Oral Cavity Squamous Cell Carcinoma Patients Research Articles

The Copenhagen Oral Cavity Squamous Cell Carcinoma database: protocol and report on establishing a comprehensive oral cavity cancer database.

ObjectiveThe aim was to establish a large comprehensive database of patients with oral cavity squamous cell carcinoma (OSCC) to enable surveillance and research of the disease.MethodsAll patients diagnosed and/or treated for OSCC at Rigshospitalet, University of Copenhagen, Denmark in the period 2000–2014 were included. Rigshospitalet is a tertiary treatment center and covers the Eastern Denmark region, comprising nearly half of the approximately 5.8 million inhabitants of Denmark. Data on numerous variables regarding general information of the patients at diagnosis, their primary cancer, recurrence, treatment, prior cancers, and secondary cancers were collected from the Danish Pathology Register and by evaluation of medical charts.ResultsOne thousand three hundred and ninety-nine OSCC patients were included in the database (62% males). The median age at diagnosis was 63 years (range: 23–99 years). The most common anatomical location was the floor of mouth (38%). Among patients with known stage, 70.0% were diagnosed in T-stage 1 or 2 and 64.9% were diagnosed in N-stage 0. Most patients were treated with primary surgery (81.7% among patients with known treatment), of these 44% received adjuvant radiotherapy after surgery. The overall age-standardized incidence of OSCC per 100,000 increased from 2.15 in 2000 to 3.04 in 2014, with a significant annual percent change of 3.2%.ConclusionWe have established a consecutive, population-based database of 1,399 OSCC patients. This creates a basis for multiple studies that will elaborate our understanding of OSCC, and hopefully improve diagnosis, treatment, and rehabilitation of OSCC patients.

Tumor-related leukocytosis predictive of recurrence and survival in patients with oral cavity squamous cell carcinoma.

To evaluate the prognostic values of tumor-related leukocytosis (TRL) as a reliable biomarker predictive of recurrence and survival after definitive surgery for oral cavity squamous cell carcinoma (OSCC). This retrospective study involved 322 patients who underwent tumor extirpation combined with neck dissection for treatment-naïve OSCC between 2006 and 2014. Multivariate binary logistic regression analyses were used to analyze the relationship between TRL and pathological variables. Cox proportional hazard regression analyses were used to find associations between factors and disease-free survival (DFS) or overall survival (OS). TRL was significantly related to advanced disease status, tumor size, invasion depth, poor differentiation, and T and N classifications, resulting in increased post-treatment recurrence rate, particularly in the distant site. Multivariate logistic regression analyses showed that only the T classification was significantly associated with baseline TRL (p=0.018). Multivariate analyses also showed that the tumor depth of invasion, pathological N classification, extranodal extension, and TRL remained the independent variables predictive of DFS and OS (all p<0.05). TRL was related to a more than twofold increased risk of post-treatment recurrence and mortality. TRL is associated with advanced tumor disease and increased recurrence and mortality in OSCC patients.

Predictive score for recurrence after complete resection in locally advanced oral cavity squamous cell carcinoma.

e17536 Background: Early progression, usually defined disease-free interval (DFI) less than six months after completing adjuvant platinum-based chemoradiotherapy (CRT), has very poor outcome for oral cavity squamous cell carcinoma (OCSCC). But there are no biomarkers to predict such early progression. Methods: Locally advanced OCSCC patients, after complete surgical resection and followed-up platinum-based adjuvant CRT, were retrospectively enrolled from Chung Shan Medical University Hospital (CSMUH, training cohort) and Taipei Veterans General Hospital (TPE-VGH, validating cohort) in Taiwan. Clinicopathologic variables of patients with DFI &lt; or ≥ 6 months were compared by using the χ2 test. The Cox proportional hazards model was applied to identify independent factors for DFI. Survival was estimated using the Kaplan-Meier method and log-rank test. Results: A total of 350 high-risk OCSCC patients were enrolled, including 146 patients in training cohort and 204 in validating cohort. In multivariate Cox regression, pN &gt; 0, extracapular spread, and depth of invasion ( ≥ 1cm) were independent factors for DFI in training cohort. If each factor scored one point, the scoring system could effectively predict early progression that sensitivity/specificity/area under curve (AUC) of training and validating cohort were 57.7%/91.2%/0.771 and 58.1%/83.9%/0.730, respectively (the cutoff level ≤ 2 or &gt; 2). DFI between lower- (score 0–2) and high- (score 3) risk groups were also significantly different in both training (median DFI, 59.6 vs. 4.5 months, P &lt; 0.001) and validating cohorts (NA vs. 9.3 months, P &lt; 0.001). Conclusions: The established score system was effective to predict early progression after adjuvant CRT for locally advanced OCSCC.

