Risk stratification for radioactive iodine refractoriness using molecular alterations in distant metastatic differentiated thyroid cancer

Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.

Clinical applications of free medial tibial flap with posterior tibial artery for head and neck reconstruction after tumor resection

Tumor resection causes damage in the head and neck which creates problems in swallowing, chewing, articulation, and vision, all of which seriously affect patients' quality of life. In this work, we evaluated the application of a free medial tibial flap in reconstruction of head and neck defects after tumor resection. We discussed the anatomy, surgical technique, and the advantages and disadvantages of the flap. We found several benefits for the flap, such as, it is especially effective for the defects that require thin-layer epithelium to cover or the separated soft tissue defect; a two-team approach can be used because the donor site is far away from the head and neck; and the flap is easy to integrate because of the subcutaneous fat layer of the free medial tibial flap is thin and the flap is soft. Thus, the medial tibial flap could replace the forearm flap for certain applications.

Microarray gene expression analysis of chemosensitivity for docetaxel,cisplatin and 5-fluorouracil(TPF)combined chemotherapeutic regimen in hypopharyngeal squamous cell carcinoma

Objective: To screen out a set of candidate genes which could help to determine whether patients with hypopharyngeal squamous cell carcinoma (HSCC) could benefit from docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy. Methods: Gene-expression profiles in 12 TPF-sensitive patients were compared to 9 resistant controls by microarray analysis. Subsequently, expression levels of potential biomarkers in chemosensitive cell line FaDu after TPF treatment were observed by quantitative real-time polymerase chain reaction (qRT-PCR). Results: Through microarray analysis, 1,579 differentially expressed genes were identified, of which 815 were up-regulated in TPF chemotherapy-responsive tissues whereas 764 were down-regulated. Gene ontology (GO) analysis suggested these genes participating in physiological processes including transcription and its regulation, cellular signal transduction and metabolic process. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed that MAPK and Jat/STAT signaling pathways occupied important roles in TPF chemotherapeutic sensitivity. Moreover, in vitro cell culture experiments revealed the expression alternations of IL-6, MAPK14, JUN, CDK5 and CAMK2A exposed to TPF treatment by qRT-PCR, whilst providing an insight into the mechanism underlying TPF chemotherapeutic response in HSCC. Conclusions: These results provided a battery of genes related to TPF chemotherapeutic sensitivity and might act as molecular targets in HSCC treatment. Moreover, these candidate biomarkers could contribute to HSCC individualized treatment.

Factors contributing to lymph node occult metastasis in supraglottic laryngeal carcinoma cT2-T4 N0M0 and metastasis predictive equation

Objective： To investigate factors that contribute to lymph node metastasis（LNM） from clinical cT2-T4 N0M0（cN0） supraglottic laryngeal carcinoma（SLC）, and to predict the risk of occult metastasis before surgery.Methods： A total of 121 patients who received surgery were retrospectively analyzed. Relevant factors regarding cervical LNM were analyzed. Multivariate analyses were conducted to predict the region where the metastasis occurred and prognosis. Results： The overall metastatic rate of c N0 SLC was 28.1%. Metastatic rates were 15.4%, 32.5% and 35.7% for T2, T3 and T4, respectively. Metastatic rates for SLC levels II, III and IV were 19.6%, 17.2% and 3.6%, respectively. A regression equation was formulated to predict the probability of metastasis in cN0 SLC as follows： Pn=e（–3.874＋0.749T3＋1.154T4＋1.935P1＋1.750P2）/[1＋e（–3.874＋0.749T3＋1.154T4＋1.935P1＋1.750P2）]. Approximately 0.2% of patients experienced LNM with no recurrence of laryngeal cancer. Comparison of the intergroup survival curves between patients with and without LNM indicated a statistically significant difference（P=0.029）.Conclusions： Cervical lymph node metastatic rates tended to increase in tandem with T stage in patients with LNM in cN0 SLC, and neck dissection is advised for these patients. Moreover, cervical LNM in cN0 SLC showed a sequential pattern and may be predicted.

Construction of a novel six-gene signature to predict tumour response to induction chemotherapy and overall survival in locoregionally advanced laryngeal and hypopharyngeal carcinoma

Locoregionally advanced laryngeal and hypopharyngeal cancers(LA-LHCs)are traditionally treated with surgery followed by postoperative radiotherapy,which impairs speech and swallowing functions and reduces the quality of life.^(1,2)The use of induction chemotherapy(IC)as a larynxpreserving approach for LA-LHCs has been verified and refined.^(3)However,the short-term tumor response to IC varies,non-responders usually show poor survival and little benefit.

Screening of molecular markers of induced chemotherapy in supraglottic laryngeal squamouscell carcinoma

Objective:To investigate the expressions of MAPK10,c-Jun and Itga6 in laryngeal carcinoma and its influence on the sensitivity to docetaxel,cisplatin and 5-fluorouracil(TPF)chemotherapy.Methods:Fifty-seven patients with supraglottic squamous cell carcinoma,who were treated by two cycles of TPF induction chemotherapy in our hospital,were enrolled in this study and divided into groups by chemotherapy resistance or chemotherapy sensitivity.The expressions of mRNA and protein of MAPK10,c-Jun and Itga6 in tumor tissues were evaluated by immunohistochemistry.The consistency of mRNA and protein expressions was tested,and the relation with the clinicopathological features was analyzed.Results:The positive rates of MAPK10 andc-Jun in the tumor tissues of the sensitive group were significantly higher than those of there assistant group,which was 90.48%and 100.00%,respectively.The expression rate of Itga6 was significantly higher in the resistant group,which was 83.33%(P<0.05).The mRNA levels of MAPK10 and c-Jun were significantly lower in the resistant group than in the sensitive group,whilethemRNA levelof Itga6was significantly higher in the resistant group(P<0.05).The protein expressions of MAPK10,c-Jun and Itga6 were consistent with their mRNA expressions(P<0.05).The expressions of MAPK10,c-Jun and Itga6 were not correlatedwithage,gender and tumor diameter(P>0.05).However,the expressions of MAPK10 and c-Jun were negatively correlated withclinical stage and pathological grading(P<0.05).Negative correlations between MAPK 10 and Itga6,and between c-Jun and Itga6in tumor tissues were found by Spearman’srank correlation coefficient(P<0.05).The correlation was also negative in the resistant tumor tissues(P<0.05).Conclusion:The MAPK10 and c-Jun expressions were down-regulated,while the Itga6 expression was up-regulated in the chemo-resistant laryngeal carcinoma,and the expression levels of different factors were correlated witheach other.These factorsmight be important biomarkers for predicting outcomes of TPF chemotherapy in laryngeal carcinoma in the future.