Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels ...of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to γ irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients.
Background
Biomarkers in head and neck squamous cell carcinoma (HNSCC) emerge rapidly in recent years, especially for new targeted therapies and immunotherapies.
Methods
Recent, relevant ...peer‐reviewed evidence were critically reviewed and summarized.
Results
This review article briefly introduces essential biomarker concepts, including purposes and classifications (predictive, prognostic, and diagnostic markers), and the phases of biomarker development. We summarize current biomarkers in order of clinical utility; p16 and human papillomavirus status remain the most important and validated biomarkers in HNSCC. The rationale for biomarker study design continues to evolve with technological advances, especially whole‐exome or whole‐genomic sequencing. Noninvasive body fluid and liquid biopsy biomarkers appear to hold strong potential for development as tools for early cancer detection, cancer diagnosis, monitoring of disease recurrence, and outcome prediction. In light of discrepancies among different technologies, standardized approaches are needed.
Conclusion
Biomarkers from cancer tissue or blood in HNSCC could direct new anticancer therapies.
Increasing evidence indicates that inflammation plays a crucial role in cancer development. A novel scoring system based on albumin and the neutrophil-to-lymphocyte ratio (NLR) was developed and ...incorporated into a nomogram to create a more accurate prognostic tool for oral cavity squamous cell carcinoma (OSCC) patients. A retrospective review was performed on 613 consecutive patients undergoing ablative surgery for OSCC between September 2005 and December 2014. NLR and albumin were determined and used to calculate an albumin/NLR score (ANS). The nomogram was based on the ANS and several clinicopathological manifestations, and its accuracy was determined by the concordance index (c-index). A high ANS was significantly associated with aggressive tumor behaviors, such as T status, overall stage, extranodal extension, perineural invasion, tumor depth, and decreased overall survival (OS). Multivariate analysis indicated that age, overall stage, extranodal extension, and ANS were independent factors for OS. The c-index for OS prognosis was 0.750 using this nomogram compared to 0.688 using TNM staging alone. The prognostic accuracy for OS in OSCC patients can be significantly improved using a nomogram that incorporates the novel ANS and other clinicopathological variables.
Objectives/Hypothesis
The role of tumor‐associated tissue eosinophilia (TATE) in oral cavity cancer remains quite controversial. This study investigated the potential role of TATE in tongue squamous ...cell carcinoma (TSCC).
Study Design
Retrospective case series.
Methods
This study retrospectively enrolled 259 consecutive TSCC patients who underwent surgery between July 2004 and December 2015. Histopathological examinations for TATE in TSCC tumors were reviewed, and the association of TATE with different clinicopathological factors was evaluated. A nomogram was generated based on several major clinicopathological factors and TATE to improve the accuracy of prognostic prediction.
Results
Higher levels of TATE were significantly associated with male sex, alcohol consumption, cigarette smoking, higher pT classification, advanced disease stage, and tumor depth (P = .006, .003, .024, .041, .013 and .006, respectively). Our results indicated that extranodal extension, cell differentiation, and TATE were independent predictors of overall survival (P < .001, .004, and .032, respectively) and disease‐free survival (P < .001, .012, and .013, respectively). TATE levels significantly correlated with circulating eosinophils (r = 0.139, P = .040), and the c‐index of our nomogram foroverall survival was 0.786, which demonstrates better accuracy in prognosis prediction than the TNM stage only (c‐index = 0.738).
Conclusions
Higher levels of TATE were associated with several clinicopathological factors and poorer survival rates, and a nomogram incorporating TATE levels may strengthen the prediction accuracy of prognosis in TSCC patients.
Level of Evidence
4 Laryngoscope, 129:1123–1129, 2019
Objectives
Lymph node burden has been proposed to estimate the cumulative adverse effect of nodal metastasis. In this study, a meta‐analysis was conducted to evaluate the prognostic value of lymph ...node burden in oral cavity squamous cell carcinoma.
Study Designs
Systemic review and meta‐analysis.
Methods
PubMed, EMBASE and the Cochrane Library as well as manual searches were performed until April 2020. The adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival, disease‐specific survival, and disease‐free survival were extracted and pooled.