Immune signatures associated with response to neoadjuvant PD-1 blockade in oral cavity cancer.

6055 Background: PD-1 inhibition therapy has revolutionized clinical medicine as it can mediate durable responses in a small cohort of patients. Yet, it remains incompletely understood why these patients respond. To address this question, we studied patients with oral cavity squamous cell carcinoma (OCSCC) to elucidate immune phenotypes associated with response to nivolumab. Methods: We defined the immune profile from the blood and tumor of patients on neoadjuvant nivolumab. We tested if tumor-infiltrating lymphocytes (TIL) could be preferentially expanded ex vivo from nivolumab-responsive patients versus those who were either non-responsive or had never received nivolumab. During the course of therapy, we comprehensively profiled a number of surface markers on patients’ T cells to define their activation status, cytotoxic capacity and memory phenotype. Moreover, the immune profile of the peripheral blood was assessed pre- and post-nivolumab using high dimensional mass cytometry. Results: Regardless of PD-1 therapy, TIL were successfully expanded from 11 of the 12 patients. TIL were comprised of both CD4+ and CD8+ T cells. Additional investigation revealed that the frequency of CD4+ T cells and effector memory T cells in TIL correlated with disease progression (CD4: p = 0.04, r = 0.74, effector memory: p = 0.046, r = 0.74). TILs from responders expressed higher CD26 (p = 0.007, r = -0.88) and Tim3 (p = 0.045, r = -0.74) while PD-1, Lag3, and Ox40 were not differentially expressed based on response. Spearman correlation and Mann Whitney U test were used to assess phenotypic differences. Conclusions: We demonstrate, for the first time, that TIL can be reliably expanded from OCSCC patients on neoadjuvant nivolumab. Moreover, individuals who were responsive to PD-1 blockade had TIL expressing high levels of CD26 and Tim3. Future studies will explore if these markers are predictive of responses and if they contribute to treatment outcome.

Prognostic Roles of SCC Antigen, CRP and CYFRA 21-1 in Oral Cavity Squamous Cell Carcinoma.

Tumor-related and inflammation-related markers were reported to be prognostic in cancer patients. In this study, we evaluated squamous cell carcinoma antigen (SCC-Ag), cytokeratin 19 fragment (CYFRA 21-1) and C-reactive protein (CRP) simultaneously in oral cavity squamous cell carcinoma (OSCC) patients. Two hundred and forty-six newly diagnosed OSCC patients were retrospectively recruited between December 2010 and December 2016. The elevation of CRP levels (≥5.0 mg/l) and SCC-Ag levels (≥2.0 ng/ml) were significantly related with tumor invasion parameters and metastatic factors. In contrast, the elevation of CYFRA 21-1 levels (≥3.3 ng/ml) was related with extranodal extension alone. For patients with all three markers being elevated before surgery, their overall survival and disease-free survival were significantly worse than others. Concurrent elevation of preoperative SCC-Ag, CYFRA 21-1 and CRP serum levels can be correlated with worse survival rates in OSCC.

Activin A regulates the epidermal growth factor receptor promoter by activating the PI3K/SP1 pathway in oral squamous cell carcinoma cells

