Background: The aim of this study was to evaluate the impact of adverse lifestyle factors on outcomes in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). Methods: From 2010 to 2019, 150 consecutive non-metastatic OPSCC patients receiving curative treatment in our institution were retrospectively enrolled. HPV positivity was defined as p16 expression ≥75%. The effects of adverse lifestyle factors on overall survival (OS) and disease-free survival (DFS) on OPSCC patients were determined. Results: The median follow-up duration was 3.6 years. Of the 150 OPSCCs, 51 (34%) patients were HPV-positive and 99 (66%) were HPV-negative. The adverse lifestyle exposure rates were 74.7% (n = 112) alcohol use, 57.3% (n = 86) betel grid chewing, and 78% (n = 117) cigarette smoking. Alcohol use strongly interacted with HPV positivity (HR, 6.00; 95% CI, 1.03–35.01), leading to an average 26.1% increased risk of disease relapse in patients with HPV-positive OPSCC. Heavy smoking age ≥30 pack-years was associated with increased risk of death (HR, 2.05; 95% CI, 1.05–4.00) and disease relapse (HR, 1.99; 95% CI, 1.06–3.75) in OPSCC patients. In stratified analyses, the 3-year absolute risk of disease relapse in HPV-positive OPSCC patients reached up to 50% when alcohol use and heavy smoking for ≥30 pack-years were combined. Conclusions: Alcohol acted as a significant treatment-effect modifier for DFS in HPV-positive OPSCC patients, diluting the favorable prognostic effect of HPV positivity. Heavy smoking age ≥30 pack-years was an independent adverse prognostic factor of OS and DFS in OPSCC patients. De-intensification treatment for HPV-related OPSCC may be avoided when these adverse lifestyle factors are present.

Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that can regulate immune responses in the tumor microenvironment (TME); however, the clinical applications of PD-L1 in early-stage colorectal cancer (CRC) remain unclear. In this study, we aimed to investigate the relationship between PD-L1 expression and survival outcome and explore its relevant immune responses in CRC. PD-L1 expression was evaluated by immunohistochemical staining to determine the tumor proportion score and combined positive score (CPS) in a Taiwanese CRC cohort. The oncomine immune response research assay was conducted for immune gene expression analyses. CRC datasets from the TCGA database were reappraised for PD-L1-associated gene enrichment analyses using GSEA. The high expression of PD-L1 (CPS ≥ 5) was associated with longer recurrence-free survival (p = 0.031) and was an independent prognostic factor as revealed by multivariate analysis. High PD-L1 expression was related to six immune-related gene signatures, and CXCL9 is the most significant overexpressed gene in differential analyses. High CXCL9 expression correlated with increased infiltration levels of immune cells in the TME, including CD8+ T lymphocytes and M1 macrophages. These findings suggest that high PD-L1 expression is a prognostic factor of early-stage CRC, and CXCL9 may play a key role in regulating PD-L1 expression.

Intratumoral heterogeneity in epidermal growth factor receptor (EGFR)-mutant mutant non-small-cell lung cancer (NSCLC) explains the mixed responses to EGFR-tyrosine kinase inhibitors (TKIs). However, some studies showed tumors with low abundances of EGFR mutation still respond to EGFR-TKI, and the mechanism remained undetermined. Extracellular vesicles (EVs) can transmit antiapoptotic signals between drug-resistant and drug-sensitive cells. Herein, we profiled EVs from EGFR-mutant cells to identify a novel mechanism explaining why heterogenous EGFR-mutant NSCLC patients still respond to EGFR-TKIs. We first demonstrated that the EVs from EGFR-mutant changes the wild-type cells’ sensitivity to gefitinib by adding EV directly or coculturing EGFR wild-type (CL1-5) cells and EGFR-mutant (PC9) cells. In animal studies, only the combined treatment of PC9 EV and gefitinib delayed the tumor growth of CL1-5 cells. MicroRNA analysis comparing EV miRNAs from PC9 cells to those from CL1-5 cells showed that mir200 family members are most abundant in PC9 EVs. Furthermore, mir200a and mir200c were found upregulated in plasma EVs from good responders to EGFR-TKIs. Finally, the transfection of CL1-5 cells with miR200c inactivates downstream signaling pathways of EGFR, the EMT pathway, and enhances gefitinib sensitivity. Overall, our results suggest that in heterogeneous EGFR-mutant NSCLC, tumor cells transmit EV miRNAs that may affect sensitivity to EGFR-TKIs and provide potential prognostic biomarkers for EGFR-mutant NSCLC.