Results
Eleven included studies were published between 2009 and 2019. The cumulative number of patients was 20,607 (range 35–14,554). Extranodal extension was adjusted or evaluated in all of the studies. The meta‐analysis indicated that a higher lymph node burden was significantly related to worse overall survival (HR 2.62, 95% CI 2.12–3.25), worse disease‐specific survival (HR 3.14, 95% CI 1.85–5.33) and worse disease‐free survival (HR 2.30, 95% CI 1.62–3.26). The highest hazard ratio was observed when the cutoff value was 3 for overall survival, 3 for disease‐specific survival, and 4 for disease‐free survival. The hazard ratio showed an upward trend before the cutoff value of 3 but no significant incremental change when the cutoff exceeded 3.
Conclusions
In oral squamous cell carcinoma, lymph node burden is an independent prognosticator for survival outcomes. However, more prospective or high‐quality studies are required to determine the optimal cutoff.
Level of Evidence
NA Laryngoscope, 132:88–95, 2022
Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer and the fourth leading malignancy among males in Taiwan. Some pathogenic bacteria are associated with periodontitis and oral cancer. ...However, the comprehensive profile of the oral microbiome during the cancer's progression from the early stage to the late stage is still unclear. We profiled the oral microbiota and identified bacteria biomarkers associated with OSCC. The microbiota of an oral rinse from 51 healthy individuals and 197 OSCC patients at different stages were investigated using 16S rRNA V3V4 amplicon sequencing, followed by bioinformatics and statistical analyses. The oral microbiota communities from stage 4 patients showed significantly higher complexity than those from healthy controls. The populations also dynamically changed with the cancer's progression from stage 1 to stage 4. The predominant phyla in the oral samples showed variation in the relative abundance of
, and
. The abundance of
increased significantly with the progression of oral cancer from the healthy controls (2.98%) to OSCC stage 1 (4.35%) through stage 4 (7.92%). At the genus level, the abundance of
increased, while the number of
, and
decreased with cancer progression.
, and
were associated with OSCC, and they progressively increased in abundance from stage 1 to stage 4. The abundances of
, and
were inversely associated with OSCC progression. We selected a bacterial marker panel of three bacteria (upregulated
, down-regulated
, and
), which had an AUC of 0.956 (95% CI = 0.925-0.986) in discriminating OSCC stage 4 from the healthy controls. Furthermore, the functional prediction of oral bacterial communities showed that genes involved in carbohydrate-related metabolism, such as methane metabolism, and energy-metabolism-related parameters, such as oxidative phosphorylation and carbon fixation in photosynthetic organisms, were enriched in late-stage OSCC, while those responsible for amino acid metabolism, such as folate biosynthesis and valine, leucine, and isoleucine biosynthesis, were significantly associated with the healthy controls. In conclusion, our results provided evidence of oral bacteria community changes during oral cancer progression and suggested the possibility of using bacteria as OSCC diagnostic markers.
Globally, oral cavity squamous cell carcinoma (OSCC) is one of the most common fatal illnesses. Its high mortality is ascribed to the fact that the disease is often diagnosed at a late stage, which ...indicates an urgent need for approaches for the early detection of OSCC. The use of salivary autoantibodies (autoAbs) as OSCC biomarkers has numerous advantages such as easy access to saliva samples and efficient detection of autoAbs using well‐established secondary reagents. To improve OSCC screening, we identified OSCC‐associated autoAbs with the enrichment of salivary autoAbs combined with affinity mass spectrometry (MS). The salivary IgA of healthy individuals and OSCC patients was purified with peptide M‐conjugated beads and then applied to immunoprecipitated antigens (Ags) in OSCC cells. Using tandem MS analysis and spectral counting‐based quantitation, the level of 10 Ags increased in the OSCC group compared with the control group. Moreover, salivary levels of autoAbs to the 10 Ags were determined by a multiplexed bead‐based immunoassay. Among them, seven were significantly higher in early‐stage OSCC patients than in healthy individuals. A marker panel consisting of autoAbs to LMAN2, PTGR1, RAB13, and UQCRC2 was further developed to improve the early diagnosis of OSCC.