Epidermal growth factor receptor (EGFR) and activin A are both overexpressed in oral cavity squamous cell carcinoma (OSCC). We evaluated their clinical correlation and activin A-mediated EGFR regulation in this study. Overexpression of both transcripts/proteins indicated a poorer prognosis in OSCC patients. Knockdown of endogenous INHBA repressed the expression of EGFR and inhibited activin A-mediated canonical Smads, noncanonical phosphorylation of AKT (ser473) (p-AKT ser473) and SP1. Inhibition of PI3K signaling via its inhibitor attenuated p-AKT ser473 and in turn reduced SP1 and EGFR expression in the presence of recombinant activin A (rActivin A) in OSCC cells, as revealed via a luciferase assay and western blotting. However, canonical Smad signaling repressed the EGFR promoter, as revealed by a luciferase assay. The transcription factor SP1, its coactivator CBP/p300, and Smad proteins were recruited to the EGFR proximal promoter following rActivin A treatment, as revealed by chromatin immunoprecipitation (ChIP). Smad2/3/4 dramatically outcompeted SP1 binding to the EGFR proximal promoter following mithramycin A treatment. Activin A activates the PI3K and Smad pathways to compete for binding to overlapping SP1 consensus sequences on the EGFR proximal promoter. Nevertheless, canonical p-Smad2 was largely repressed in OSCC tumor tissues, suggesting that the activin A-mediated noncanonical pathway is essential for the carcinogenesis of OSCC.

Number of positive lymph nodes better predicts survival for oral cavity cancer.

We compared the predictive ability of our proposed N classification with that of the American Joint Committee on Cancer (AJCC) nodal (N) classification for oral cavity squamous cell carcinoma (OCC). We assessed 345 OCC patients who underwent primary tumor extirpation and neck lymph node (LN) dissection. N classification was analyzed by recursive partitioning analysis and compared with the AJCC N classification by c-index. Cox proportional hazards regression analyses were used to determine associations between tumor or nodal factors and disease-free survival (DFS) or overall survival (OS). Positive LNs were found in 149 patients (43.2%). In multivariate models, the number of positive LNs and LN ratio strongly associated with DFS and OS (P < 0.001). Our new N classification was proposed with four categories of N0, N1 (1 positive LN), N2 (2-4 positive LNs or extranodal extension > 2 mm), and N3 (≥5 positive LNs). The c-index for the proposed N classification showed improvement in survival predictions (0.735; 95% CI, 0.703-0.767) compared with the AJCC N classification (0.701; 0.667-0.735). The number of positive LNs and LN ratios strongly associated with posttreatment recurrence and survival for OCC. Using positive LN numbers with the N classification improves OCC survival predictions.

Does anatomic subsite influence oral cavity cancer mortality? A SEER database analysis.

To determine if there are differences in mortality from oral cavity squamous cell carcinoma (OCSCC) based on oral cavity (OC) subsites. Using the Surveillance, Epidemiology, and End Results Program (SEER) 9 database, patients with sequence number 0 or 1 squamous cell OCSCC were analyzed by OC subsite for 5-year cause-specific mortality (CSM) from OCSCC. Proportional hazards regression determined the association between 5-year CSM and OC subsites while controlling for treatment modality, stage, and demographic characteristics using hazard ratios. Significance was set at alpha = 0.05. 20,647 OC patients were included in the regression analysis. The most commonly diagnosed sites were floor of mouth (34.4%) and oral tongue (34.3%). Floor of mouth, upper gum, and retromolar trigone were associated with lower CSM compared to oral tongue. Not receiving surgery and receiving radiation were associated with increased CSM, and CSM increased with cancer staging when distant or regional disease was compared to localized disease. Also, patients diagnosed at 60 years or older and black patients had increased CSM. Among OCSCC patients, those with oral tongue cancer are more likely to experience CSM than patients with floor of mouth, upper gum, and retromolar trigone cancer. It is important to understand these mortality related differences in the management of OCSCC patients. Understanding subsite-specific mortality may benefit prognosis counseling of OCSCC patients and elicit subsite-directed research as a means to improve outcomes. NA Laryngoscope, 129:1400-1406, 2019.

Integrated analyses utilizing metabolomics and transcriptomics reveal perturbation of the polyamine pathway in oral cavity squamous cell carcinoma

