Oral Cavity Squamous Cell Carcinoma Patients Research Articles

Prognostic factors associated with overall survival in patients with oral cavity squamous cell carcinoma.

Low socioeconomic status, increasing age, and poor lifestyle behaviors are associated with poor survival in patients with oral cavity squamous cell carcinoma (OCSCC). To determine the overall survival (OS) and the risk of OCSCC death by tumor subsite. A retrospective cohort study of OCSCC patients diagnosed from 2007 to 2009 and treated at a single cancer center in Rio de Janeiro, Brazil. Patient information was obtained from the Hospital Cancer Registry (HCR) database and complemented by individual search of physical and electronic medical records. Descriptive statistics of population characteristics were computed. OS was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression analyses were used to estimate the risk of death by tumor subsite. Seven hundred and three patients with OCSCC were identified. Most patients were men (77.4%) with low levels of education (67.5%), who drank (73.9%) and smoked (79.7%). The most prevalent tumor site was the tongue (45.4%), 73.4% of patients had advanced (clinical stage III or IV) OCSCC at diagnosis and 74.1% died during follow-up. For the entire cohort, the OS was 39.1% at two years and 27.9% at five years. The median survival time was 1.4 years (95%CI: 1.2‒1.5). Non-operative treatment (HR: 3.11; 95%CI: 2.26‒4.29; p<0.001), advanced stage (HR 2.14; 95%CI 1.68-2.74; p<0.001), and age >60 years at diagnosis (HR: 1.37; 95%CI: 1.15‒1.64; p<0.001) were independently associated with the risk of death. However, these factors varied by tumour subsite. Analysis of specific subsites of the oral cavity revealed substantial differences in prognostic factors associated with poor survival in OCSCC.

The impact of preoperative glycated hemoglobin levels on outcomes in oral squamous cell carcinoma.

This study aimed to investigate the association between preoperative glycated hemoglobin (HbA1c) levels and the treatment outcomes of oral cavity squamous cell carcinoma (OSCC). Three hundred and fifty-eight OSCC patients were consecutively enrolled between July 2004 and July 2016. Clinicopathological parameters and survival outcomes were analyzed following HbA1c stratification of 6.5% (HbA1c≥6.5%: n=74, 20.6%) and 7.0% (HbA1c≥7.0%: n=53, 14.8%). Higher HbA1c levels were associated with elevated body mass index, lower albumin levels, wider surgical margins, and prolonged hospital stays (HbA1c 6.5%: p=.001, .048, .030, .009, respectively; HbA1c 7.0%: p=.092, .032, .009, .015, respectively). Survival rates stratified by HbA1c 6.5% were as follows: locoregional recurrence-free survival, p=.014; distant metastasis-free survival, p=.013; second primary cancer-free survival, p=.015; overall survival, p=.014; disease-specific survival, p=.002 and HbA1c 7.0%: locoregional recurrence-free survival, p=.013; distant metastasis-free survival, p=.013; second primary cancer-free survival, p=.014; overall survival, p=.015; disease-specific survival, p=.004. Multivariate analyses identified HbA1c as an independent prognostic factor for overall and disease-specific survival (HbA1c 6.5%: p=.014 and .002, respectively; HbA1c 7.0%: p=.036 and .013, respectively). Oral squamous cell carcinoma patients with higher preoperative HbA1c levels had longer hospitalization and worse survival outcomes.

A retrospective study on the prognostic value of preoperative C-reactive protein to albumin ratio in patients with oral cavity squamous cell carcinoma.

