo , Espectrometría de Masas en TándemAsunto(s)
Síndrome de Down/complicaciones , Dosificación de Gen , Leucemia Mieloide/genética , Enfermedad Aguda , Preescolar , Aberraciones Cromosómicas , Femenino , Amplificación de Genes , Eliminación de Gen , Predisposición Genética a la Enfermedad , Humanos , Lactante , Cariotipificación , Leucemia Megacarioblástica Aguda/etiología , Leucemia Megacarioblástica Aguda/genética , Leucemia Mieloide/etiología , Masculino , ARN/genética , Telomerasa/genética , Telómero/ultraestructuraRESUMEN
Nuclear protein in testis midline carcinomas (NMC) are highly aggressive carcinomas typically arising in midline structures in young individuals. These carcinomas are characterized by the presence of a chromosomal rearrangement of nuclear protein in testis the (NUT) gene on chromosome 15 (15q14), resulting from a chromosomal translocation most commonly involving the BRD4 gene on chromosome 19p13. Rarely, in about 1/3 of cases, other translocation partners are involved (termed NUT-variants). Most cases have involved midline structures and with few exceptions were located in the upper aerodigestive tract and the mediastinum. Except for a single case, all reported NMC have been fatal, proving resistant to multimodality treatment. We report an exceptional case of a NMC presenting outside of midline structures in the parotid gland and showing mesenchymal chondroid differentiation in a 15-year-old male. The presence of the t(15;19) chromosomal translocation in the chondroid component was confirmed by fluorescence in situ hybridization analysis and immunohistochemical staining, indicating mesenchymal transdifferentation of the tumor. The findings demonstrate the first case of NMC arising within salivary gland, and the first example of mesenchymal differentiation in this group of tumors.
Asunto(s)
Carcinoma/genética , Carcinoma/patología , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Parótida/genética , Neoplasias de la Parótida/patología , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/terapia , Proteínas de Ciclo Celular , Diferenciación Celular , Terapia Combinada , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Mesodermo/patología , Proteínas de Neoplasias , Proteínas Oncogénicas/genética , Procedimientos Quirúrgicos Orales , Neoplasias de la Parótida/terapia , Radioterapia , Factores de Transcripción/genética , Translocación GenéticaRESUMEN
Cancer of the esophagus is the seventh leading cause of cancer death worldwide. Esophageal carcinoma cell lines are useful models to study the biological and genetic alterations in these tumors. An important prerequisite of cell line research is the authenticity of the used cell lines because the mistaken identity of a cell line may lead to invalid conclusions. Estimates indicate that up to 36% of the cell lines are of a different origin or species than supposed. The TE series, established in late 1970s and early 1980s by Nishihira et al. in Japan, is one of the first esophageal cancer cell line series that was used throughout the world. Fourteen TE cell lines were derived from human esophageal squamous cell carcinomas and one, TE-7, was derived from a primary esophageal adenocarcinoma. In numerous studies, this TE-7 cell line was used as a model for esophageal adenocarcinoma because it is one of the few esophageal adenocarcinoma cell lines existing. We investigated the authenticity of the esophageal adenocarcinoma cell line TE-7 by xenografting, short tandem repeat profiling, mutation analyses, and array-comparative genomic hybridization and showed that cell line TE-7 shared the same genotype as the esophageal squamous cell carcinoma cell lines TE-2, TE-3, TE-12, and TE-13. In addition, for more than a decade, independent TE-7 cultures from Japan, United States, United Kingdom, France, and the Netherlands had the same genotype. Examination of the TE-7 cell line xenograft revealed the histology of a squamous cell carcinoma. We conclude that the TE-7 cell line, used in several laboratories throughout the world, is not an adenocarcinoma, but a squamous cell carcinoma cell line. Furthermore, the cell lines TE-2, TE-3, TE-7, TE-12, and TE-13 should be regarded as one single squamous cell carcinoma cell line.