Oral cavity squamous cell carcinoma (OSCC), the most common malignancy of the oral cavity, is associated with poor prognosis and high mortality worldwide. Moreover, knowledge of the metabolic alterations that occur in OSCC is still limited. In the present study, we used a quantitative metabolomic approach with chemical isotope labeling (CIL) to analyze alterations in the metabolite levels in paired cancerous (T) and adjacent noncancerous (AN) tissues from 31 OSCC patients. Using volcano plot and orthogonal projections to latent structure-discriminant analysis (OPLS-DA), we uncovered 99 dysregulated metabolites in OSCC and verified the identities of seven metabolites via comparison with authenticated standards. From these seven metabolites, we constructed a 3-marker panel, consisting of putrescine, glycyl-leucine, and phenylalanine, using a support vector machine (SVM) model that can discriminate T from AN with high sensitivity and specificity based on receiver operator characteristic (ROC) analysis. Furthermore, by integrating the metabolomics profiles with transcriptomics data obtained from the same sample set, we revealed the dysregulation of the polyamine pathway in OSCC. Our findings provide insights into the metabolic perturbations present in OSCC and have uncovered potential metabolic biomarkers and therapeutic targets for use in the treatment of OSCC.

Outcomes after Salvage Therapy in Oral Cavity Squamous Cell Carcinoma (OCSCC) Patients Who Developed Locoregional Failure (LRF) after Definitive Surgery and Adjuvant (chemo)Radiotherapy: A Multi-Institutional Collaborative Study

We conducted a multi-institutional study to review salvage therapy outcomes in OCSCC patients who developed LRF after upfront surgery and adjuvant (chemo)radiotherapy. A collaborative patient database with primary OCSCC stage I-IVB (AJCC 7th Ed) treated with primary surgical resection between 1/1/2005 and 1/1/2015 was collected from 6 academic centers. From a total of 1282 patients, we identified patients who developed LRF after primary surgery and adjuvant (chemo)radiotherapy. The exclusion criteria were: missing information on LRF, distant failure within 30 days of LRF, and LRF before completing initial adjuvant therapy. Cox proportional hazard analysis was performed to estimate hazard ratio (HR). 156 patients were selected: 60 females (38%), 126 Whites (81%), and 63 (40%) oral tongue primaries. Median age at initial diagnosis was 61 years. 152 (97%) smoked or chewed tobacco and 103 (66%) used alcohol. 54 (34 %) had pT4 and 76 (49%) pN2b-c disease. 33 (21%) had a positive margin at the initial surgery and 55 (15%) had extranodal spread. All received adjuvant radiation with a median dose of 60Gy and 66 (42%) patients also had concurrent chemotherapy. With a median follow up of 22.5 months, 82 (53%) developed only local failure, 39 (25%) had only neck failure, and 35 (22%) had both local and regional nodal failures. The median time to LRF was 13 months (range: 4-130). 104 of 156 (67%) underwent salvage surgery and 28 (27%) of surgically salvaged patients also received adjuvant re-irradiation. Patients who had any regional failure were more likely to receive adjuvant re-irradiation than those without (88% vs 11%, p=0.001). 49 (31%) patients received salvage chemotherapy. 38 (24%) patients had a 2nd LRF after salvage therapy. Median OS after 1st LRF for all patients was 7.7 months. Time from initial diagnosis to 1st LRF was not associated with OS. In multivariable analysis controlling for age, gender, re-irradiation, and salvage chemotherapy, lack of salvage surgery was independently associated with worse OS (HR=4.3, 95%CI=2.5-7.1). About 30% of surgically salvaged patients were alive at 125 months after 1st LRF. Among those who received salvage surgery, positive surgical margin (HR=2.3, 95%CI=1.1-4.8) and perineural invasion (PNI) (HR=2.3, 95%CI=1.1-4.6) were independently correlated with worse OS. Receipt of adjuvant re-irradiation showed a trend toward more favorable OS (HR=0.5, 95%CI=0.2-1.0) after further accounting for nodal failure status. Patients who were selected to receive salvage surgery had more favorable outcomes than those who were not. Positive salvage surgical margin and PNI were associated with worse OS. Adjuvant re-irradiation showed a trend towards improved OS after accounting for nodal failure status.