BackgroundAlthough the C-reactive protein-to-albumin ratio (CAR) can predict poor outcomes in assorted cancers, its prognostic value in oral cavity squamous cell carcinoma (OSCC) remains unclear. We explored the value of preoperative CAR in predicting clinical outcomes in OSCC patients treated with radical surgery.MethodsAll the recommended cutoff values were defined analyzing receiver operating characteristic curves or overall survival (OS). Dichotomization was performed on the basis of optimal CAR cutoff, and we compared the clinicopathological features between groups. Kaplan–Meier analysis was also performed to compare OS curves between the two groups. Univariate and multivariate analyses using the Cox proportional hazards model were conducted to find the clinical characteristics that were most closely correlated with disease free survival (DFS) and overall survival (OS). A nomogram incorporated CAR and several clinicopathological factors was established to predict prognosis and its accuracy was evaluated using concordance index (c-index).ResultsIn this retrospective study, a total of 326 patients with newly diagnosis of OSCC and received primary surgery between 2008 and 2017 were enrolled. Through the executed ROC curve analyses, the optimal CAR cutoff derived was 0.195 (area under the curve = 0.718, p < 0.001), with this cutoff exhibiting a discrimination ability superior to that of other inflammation-based prognostic scores after comparing the area under curves. Multivariate analysis demonstrated that CAR (≥0.195/<0.195) was associated with OS (hazard ratio 3.614; 95% CI [1.629–8.018]; p = 0.002) and DFS (hazard ratio 1.917; 95% CI [1.051–3.863]; p = 0.029). Kaplan–Meier analysis and log rank test revealed a significant difference in DFS and OS curves between patients with low CAR (<0.195) and those with high CAR (≥0.195; both p < 0.001). The c-index of the nomogram based on TNM system alone was 0.684 and could be increased to 0.801 if CAR and other clinicopathological factors were included.ConclusionsPreoperative CAR could constitute an independent prognostic indicator for OS and DFS prediction in OSCC patients treated with curative surgery. The established nomogram that incorporated CAR and prognostic factors might increase the accuracy of prognostic prediction for patients with OSCC.

Detection of somatic mutations in saliva of patients with oral cavity squamous cell carcinoma.

6562 Background: Oral cavity squamous cell carcinoma (OCSCC) frequently presents as clinically advanced disease with poor prognosis. When diagnosed at early stages, survival rates approach 80%, underscoring the need for validated, cost-effective detection methods. OCSCC is driven by the serial acquisition of genetic alterations. Tumor-defining somatic mutations are attractive biomarkers and hence their presence in saliva may be associated with malignancy as shown in a few proof-of-concept studies, including our previous work. Based on this premise, we present a low-cost, accurate, next generation sequencing (NGS) test with high clinical utility aimed at detecting mutations in the saliva for early diagnosis and potential screening of OCSCC. Methods: We have designed a custom NGS panel that covers exons of 7 most frequently mutated genes in OSCC. This minimal gene set derived from the analysis from 3 public datasets, predicted incidence of at least one somatic aberration in 89% of patients. We recruited 91 treatment-naïve OCSCC patients and profiled DNA from tissue and matched pre-operative saliva using this test. We also tested DNA from 12 subjects with premalignant lesions with high-grade oral dysplasia and matched saliva. Results: Using stringent variant calling criteria, at least one somatic variant was detected in 88 (96%) of the 91 primary tumors. 90.9% of the matched saliva were concordant, with only a minor decrease in early stage disease. Tumor-specific mutations (≥5% AF) in driver genes were detected in 10 (83.3%) dysplastic lesions, suggesting that driving clonal events may occur early in disease development. Interestingly, in 3 matched saliva of the dysplastic samples, the same mutations were detected. To ensure a variant is not a false positive call, we performed a vigorous multistep analytical validation of this saliva-based test: (i) independent re-sequencing of 24 saliva confirmed 94% reproducibility; (ii) no functionally relevant variants were detected in saliva from 12 of 13 healthy subjects without history of tobacco and alcohol usage; (iii) reproducibility, sensitivity, and specificity were confirmed using a positive control with 7 loci at 0.25% AF across 8 independent saliva sequencing runs and a certified negative control and was found to be on par with droplet digital PCR. Conclusions: These data highlight the feasibility of saliva-based testing for early diagnosis of OCSCC and premalignant lesions.

