RESUMEN

OBJECTIVE: To analyze the impact of nutritional counseling on the development of hypothyroidism after (chemo)radiotherapy in head and neck cancer patients to propose a new normal tissue complication probability (NTCP) model. MATERIALS AND METHODS: At baseline, at the end of (chemo)radiotherapy, and during follow-up, thyroid-stimulating hormone (TSH) with free thyroxin (fT3 and fT4), nutritional status, and nutrient intake were prospectively analyzed in 46 out of 220 screened patients. Patients received (chemo)radiotherapy within an intervention (individual nutritional counseling every 2 weeks during therapy) and a control group (no nutritional counseling). RESULTS: Overall median follow-up was 16.5 [IQR: 12; 22] months. Fourteen patients (30.4%) presented with hypothyroidism after 13.5 [8.8; 17] months. During (chemo)radiotherapy, nutritional status worsened in the entire cohort: body mass index (p < 0.001) and fat-free mass index (p < 0.001) decreased, calorie deficit (p = 0.02) increased, and the baseline protein intake dropped (p = 0.028). The baseline selenium intake (p = 0.002) increased until the end of therapy. Application of the NTCP models by Rønjom, Cella, and Boomsma et al. resulted in good performance of all three models, with an AUC ranging from 0.76 to 0.78. Our newly developed NTCP model was based on baseline TSH and baseline ferritin. Model performance was good, receiving an AUC of 0.76 (95% CI: 0.61-0.87), with a sensitivity of 57.1% and specificity of 96.9% calculated for a Youden index of 0.73 (p = 0.004; area = 0.5). CONCLUSION: Baseline TSH and ferritin act as independent predictors for radiotherapy-associated hypothyroidism. The exclusion of such laboratory chemistry parameters in future NTCP models may result in poor model performance.

Asunto(s)

Neoplasias de Cabeza y Cuello , Hipotiroidismo , Consejo , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Hipotiroidismo/etiología , Hipotiroidismo/prevención & control , Estudios Prospectivos

RESUMEN

The oncogene epidermal growth factor receptor variant III (EGFRvIII) is frequently expressed in glioblastomas (GBM) but its impact on therapy response is still under controversial debate. Here we wanted to test if EGFRvIII influences the sensitivity towards the alkylating agent temozolomide (TMZ). Therefore, we retrospectively analyzed the survival of 336 GBM patients, demonstrating that under standard treatment, which includes TMZ, EGFRvIII expression is associated with prolonged survival, but only in patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated tumors. Using isogenic GBM cell lines with endogenous EGFRvIII expression we could demonstrate that EGFRvIII increases TMZ sensitivity and results in enhanced numbers of DNA double-strand breaks and a pronounced S/G2-phase arrest after TMZ treatment. We observed a higher expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cells and patient tumor samples, which was most pronounced for MSH2 and MSH6. EGFRvIII-specific knockdown reduced MMR protein expression thereby increasing TMZ resistance. Subsequent functional kinome profiling revealed an increased activation of p38- and ERK1/2-dependent signaling in EGFRvIII expressing cells, which regulates MMR protein expression downstream of EGFRvIII. In summary, our results demonstrate that the oncoprotein EGFRvIII sensitizes a fraction of GBM to current standard of care treatment through the upregulation of DNA MMR.

Asunto(s)

Neoplasias Encefálicas/terapia , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Resistencia a Antineoplásicos/genética , Glioblastoma/terapia , Temozolomida/farmacología , Proteínas Supresoras de Tumor/genética , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Línea Celular Tumoral , Quimioradioterapia/métodos , Estudios de Cohortes , Metilación de ADN , Reparación de la Incompatibilidad de ADN/efectos de los fármacos , Reparación de la Incompatibilidad de ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Glioblastoma/genética , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Sistema de Señalización de MAP Quinasas/genética , Ratones , Proteína 2 Homóloga a MutS/genética , Mutación , Regiones Promotoras Genéticas/genética , Estudios Retrospectivos , Temozolomida/uso terapéutico , Proteínas Supresoras de Tumor/metabolismo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto

Asunto(s)

Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Traumatismos por Radiación , Bevacizumab , Encéfalo , Humanos