Pathological risk factors stratification in pN3b oral cavity squamous cell carcinoma: Focus on the number of positive nodes and extranodal extension

ObjectiveAccording to the AJCC 2017 Staging Manual, oral cavity squamous cell carcinoma (OCSCC) with pN2 disease (based on the AJCC 2010 criteria) and extra-nodal extension (ENE) should be classified as pN3b. We performed a detailed outcome analyses in this patient subgroup. Material and methodsWe retrospectively reviewed the clinical records of consecutive OCSCC patients who underwent radical surgery between 1996 and 2017. Patients with pN3b disease (n = 365) were divided into a pN+ ≥8/ENE ≥5 subgroup (defined by the presence of pN+ ≥8 nodes or ENE ≥5 nodes, n = 77) and a pN+ ≤7/ENE ≤4 subgroup (defined by the presence of pN+ ≤7 nodes and ENE ≤4 nodes, n = 288). Patients with pN0/pN1/pN2 (n = 1192/179/197) disease were included for comparison purposes. ResultsPatients in the pN+ ≥8/ENE ≥5 subgroup had less favorable 5-year outcomes than those in the pN+ ≤7/ENE ≤4/pN2/pN1/pN0 groups (local control, 64%/79%/86%/83%/88%, p < 0.001; neck control, 55%/75%/80%/86%/93%, p < 0.001; distant metastases, 67%/28%/20%/12%/3%, p < 0.001; disease-free survival, 21%/51%/64%/72%/82%, p < 0.001; disease-specific survival, 25%/55%/71%/82%/92%, p < 0.001; overall survival, 19%/40%/54%/64%/82%, p < 0.001; respectively). Among patients with pN3b disease, multivariable analysis identified the pN+ ≥8/ENE ≥5 subgroup, lower neck (level IV/V) metastases, and depth of invasion ≥25 mm as independent adverse prognostic factors for 5-year distant metastases and survival rates. ConclusionsPatients in the pN+ ≥8/ENE ≥5 subgroup have an unfavorable prognosis and their classification as pN3b is advisable. In contrast, patients in the pN+ ≤7/ENE ≤4 subgroup should be classified as pN3a.

Glycopeptides as a Tool for Early Detection of Cancer.

Protein glycosylation, as one of the most common and complex posttranslational modifications, plays an important role in many biological processes. Along with the intensive progress in MS techniques and development of glycan search tools and databases, glycoproteomics has become a popular subject of studies. The possibility of simultaneous identification of amino acid sequence, glycosylation sites, and glycan composition enabled the monitoring of changes in glycosylation patterns in various pathological states. In this issue, Saraswat etal. describe MS-based investigations of glycopeptide changes in oral cavity squamous cell carcinoma (OSCC). Their findings indicate glycopeptides with changed expression levels and the presence of altered glycan forms observed in four proteins derived from OSCC patients' sera. Proteins carrying this distinctive pattern are in the group of the most abundant components of serum, IgG1, IgG4, HPT, and TRFE, which makes their identification more accessible. Described changes, characteristic for cancer serum samples, may be considered as potential diagnostic indicators of OSCC; however, there is still a need to establish a universal glycopeptide-based biomarkers database, where all glycoproteomic data can be collected from all types of cancer studies and evaluated using meta-analyses. Only then, early diagnosis of patients using MS-based approach will make sense, as those investigations are very convoluted, and all efforts made during sample preparation and analysis will pay off when comprehensive anticancer prevention will be achieved during single measurement.

Salivary metabolite profiling distinguishes patients with oral cavity squamous cell carcinoma from normal controls.

Oral cavity squamous cell carcinoma (OCC) and oropharyngeal squamous cell carcinoma (OPC) are among the most common cancers worldwide and are associated with high mortality and morbidity. The purpose of this study is to identify potential biomarkers to distinguish OCC/OPC from normal controls and to distinguish OCC patients with and without nodal metastasis. We tested saliva samples from 101 OCC, 58 OPC, and 35 normal controls using four analytical platforms (NMR, targeted aqueous by LC-MS/MS, global aqueous and global lipidomics by LC-Q-TOF). Samples from OCC and normal controls were divided into discovery and validation sets. Using linear regression adjusting for age, sex, race and experimental batches, we found the levels of two metabolites (glycine and proline) to be significantly different between OCC and controls (FDR < 0.1 for both discovery and validation sets) but did not find any appreciable differences in metabolite levels between OPC and controls or between OCC with and without nodal metastasis. Four metabolites, including glycine, proline, citrulline, and ornithine were associated with early stage OCC in both discovery and validation sets. Further study is warranted to confirm these results in the development of salivary metabolites as diagnostic markers.

Nomogram based on albumin and neutrophil-to-lymphocyte ratio for predicting the prognosis of patients with oral cavity squamous cell carcinoma

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.