Predictive scoring systems for distant metastases in oral cavity squamous cell carcinoma.

e18536 Background: At least 10% of patients with oral cavity squamous cell carcinoma (OCSCC) would progress to distant metastases (DM). Median overall survival (OS) after distant metastases is only one year and rare biomarkers are available to predict distant metastatic events. Methods: A total of 595 OCSCC patients who underwent curative surgical resection at Chung Shan Medical University Hospital were enrolled from Jan 2010 to Dec 2016. The clinical–pathological variables were compared using the χ2 test. Cox proportional-hazards analyses were performed for distant metastatic free survival (DMFS), defined from the date of initial diagnosis to the date of distant metastasis. Two scoring systems for predicting distant metastases were established for patients with pathologic regional lymph node –positive (pN+) or –negative (pN–), separately. Results: Nearly 10% (8.9%, 53/595) of patients with OCSCC would progress to DM during follow-up [20.6% (28/136) and 5.4% (25/459) for patients with pN+ and pN–, respectively]. Most of the distant metastatic lesions developed within 3 years after initial diagnosis (overall, 84.9%, 45/53; patients with pN+, 92.9%, 26/28; patients with pN–, 76.0%, 19/25). For patients with pN+, rapidly locoregional recurrence (≦6 months), lymphovascular invasion, and lymphocyte-monocyte ratio(&lt;2.5) were the independent factors for DMFS. In addition, rapidly locoregional recurrence, elderly (age &gt; 65), and close surgical margin(≦5mm) were independent for those with pN–. If each of the independent factors was scored one point to predict DM occurring within 3 years after the initial diagnosis, two scoring systems were established for the corresponding patients with pN+ or pN–, separately. The area under the curves of these two scoring systems for the corresponding patients with pN+ and pN– were 0.737 and 0.825, respectively (Table). Conclusions: The established scoring systems effectively predict distant metastases for OCSCC patients. [Table: see text]

Correlation of pathologic tumor grade with survival in oral cavity squamous cell carcinoma.

e18557 Background: Pathologic tumor grade is a well-established prognostic risk factor that impacts staging and standard-of-care treatment decisions across multiple cancer types. However, the significance of tumor grade in cancers of the head and neck is less certain. Even in oral cavity squamous cell carcinoma (OCSCC), the head and neck cancer subsite with largest body of literature regarding the predictive value of tumor grade is, the prognostic significance of tumor grade remains controversial. Thus, we sought to better elucidate the prognostic importance of tumor grade in OCSCC. Methods: Patients with OCSCC diagnosed from 2004-2015 and undergoing primary surgery with or without adjuvant treatment in the National Cancer Data Base (NCDB) were identified. Overall survival (OS) was estimated using the Kaplan-Meier method with and without propensity score matching (PSM). Univariate and multivariable survival analyses were performed using Cox regression. Analyses were adjusted for multiple clinicopathologic factors, including age, sex, comorbidity status, year of diagnosis, pathologic staging, margin status, number of lymph nodes (LN) examined/positive, extranodal extension (ENE), lymphovascular invasion (LVI), adjuvant radiation, and concomitant chemotherapy. Results: Median follow-up was 40.7 months. Of 13,941 patients with OCSCC, 2,883 had low-grade tumors, 8,716 had intermediate-grade tumors, and 2,342 had high-grade tumors. Higher tumor grade was strongly associated with decreased survival. Specifically, five year OS was 62.7%, 52.8%, and 42.5% in low-grade (LG), intermediate-grade (IG), and high-grade (HG) OCSCC, respectively (p-value &lt; 0.001). In PSM cohorts, OCSCC patients with high-grade had significantly worse 5 year OS (47.7% vs. 57.7%, p &lt; 0.001) in comparison to those with LG OCSCC. Similarly, patients with IG tumors has worse 5-year OS (55.6% vs. 60.3%, p = 0.001) than patients with LG tumors in PSM cohorts. In multivariable analysis, both HG (HR 1.38, 95% CI 1.25-1.52, p &lt; 0.001) and IG (HR 1.17, 95% CI 1.08-1.26, p &lt; 0.001) OCSCC was associated with worse survival than what was observed in LG tumors. The magnitude of the independent effect of tumor grade in multivariable analysis was greater than or equal to what was observed with other well-established prognostic factors like margin positivity (HR 1.34), ENE (HR 1.35), and LVI (HR 1.18). Conclusions: Pathologic tumor grade is a strong predictor of survival among patients with OCSCC. Tumor grade should be considered when making therapeutic recommendations for OCSCC.