Virus-encoded microRNAs (miRNAs) have been shown to regulate a variety of biological processes involved in viral infection and viral-associated pathogenesis. Epstein-Barr virus (EBV) is a herpesvirus ...implicated in nasopharyngeal carcinoma (NPC) and other human malignancies. EBV-encoded miRNAs were among the first group of viral miRNAs identified. To understand the roles of EBV miRNAs in the pathogenesis of NPC, we utilized deep sequencing technology to characterize the EBV miRNA transcriptome in clinical NPC tissues. We obtained more than 110,000 sequence reads in NPC samples and identified 44 EBV BART miRNAs, including four new mature miRNAs derived from previously identified BART miRNA precursor hairpins. Further analysis revealed extensive sequence variations (isomiRs) of EBV miRNAs, including terminal isomiRs at both the 5' and 3' ends and nucleotide variants. Analysis of EBV genomic sequences indicated that the majority of EBV miRNA nucleotide variants resulted from post-transcriptional modifications. Read counts of individual EBV miRNA in NPC tissue spanned from a few reads to approximately 18,000 reads, confirming the wide expression range of EBV miRNAs. Several EBV miRNAs were expressed at levels similar to highly abundant human miRNAs. Sequence analysis revealed that most of the highly abundant EBV miRNAs share their seed sequences (nucleotides 2-7) with human miRNAs, suggesting that seed sequence content may be an important factor underlying the differential accumulation of BART miRNAs. Interestingly, many of these human miRNAs have been found to be dysregulated in human malignancies, including NPC. These observations not only provide a potential linkage between EBV miRNAs and human malignancy but also suggest a highly coordinated mechanism through which EBV miRNAs may mimic or compete with human miRNAs to affect cellular functions.
Most cases of oral squamous cell carcinoma (OSCC) develop from visible oral potentially malignant disorders (OPMDs). The latter exhibit heterogeneous subtypes with different transformation ...potentials, complicating the early detection of OSCC during routine visual oral cancer screenings. To develop clinically applicable biomarkers, we collected saliva samples from 96 healthy controls, 103 low-risk OPMDs, 130 high-risk OPMDs, and 131 OSCC subjects. These individuals were enrolled in Taiwan’s Oral Cancer Screening Program. We identified 302 protein biomarkers reported in the literature and/or through in-house studies and prioritized 49 proteins for quantification in the saliva samples using multiple reaction monitoring-MS. Twenty-eight proteins were successfully quantified with high confidence. The quantification data from non-OSCC subjects (healthy controls + low-risk OPMDs) and OSCC subjects in the training set were subjected to classification and regression tree analyses, through which we generated a four-protein panel consisting of MMP1, KNG1, ANXA2, and HSPA5. A risk-score scheme was established, and the panel showed high sensitivity (87.5%) and specificity (80.5%) in the test set to distinguish OSCC samples from non-OSCC samples. The risk score >0.4 detected 84% (42/50) of the stage I OSCCs and a significant portion (42%) of the high-risk OPMDs. Moreover, among 88 high-risk OPMD patients with available follow-up results, 18 developed OSCC within 5 y; of them, 77.8% (14/18) had risk scores >0.4. Our four-protein panel may therefore offer a clinically effective tool for detecting OSCC and monitoring high-risk OPMDs through a readily available biofluid.
Objective
There is no useful tool to clinically predict the occurrence of osteoradionecrosis (ORN) of the mandible quantitatively. The aim was to investigate the risk factors, including different ...modalities of radiotherapy, for developing mandibular ORN in patients undergoing marginal mandibulectomy and postoperative radiotherapy.
Methods
Between January 2006 and December 2012, 167 subjects who underwent marginal mandibulectomy and postoperative radiotherapy with different modalities were enrolled. The association of ORN with mandibular bone measurements and patient variables was analyzed, and a nomogram was established.
Results
Fifteen (8.98%) of the 167 patients developed ORN during the follow‐up period, and ORN was significantly associated with diabetes mellitus (DM), body mass index (BMI), remaining bone height, remaining bone height to original bone height ratio, resected bone height to original bone height ratio, and mandibular dose (P: < 0.001, 0.004, 0.042, 0.018, 0.010, 0.020, respectively). Interestingly, the risk of ORN had no significant difference between conformal and intensity modulation radiation therapy (P = 0.407). Multivariate analysis revealed that DM and resected bone height to original bone height ratio ≥ 50% were independent risk factors for postoperative ORN. A nomogram consisting of BMI, DM, resected bone height to original bone height ratio, mandibulotomy, and mandibular dose for predicting the ORN‐free probability was established; and the c‐index of the nomogram for ORN status was 0.803.
Conclusion
A nomogram based on the risk factors was plotted to strengthen the prediction of ORN quantitatively. Surgeons should be more discrete regarding the treatment plan for patients with higher probability of ORN.
Level of Evidence
3b Laryngoscope, 130:101–107, 2020
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