Comparison of psychosocial factors over time among HPV+ oropharyngeal cancer and tobacco-related oral cavity cancer patients

IntroductionThe role of human papilloma virus (HPV) in the pathogenesis of oropharyngeal squamous cell carcinoma (OPSCC) is well documented, as is the excellent prognosis of patients with HPV-associated disease; in contrast, oral cavity squamous cell carcinoma (OCSCC) is associated with tobacco and alcohol use and has a worse prognosis. While causative factors, staging, and treatment guidelines differ between these cancer subsets, few studies have compared psychosocial factors in these groups. ObjectiveTo explore differences in psychosocial factors between HPV+ OPSCC patients versus OCSCC smokers. MethodsA prospective cohort study at a single multidisciplinary, tertiary care HNC center was completed with recruitment from 2010 to 2013 using self-administered questionnaires before treatment and at 12 months. Patients were included with a diagnosis of HPV+ OPSCC or OCSCC with a smoking history. 38 (21 HPV+ OPSCC/17 OCSCC) met criteria. The main outcomes included self-efficacy, symptom severity, cancer worry, and depression. ResultsA total of 38 (21 HPV+ OPSCC/17 OCSCC) patients (mean age: 57 [32–76], 73.7% male, 78.9% Caucasian, 71% stage IV) met inclusion criteria. OPSCC patients tended to be of male sex, Caucasian race, and single. Furthermore, OPSCC patients were more likely than OCSCC patients to have private insurance, be employed, and use alcohol and tobacco less frequently. Regarding psychosocial factors, HPV+ OPSCC patients reported lower symptom severity (2.7 versus 3.3), depression (12.0 versus 14.0) and cancer worry (2.8 versus 3.2) at baseline compared to OCSCC patients. Depression decreased significantly over time in OPSCC patients (12.0 to 9.9; effect size: −3.2 (95% CI: −5.9 to −0.4)). Although not statistically significant, cancer worry decreased in both groups (2.8 to 2.4 and 3.2 to 2.7, respectively, effect sizes: −0.3 (95% CI: −0.7–0.08) and −0.6 (95% CI: −1.2–0.05), respectively). No statistically significant differences in patterns of change over time were noted between groups. Conclusions and relevanceThis pilot study highlighted a pattern of reduced quality of life parameters in OCSCC patients at baseline with similar improvements over time compared to the OPSCC cohort. Although different in cancer etiology and treatment plans, HPV+ OPSCC and tobacco-related OCSCC patients both require multidisciplinary cancer care plans that address psychosocial concerns.Level of evidence: 2B

Tongue Cancer Patients Can be Distinguished from Healthy Controls by Specific N-Glycopeptides Found in Serum.

There are no blood biomarkers to detect early-stage oral cavity squamous cell carcinoma (OSCC) prior to clinical signs. Most OSCC incidence is associated with significant morbidity and poor survival. The authors aimed to use mass-spectrometry (MS) technology to find specific N-glycopeptides potentially serving as serum biomarkers for preclinical OSCC screening. Serum samples from 14 patients treated for OSCC (stage I or stage IV) with 12 age- and sex-matched controls are collected. Quantitative label-free N-glycoproteomics is performed, with MS/MS analysis of the statistically significantly different N-glycopeptides. Combined with a database search using web-based software (GlycopeptideID), MS/MS provided detailed N-glycopeptide information, including glycosylation site, glycan composition, and proposed structures. Thirty-eight tryptic N-glycopeptides are identified, having 19 unique N-glycosylation sites representing 14 glycoproteins. OSCC patients, including stage I tumors, can be differentiated from healthy controls based on the expression levels of these glycoforms. N-glycopeptides of IgG1, IgG4, haptoglobin, and transferrin have statistically significant different abundances between cases and controls. The authors are the first to suggest specific N-glycopeptides to serve as potential serum biomarkers to detect preclinical OSCC in patients. These N-glycopeptides are the lead candidates for validation as future diagnostic modalities of OSCC as early as stage I.

Adjuvant radiotherapy after curative surgery for oral cavity squamous cell carcinoma and treatment effect of timing and duration on outcome-A Taiwan Cancer Registry national database analysis.