High expression of oxidative phosphorylation genes predicts improved survival in squamous cell carcinomas of the head and neck and lung

Mitochondrial activity is a critical component of tumor metabolism, with profound implications for tumorigenesis and treatment response. We analyzed clinical, genomic and expression data from patients with oral cavity squamous cell carcinoma (OCSCC) in order to map metabologenomic events which may correlate with clinical outcomes and identified nuclear genes involved in oxidative phosphorylation and glycolysis (OXPHOG) as a critical predictor of patient survival. This correlation was validated in a secondary unrelated set of lung squamous cell carcinoma (LUSC) and was shown to be driven largely by over-expression of nuclear encoded components of the mitochondrial electron transport chain (ETC) coordinated with an increase in tumor mitochondrial DNA copy number and a strong threshold effect on patient survival. OCSCC and LUSC patients with a favorable OXPHOG signature demonstrated a dramatic (>2fold) improvement in survival compared to their counterparts. Differential OXPHOG expression correlated with varying tumor immune infiltrates suggesting that the interaction between tumor metabolic activity and tumor associated immunocytes may be a critical driver of improved clinical outcomes in this patient subset. These data provide strong support for studies aimed at mechanistically characterizing the interaction between tumor mitochondrial activity and the tumor immune microenvironment.

Prognostic factors associated with overall survival in patients with oral cavity squamous cell carcinoma

Background Low socioeconomic status, increasing age, and poor lifestyle behaviors are associated with poor survival in patients with oral cavity squamous cell carcinoma (OCSCC). To determine the overall survival (OS) and the risk of OCSCC death by tumor subsite. Material and Methods A retrospective cohort study of OCSCC patients diagnosed from 2007 to 2009 and treated at a single cancer center in Rio de Janeiro, Brazil. Patient information was obtained from the Hospital Cancer Registry (HCR) database and complemented by individual search of physical and electronic medical records. Descriptive statistics of population characteristics were computed. OS was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression analyses were used to estimate the risk of death by tumor subsite. Results Seven hundred and three patients with OCSCC were identified. Most patients were men (77.4%) with low levels of education (67.5%), who drank (73.9%) and smoked (79.7%). The most prevalent tumor site was the tongue (45.4%), 73.4% of patients had advanced (clinical stage III or IV) OCSCC at diagnosis and 74.1% died during follow-up. For the entire cohort, the OS was 39.1% at two years and 27.9% at five years. The median survival time was 1.4 years (95%CI: 1.2‒1.5). Non-operative treatment (HR: 3.11; 95%CI: 2.26‒4.29; p <0.001), advanced stage (HR 2.14; 95%CI 1.68-2.74; p <0.001), and age >60 years at diagnosis (HR: 1.37; 95%CI: 1.15‒1.64; p <0.001) were independently associated with the risk of death. However, these factors varied by tumour subsite. Conclusions Analysis of specific subsites of the oral cavity revealed substantial differences in prognostic factors associated with poor survival in OCSCC. Key words:Squamous cell carcinoma, oral cavity cancer, survival, prognosis.

Pretreatment peripheral blood leukocytes are independent predictors of survival in oral cavity cancer.

Inflammation and immune surveillance evasion are cancer hallmarks. Peripheral blood leukocytes (PBLs) represent both. The aim of the current study was to examine PBLs as predictors of outcomes in oral cavity squamous cell carcinoma (OSCC), and to find specific cutoffs with the goal of including PBLs as host factor in patients' preoperative risk assessment. Previously established head and neck squamous cell carcinoma (HNSCC) cutoffs were examined in an independent cohort of 1369 OSCC patients. Then optimal OSCC cutoffs were found and validated in the subset of patients with OSCC (n = 119) from the external HNSCC cohort. The PBLs analyzed were neutrophils, monocytes, and lymphocytes individually, the neutrophil-to-lymphocyte ratio (NLR), and a combined index using all PBLs called Systemic Inflammation Response Index (SIRI). All parameters were significant predictors of survival using the previous cutoffs. However, OSCC cutoffs stratified survival outcomes better. Considering neutrophils ≤4.8×109 /L as reference, patients with 4.8-9.1×109 /L neutrophils had 1.536 times higher risk of death (95% CI, 1.295-1.822), and patients with ≥9.1×109 /L had 3.076 times higher risk (95% CI: 2.170-4.360). All PBLs maintained independent prognostic capacity in multivariable analysis. Neutrophils, NLR, and SIRI were significant predictors of survival when validating OSCC cutoffs in the external validation cohort. Pretreatment peripheral blood neutrophils, NLR, and SIRI are the most robust independent predictors of overall survival among all PBLs in OSCC. The authors report externally validated cutoffs that demonstrate the feasibility of including PBLs as host features in the preoperative prognostication of OSCC.