We investigated the risk of thyroid disorders, namely hypothyroidism, thyrotoxicosis and thyroiditis, in head and neck cancer patients undergoing multimodal treatment. A cohort study design using Taiwan’s National Health Insurance Research Database was used to assess head and neck cancer patients over 20 years old. The cohort was divided into one group who underwent primary tumor excision only (PTE) and another with additional neck dissection (PTE + ND). The tumor sites were stratified to estimate the tumor-site-specific risk of thyroid disorders. The effect of subsequent resurgery, radiotherapy (RT), chemotherapy (CT), and concomitant (CCRT) or sequential chemoradiation therapy (sequential CT+ RT) on the risk of thyroid disorders was explored. For 1999–2012, 7460 patients who underwent PTE + ND and 3730 who underwent PTE were enrolled and followed-up until the end of 2013. There were 122 and 50 patients in the two groups, respectively, who developed thyroid disorders, with no statistical difference between the groups. Patients with hypopharyngeal, oropharyngeal, or laryngeal cancer in the PTE + ND group had a higher risk of thyroid disorders (adjusted HR: 1.50, 95% CI: 0.67–3.38) than those in the PTE group when adjusted for covariates and mortality. Patients who underwent subsequent RT (adjusted HR: 3.64, 95% CI: 1.05–2.77) and CCRT (adjusted HR: 1.70, 95% CI: 1.05–2.77) after PTE + ND had a significantly higher risk of thyroid disorders. RT results in a major risk of subsequent thyroid disorders, and ND may exacerbate this effect. Physicians should monitor thyroid function from two years after treatment initiation, especially in patients who undergo ND and subsequent RT.

Background: To cure advanced hypopharyngeal squamous cell carcinoma (HPSCC), primary operation followed by adjuvant (chemo-)radiotherapy (OP-CRT) or definitive chemoradiation (CCRT) are the two primary options. This study aimed to compare the failure patterns and long-term survival outcomes of HPSCC patients treated with these two strategies. Patients and Methods: From 2007 to 2015, 198 pathologically confirmed HPSCC patients receiving either OP-CRT or CCRT were retrospectively reviewed. Failure patterns and survival outcomes stratified by the 7th American Joint Committee on Cancer staging system and treatment modalities were compared. Results: One hundred and eighty-nine patients (95.4%) were stage III/IV and 62 patients (31.3%) received OP-CRT. Median follow-up duration was 4.9 years. Compared with CCRT, OP-CRT provided better 3-year local relapse-free survival for T3 (93 vs 48%, p < 0.0001), T4a (88 vs 37%, p = 0.0005) and better 3-year regional relapse-free survival for N2b+2c (93 vs 60%, p < 0.0001). Of note, for stage IVA subjects, OP-CRT provided better 3-year loco-regional relapse-free survival (85 vs 37%, p < 0.0001), marginal poor 3-year distant metastasis-free survival (62 vs 79%, p = 0.06), but comparable 3-year OS (52 vs 44%, p = 0.37) and 5-year OS (44 vs 31%, p = 0.15) compared with CCRT. Conclusions: For patients with advanced HPSCC, although OP-CRT and CCRT provided similar overall survival, failure patterns were distinct. OP-CRT provided better loco-regional control but was more likely to encounter distant metastases than CCRT. The detailed analysis of failure patterns will pave the way to improve this devastating disease.

Background: Morphological evaluation of oral mucosal biopsy is sometimes inconclusive, which may delay the diagnosis and treatment of oral squamous malignancy. Immunohistochemical biomarkers denoting oral squamous malignancy would be clinically helpful in such scenario. Methods: We first studied the expression patterns of four potential biomarkers (cytokeratin 13, cytokeratin 17, Ki-67 and laminin 5 gamma 2 chain) in an exploratory cohort containing 54 surgical specimens from confirmed oral squamous malignancies. A pattern score was assigned to each specific expression pattern of these four biomarkers. A total score from each specimen was then calculated by summing up the four pattern scores. A cut-off value of total score denoting oral squamous malignancy was then determined. Another 34 oral squamous malignancies that were misdiagnosed as non-malignant lesions on their pre-treatment biopsies were used as a validation cohort to test the clinical utility of this scoring system. Results: In the exploratory cohort, fifty-two (96%) of the 54 confirmed oral squamous malignancies had a total score of 9 and above. In the validation cohort, thirty-one (91%) of the 34 pre-treatment oral biopsy specimens also had a total score of 9 or above, supporting the feasibility of using this scoring system to predict immediate risk of oral squamous malignancy. Conclusions: Our four-biomarker “oral squamous malignancy scoring system” provides reliable prediction for immediate risk of oral squamous malignancy on pre-treatment oral biopsies.