The aim of this study was to develop a multivariate logistic regression model with least absolute shrinkage and selection operator (LASSO) to make valid predictions about the incidence of moderate-to-severe patient-rated xerostomia among head and neck cancer (HNC) patients treated with IMRT. Quality of life questionnaire datasets from 206 patients with HNC were analyzed. The European Organization for Research and Treatment of Cancer QLQ-H&N35 and QLQ-C30 questionnaires were used as the endpoint evaluation. The primary endpoint (grade 3⁺ xerostomia) was defined as moderate-to-severe xerostomia at 3 (XER_3m) and 12 months (XER_12m) after the completion of IMRT. Normal tissue complication probability (NTCP) models were developed. The optimal and suboptimal numbers of prognostic factors for a multivariate logistic regression model were determined using the LASSO with bootstrapping technique. Statistical analysis was performed using the scaled Brier score, Nagelkerke R², chi-squared test, Omnibus, Hosmer-Lemeshow test, and the AUC. Eight prognostic factors were selected by LASSO for the 3-month time point: Dmean-c, Dmean-i, age, financial status, T stage, AJCC stage, smoking, and education. Nine prognostic factors were selected for the 12-month time point: Dmean-i, education, Dmean-c, smoking, T stage, baseline xerostomia, alcohol abuse, family history, and node classification. In the selection of the suboptimal number of prognostic factors by LASSO, three suboptimal prognostic factors were fine-tuned by Hosmer-Lemeshow test and AUC, i.e., Dmean-c, Dmean-i, and age for the 3-month time point. Five suboptimal prognostic factors were also selected for the 12-month time point, i.e., Dmean-i, education, Dmean-c, smoking, and T stage. The overall performance for both time points of the NTCP model in terms of scaled Brier score, Omnibus, and Nagelkerke R² was satisfactory and corresponded well with the expected values. Multivariate NTCP models with LASSO can be used to predict patient-rated xerostomia after IMRT.

To investigate the impact of physician-assessed late toxicities on patient-reported quality of life (QoL) for nasopharyngeal carcinoma (NPC) patients with long-term survival. A cross-sectional survey of QoL and late toxicities was conducted in 242 NPC patients with disease-free survival of more than 5 years after treatment. The QoL was assessed by the European Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Late toxicities including neuropathy, hearing loss, dysphagia, xerostomia, and neck fibrosis were recorded based on the criteria of Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v.4.0). The general linear model multiple analysis of variance (GLM-MANOVA) was performed to predict factors associated with the QoL. In the multifactor model of GLM-MANOVA, of the five late toxicities of CTCAE scales, neuropathy, hearing loss, and xerostomia were observed to be significantly associated with the overall outcome of the fifteen QLQ-C30 scales. A statistically significant trend (p <0.05) was observed, indicating that NPC survivors with more severe neuropathy, hearing loss or xerostomia had a worse outcome on global QoL, all five functional scales, and a variety of symptomatic scales. To improve QoL outcome for NPC survivors, the development of a modern radiotherapeutic technique should not only focus on reduction of the dose to the salivary glands, but also on anatomical structures that are involved in neuropathy and hearing loss.

Background: Nasopharyngeal carcinoma (NPC) is well-known for its highly metastatic characteristics, but little is known of its molecular mechanisms. New biomarkers that predict clinical outcome, in particular the ability of the primary tumor to develop metastatic tumors are urgently needed. The aim of this study is to investigate the role of FLJ10540 in human NPC development. Methods: A bioinformatics approach was used to explore the potentially important regulatory genes involved in the growth/metastasis control of NPC. FLJ10540 was chosen for this study. Two co-expression strategies from NPC microarray were employed to identify the relationship between FLJ10540 and osteopontin. Quantitative-RT-PCR, immunoblotting, and immunohistochemistry analysis were used to investigate the mRNA and protein expression profiles of FLJ10540 and osteopontin in the normal and NPC tissues to confirm microarray results. TW01 and Hone1 NPC cells with overexpression FLJ10540 or siRNA to repress endogenous FLJ10540 were generated by stable transfection to further elucidate the molecular mechanisms of FLJ10540-elicited cell growth and metastasis under osteopontin stimulation. Results: We found that osteopontin expression exhibited a positive correlation with FLJ10540 in NPC microarray. We also demonstrated comprehensively that FLJ10540 and osteopontin were not only overexpressed in NPC specimens, but also significantly correlated with advanced tumor and lymph node-metastasis stages, and had a poor 5-year survival rate, respectively. Stimulation of NPC parental cells with osteopontin results in an increase in FLJ10540 mRNA and protein expressions. Functionally, FLJ10540 transfectant alone, or stimulated with osteopontin, exhibited fast growth and increased metastasis as compared to vehicle control with or without osteopontin stimulation. Conversely, knockdown of FLJ10540 by siRNA results in the suppression of NPC cell growth and motility. Treatment with anti-CD44 antibodies in NPC parental cells not only resulted in a decrease of FLJ10540 protein, but also affected the abilities of FLJ10540-elicited cell growth and motility in osteopontin stimulated-NPC cells. Conclusions: These findings suggest that FLJ10540 may be critical regulator of disease progression in NPC, and the underlying mechanism may involve in the osteopontin/CD44 pathway.

The lipid-metabolizing enzymes remain underexplored in gastrointestinal stromal tumors (GISTs). Through transcriptomic reappraisal, hydroxysteroid 11-beta dehydrogenase-1 (HSD11B1) was identified as a top-upregulated, progression-associated gene. To validate the clinical relevance of HSD11B1, the informative results of Sanger sequencing (n = 58), mRNA quantification by branched-chain DNA in situ hybridization assay (n = 70), copy number assay by fluorescent in situ hybridization (n = 350), and immunohistochemistry (n = 350) were correlated with clincopathological variables, KIT/PDGFRA/BRAF genotypes, and disease-free survival (DFS). HSD11B1 was stably silenced to explore its oncogenic function. HSD11B1 mRNA varied between high-risk and non-high-risk groups (p = 0.009) and positively correlated with HSD11B1 immunoexpression (r = 0.783, p < 0.001). HSD11B1 copy-number gain (CNG), including polysomy (5.4%) and amplification (12%), associated with HSD11B1 overexpression (p < 0.001). Predominantly involving the homodimer interface-affecting exon 6 or exon 7, missense HSD11B1 mutations (17.2%) were related to high risk (p = 0.044), age ≥70 years (p = 0.007), and shorter DFS among relapsed cases (p = 0.033). CNG was related to unfavorable KIT/PDGFRA/BRAF genotypes (p = 0.015), while HSD11B1 overexpression was preferential in non-gastric cases (p < 0.001). Both abnormalities strongly associated with risk levels (both p < 0.001) and shorter univariate DFS (both p < 0.0001), and HSD11B1 CNG remained prognostically independent (p < 0.001) with a 3-fold increased hazard ratio. In vitro, HSD11B1 knockdown significantly inhibited proliferation and caused G2/M arrest. In conclusion, HSD11B1 overexpression may occur owing to CNG, confer a pro-proliferative function, and predict a worse prognosis in GISTs.