Immunohistochemical quantification of partial-EMT in oral cavity squamous cell carcinoma primary tumors is associated with nodal metastasis

ObjectivesQuantify by immunohistochemistry (IHC) a partial epithelial-to-mesenchymal transition (p-EMT) population in oral cavity squamous cell carcinoma (OCSCC) and determine its predictive value for lymph node metastasis. MethodsTissue microarrays (TMA) were created using 2 mm cores from 99 OCSCC patients (47 with low volume T2 disease, 52 with high volume T4 disease, and ∼50% in each group with nodal metastasis). IHC staining was performed for three validated p-EMT markers (PDPN, LAMB3, LAMC2) and one marker of well-differentiated epithelial cells (SPRR1B). Staining was quantified in a blinded manner by two reviewers. Tumors were classified as malignant basal subtype based on staining for the four markers. In this subset, the p-EMT score was computed as the average of p-EMT markers. Results84 tumors were classified as malignant basal. There was 87% inter-rater consistency in marker quantification. There were associations of p-EMT scores with higher grade (2.15 vs. 1.92, p = 0.04), PNI (2.13 vs. 1.83, p = 0.003), and node positivity (2.09 vs. 1.87, p = 0.02), including occult node positivity (56% vs. 19%, p = 0.005). P-EMT was independently associated with nodal metastasis in a multivariate analysis (OR 3.12, p = 0.039). Overall and disease free survival showed trends towards being diminished in the p-EMT high group. ConclusionsIHC quantification of p-EMT in OCSCC primary tumors is reliably associated with nodal metastasis, PNI, and high grade. With prospective validation, p-EMT biomarkers may aid in decision-making over whether to perform a neck dissection in the N0 neck and/or for adjuvant therapy planning.

18F-FDG PET/CT versus CT/MR imaging for detection of neck lymph node metastasis in palpably node-negative oral cavity cancer.

Subclinical lymph node (LN) metastasis is associated with poor survival outcome in oral cavity squamous cell carcinoma (OCC), which alleges elective neck LN dissection. Preoperative detection of metastatic LNs may improve prognosis and proper management of OCC. We examined the clinical usefulness of fluorine 18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) for the detection of occult neck LN metastasis in OCC patients in comparison with conventional CT/magnetic resonance (MR) imaging. A total of 178 OCC patients with negative neck palpation findings were assessed prospectively with 18F-FDG PET/CT and CT/MR imaging. Histopathological analyses of neck dissection samples served as reference. Diagnostic values of 18F-FDG PET/CT versus CT/MR imaging were compared with the McNemar test and logistic regression with generalized estimating equations. Forty-two patients (23.6%) had metastasis in 44 sides and 58 levels of the neck. The sensitivity for detection of occult metastasis was higher for 18F-FDG PET/CT than that for CT/MR imaging on a per-patient (69.1% vs 35.7%), per-side (70.5% vs 36.4%), and per-level (62.1% vs 29.3%) basis (all P ≤ 0.001). However, the specificity for metastatic detection was higher for CT/MR imaging than that for 18F-FDG PET/CT (all P < 0.005). 18F-FDG PET/CT improved detection of occult metastasis up to 33.4% in these patients compared to CT/MR imaging. 18F-FDG PET/CT can better detect occult neck metastasis than CT/MR imaging, which may potentially impact the clinical management of OCC patients.