Conduct an accurate risk assessment of resected oral cavity squamous cell carcinoma (OSCC) patients by accessing a nationwide systemic investigation is pivotal to improve treatment outcomes. In this article, we tried to determine the impact of different prognostic factors for OSCC patients who received adjuvant radiotherapy (RT) after curative surgery, using Taiwan's national cancer registry database (TCR). A nationwide, large population‐based study was conducted using TCR with patients identified from 2007 to 2015. The study variables included age, gender, cancer subsites, stage, histology grade, margin and extra‐nodal extension (ENE) status, treatment type, surgery to RT interval (ORI), total RT treatment time (RTT), and RT dose. Univariate and multivariate analysis were performed to identify predictors of the variables associated with overall survival (OS), cause‐specific survival (CSS), local‐regional relapse‐free survival (LRFS), and distant metastasis‐free survival (DMFS). 8986 OSCC patients treated with surgery and adjuvant RT were analyzed. In multivariate analysis, worse outcomes were associated with males, older age, subsite in the oral tongue, advanced stage, higher histologic grade, involved margin, and positive ENE. ORI only showed an adverse trend in LRFS, when exceeding 7 weeks (P = .06). RTT >8 weeks was a significant poor predictor in OS, CSS and LRFS (P < .001). Extreme RT dose (>70 Gy or ≤50 Gy) also demonstrated an adverse impact on the outcomes. Prolonged RT treatment time and extreme RT doses were identified as significantly poor prognostic predictors in OSCC patients who received adjuvant RT after curative surgery.

Differences in LC3B expression and prognostic implications in oropharyngeal and oral cavity squamous cell carcinoma patients

BackgroundThis study examined the prognostic significance of microtubule-associated protein light chain 3B (LC3B) expression in oropharyngeal and oral cavity squamous cell carcinoma (SCC). The prognostic significance of LC3B expression in relation to human papillomavirus (HPV) status in oropharyngeal SCC was also examined.MethodsTissue microarrays (TMAs) were constructed from formalin-fixed, paraffin-embedded oropharyngeal (n = 47) and oral cavity (n = 95) SCC tissue blocks from patients with long-term recurrence and overall survival data (median = 47 months). LC3B expression on tumour was assessed by immunohistochemistry and evaluated for associations with clinicopathological variables. LC3B expression was stratified into high and low expression cohorts using ROC curves with Manhattan distance minimisation, followed by Kaplan–Meier and multivariable survival analyses. Interaction terms between HPV status and LC3B expression in oropharyngeal SCC patients were also examined by joint-effects and stratified analyses.ResultsKaplan–Meier survival and univariate analyses revealed that high LC3B expression was correlated with poor overall survival in oropharyngeal SCC patients (p = 0.007 and HR = 3.18, 95% CI 1.31–7.71, p = 0.01 respectively). High LC3B expression was also an independent prognostic factor for poor overall survival in oropharyngeal SCC patients (HR = 4.02, 95% CI 1.38–11.47, p = 0.011). In contrast, in oral cavity SCC, only disease-free survival remained statistically significant after univariate analysis (HR = 2.36, 95% CI 1.19–4.67, p = 0.014), although Kaplan-Meier survival analysis showed that high LC3B expression correlated with poor overall and disease-free survival (p = 0.046 and 0.011 respectively). Furthermore, oropharyngeal SCC patients with HPV-negative/high LC3B expression were correlated with poor overall survival in both joint-effects and stratified presentations (p = 0.024 and 0.032 respectively).ConclusionsHigh LC3B expression correlates with poor prognosis in oropharyngeal and oral cavity SCC, which highlights the importance of autophagy in these malignancies. High LC3B expression appears to be an independent prognostic marker for oropharyngeal SCC but not for oral cavity SCC patients. The difference in the prognostic significance of LC3B between oropharyngeal and oral cavity SCCs further supports the biological differences between these malignancies. The possibility that oropharyngeal SCC patients with negative HPV status and high LC3B expression were at particular risk of a poor outcome warrants further investigation in prospective studies with larger numbers.