Proteomic Profiling of Paired Interstitial Fluids Reveals Dysregulated Pathways and Salivary NID1 as a Biomarker of Oral Cavity Squamous Cell Carcinoma*[S

Patients with oral cavity squamous cell carcinoma (OSCC) are frequently first diagnosed at an advanced stage, leading to poor prognosis and high mortality rates. Early detection of OSCC using body fluid-accessible biomarkers may improve the prognosis and survival rate of OSCC patients. As tumor interstitial fluid is a proximal fluid enriched with cancer-related proteins, it is a useful reservoir suitable for the discovery of cancer biomarkers and dysregulated biological pathways in tumor microenvironments. Thus, paired interstitial fluids of tumor (TIF) and adjacent noncancerous (NIF) tissues from 10 OSCC patients were harvested and analyzed using one-dimensional gel electrophoresis coupled with liquid chromatography-tandem mass spectrometry (GeLC-MS/MS). Using label-free spectral counting-based quantification, 113 proteins were found to be up-regulated in the TIFs compared with the NIFs. The gene set enrichment analysis (GSEA) revealed that the differentially expressed TIF proteins were highly associated with aminoacyl tRNA biosynthesis pathway. The elevated levels of 4 proteins (IARS, KARS, WARS, and YARS) involved in the aminoacyl tRNA biosynthesis were verified in the OSCC tissues with immunohistochemistry (IHC). In addition, nidogen-1 (NID1) was selected for verification as an OSCC biomarker. Salivary level of NID1 in OSCC patients (n = 48) was significantly higher than that in the healthy individuals (n = 51) and subjects with oral potentially malignant disorder (OPMD; n = 53). IHC analysis showed that NID1 level in OSCC tissues was increased compared with adjacent noncancerous epithelium (n = 222). Importantly, the elevated NID1 level was correlated with the advanced stages of OSCC, as well as the poor survival of OSCC patients. Collectively, the results suggested that TIF analysis facilitates understanding of the OSCC microenvironment and that salivary NID1 may be a useful biomarker for OSCC.

Outcomes of Oral Cavity Squamous Cell Carcinoma Patients Under the Age of 40: A Propensity Score Matched Analysis

Conflicting evidence exists regarding prognosis in younger patients with oral cavity squamous cell carcinoma (OSCC) compared to older counterparts. We compared the outcomes of OSCC patients <40 year-old (yo) to those between 40-70 yo treated at our institution. All OSCC treated between 2005 and 2017 were reviewed. Clinical characteristics and outcomes of a younger cohort (age <40 yo) were compared to the all the older (40-70 yo) patients, and then to a 1:1 matched propensity score matched older cohort. The cohorts were matched including: gender, ECOG performance status (PS), pT- and pN-categories, primary tumor subsite (oral tongue vs other subsites), resection margin status, and presence of extranodal extension (ENE). The primary endpoint was 5-yr overall survival (OS, measured by Kaplan-Meier method), and secondary endpoints were 5-yr locoregional failure (LRF, analyzed by competing risk method), and disease-free survival (DFS, evaluated by Kaplan-Meier method). A total of 57 patients were identified in the younger (< 40) cohort which had a median follow up of 4.3 (0.1-13.6) years, and 441 in the older (40-70) cohort who had a median follow up of 2.7 (0.2-9.4) years. Among the younger (< 40 yo) cohort: median age was 33 yo, 24 (42%) females, 35 (61%) non-smokers, and 25 (44%) non-drinkers; bilateral and ipsilateral neck dissection was performed in 12 (21%) and in 30 (53%), respectively. Postoperative radiation therapy was given in 23 (40%), and concurrent chemotherapy in 15 (26%). Before applying the propensity score matching, a comparison of the younger cohort (n=57) and entire older cohort (n=441) showed that younger patients, had better ECOG PS (PS 0-1 98% vs 94%, p=0.022), less smoking history (37% vs 67% p=<0.01), had more oral tongue primary tumor site (81% vs 46%, p<0.001), fewer pT3-4 (18% vs 45%, p<0.001), less frequent pN+ (42% vs 65%, p<0.001), and less pENE+ (17% vs 34%, p=0.01), a similar proportion received chemotherapy (28% v 26%, p=0.76). The young patients had better 5 year OS (82% [95% CI 71%-93%] vs (66% [60-71%] p=0.008), better 5 year DFS (66% [54%-81%] vs 54% [49%-60%] p=0.031), and less LRF (26% [16%-43%]) vs 31% [27%-37%] p=0.18). Following propensity score matching (50 patients in each matched cohort); there was no significant difference between the younger and older cohort in 5-yr OS (81% [70%-94%] vs. 71% [59%-85%], p=0.18), 5-yr DFS (63% [49%-80%] vs. 64% [52%-79%], p=0.49), and 5-yr LRF (28% [17%-47 %] vs. 32% [21%-48%], p=0.29). OSCC patients under 40 yo have better ECOG PS and pathologic features compared to the 40-70 yo counterparts. With propensity score matching, younger and older cohorts have comparable survival and tumor control. The clinical impression of poor outcomes for patients aged less than 40yrs may represent recall bias.