Radiologic-Pathologic Correlation of Extranodal Extension in Patients With Squamous Cell Carcinoma of the Oral Cavity: Implications for Future Editions of the TNM Classification

To evaluate the accuracy and prognostication of the presence of radiologic extranodal extension (rENE) versus pathologic extranodal extension (pENE) in patients with oral cavity squamous cell carcinoma (OSCC). A retrospective review was conducted for all newly diagnosed OSCC patients who underwent neck dissection in our institution from 2010 to 2015 with available records of preoperative computed tomography or magnetic resonance imaging. Two head and neck neuroradiologists reviewed the presence of rENE (defined as ill-defined lymph node borders) on imaging independently, being blinded regarding the pathology report. The impact of the imaging-surgery interval, imaging modalities, and intrarater and interrater concordance of rENE was assessed. The diagnostic accuracy of rENE versus pENE was evaluated. Overall survival (OS) was compared between those with and without rENE. Multivariate analysis evaluated the prognostic value of rENE. Among the 508 patients, rENE and pENE were identified in 57 and 121 cases, respectively. The diagnostic accuracy of rENE versus pENE was identical (73%) for cases with the imaging-surgery interval ≤4 weeks (n = 276) and 4 to 8 weeks (n = 207) but lower (48%) for those >8 weeks (n = 25). Computed tomography displayed higher accuracy on rENE assessment versus magnetic resonance imaging (80% vs 63%, P = .011). Interrater and intrarater concordance (n = 93) was good (κ = 0.79) and excellent (κ = 0.94), respectively. Excluding the 25 cases with a >8 weeks imaging-surgery interval, the sensitivity, specificity, positive predictive value, and negative predictive value of rENE versus pENE in the remaining 483 cases were 52%, 96%, 93%, and 66%, respectively. Patients with rENE (n = 55) had inferior OS versus those without rENE (n = 202), and both had lower OS than node-negative (n = 226) patients (3-year OS: 31% vs 68% vs 81%, P < .001). Multivariate analysis, adjusted for age, T category, N category, and performance status, confirmed the prognostic value of rENE for OS (hazard ratio 3.3, 95% confidence interval 2.4-5.3, P < .001). This large cohort study shows a high specificity but low sensitivity of rENE for pENE. Similar to pENE, the presence of rENE is associated with reduced survival in OSCC.

Long-term outcomes in oral cavity squamous cell carcinoma with adjuvant and salvage radiotherapy after surgery.

Early-stage oral cavity squamous cell carcinoma (OCSCC) represents a heterogeneous group of patients, and locoregional recurrence rates are as high as 25% with surgery alone. Radiotherapy (RT) is typically reserved as part of salvage multimodality therapy after salvage surgery because it is generally thought that there is no significant detriment to salvage therapy. Our aim was to examine outcomes for recurrent OCSCC treated with salvage surgery and radiation and compare them to outcomes for patients treated with adjuvant postoperative RT upfront. We identified 425 patients with OCSCC treated with postoperative RT at our institution. The 5-year rates of local failure, locoregional failure (LRF), survival, and distant metastasis (DM) were the main outcome measures. We performed a landmark analysis and examined the same outcomes in the adjuvant versus salvage cohorts using Cox proportional hazards and Fine-Gray competing risk method. The adjuvant cohort had higher tumor (T) (P < 0.0001) and nodal (N) (P < 0.0001) stage than the salvage cohort's stage at initial presentation. On multivariate analysis, a strategy of salvage RT experienced poorer overall survival (OS) compared to upfront adjuvant RT (hazard ratio [HR] 1.84; 95% confidence interval [CI], 1.26-2.70; P = 0.002). Moreover, salvage surgery followed by RT patients experienced increasing risk of LRF (HR 1.56; 95% CI, 1.18-2.06; P = 0.002) and (DM) (HR 1.53; 95% CI, 1.08-2.17; P = 0.02) on multivariate analysis. Additional analysis was performed excluding salvage cohort with advanced disease at initial presentation (T3-T4 and N2). Salvage RT treatment selection for early-stage OCSCC continued to experience significantly poorer OS as compared to adjuvant RT (HR 1.48; 95% CI, 1.002-2.19; P = 0.049). Early-stage OCSCC patients who are observed and experienced recurrence requiring salvage therapy (surgery and RT) have worse oncologic outcomes than locally advanced patients receiving upfront adjuvant RT. Prospective randomized studies are needed to identify high-risk subset of early-stage OCSCC comparing adjuvant RT versus observation, followed by salvage surgery and RT at recurrence. 4. Laryngoscope, 2539-2545, 2018.