Identification of Salivary Biomarkers for Oral Cancer Detection with Untargeted and Targeted Quantitative Proteomics Approaches

Oral cavity squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. In Taiwan, OSCC is the fifth leading cause of cancer-related mortality and leads to 2800 deaths per year. The poor outcome of OSCC patients is principally ascribed to the fact that this disease is often advanced at the time of diagnosis, suggesting that early detection of OSCC is urgently needed. Analysis of cancer-related body fluids is one promising approach to identify biomarker candidates of cancers. To identify OSCC biomarkers, salivary proteomes of OSCC patients, individuals with oral potentially malignant disorders (OPMDs), and healthy volunteers were comparatively profiled with isobaric tags for relative and absolute quantitation (iTRAQ)-based mass spectrometry (MS). The salivary levels of 67 and 18 proteins in the OSCC group are elevated and decreased compared with that in the noncancerous group (OPMD and healthy groups), respectively. The candidate biomarkers were further selected using the multiple reaction monitoring (MRM)-MS and validated with the immunoassays. More importantly, the higher salivary level of three proteins, complement factor H (CFH), fibrinogen alpha chain (FGA), and alpha-1-antitrypsin (SERPINA1) was correlated with advanced stages of OSCC. Our results indicate that analysis of salivary proteome is a feasible strategy for biomarker discovery, and the three proteins are potential salivary markers for OSCC diagnosis.

A combined analysis of maximum standardized uptake value on FDG-PET, genetic markers, and clinicopathological risk factors in the prognostic stratification of patients with resected oral cavity squamous cell carcinoma.

Clinical outcomes of patients with resected oral cavity squamous cell carcinoma (OCSCC) chiefly depend on the presence of specific clinicopathological risk factors (RFs). Here, we performed a combined analysis of FDG-PET, genetic markers, and clinicopathological RFs in an effort to improve prognostic stratification. We retrospectively reviewed the clinical records of 2036 consecutive patients with first primary OCSCC who underwent surgery between 1996 and 2016. Of them, 345 underwent ultra-deep targeted sequencing (UDTS, between 1996 and 2011) and 168 whole exome sequencing (WES, between 2007 and 2016). Preoperative FDG-PET imaging was performed in 1135 patients from 2001 to 2016. Complete data on FDG-PET, genetic markers, and clinicopathological RFs were available for 327 patients. Using log-ranked tests based on 5-year disease-free survival (DFS), the optimal cutoff points for maximum standardized uptake values (SUV-max) of the primary tumor and neck metastatic nodes were 22.8 and 9.7, respectively. The 5-year DFS rates were as follows: SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7 (n = 77) versus SUVtumor-max < 22.8 and SUVnodal-max < 9.7 (n = 250), 32%/62%, P < 0.001; positive UDTS or WES gene panel (n = 64) versus negative (n = 263), 25%/62%, P < 0.001; pN3b (n = 165) versus pN1-2 (n = 162), 42%/68%, P < 0.001. On multivariate analyses, SUVtumor-max ≥ 22.8 or SUVnodal-max ≥ 9.7, a positive UDTS/WES gene panel, and pN3b disease were identified as independent prognosticators for 5-year outcomes. Based on these variables, we devised a scoring system that identified four distinct prognostic groups. The 5-year rates for patients with a score from 0 to 3 were as follows: loco-regional control, 80%/67%/47%/24% (P < 0.001); distant metastases, 13%/23%/55%/92% (P < 0.001); DFS, 74%/58%/28%/7% (P < 0.001); and disease-specific survival, 80%/64%/35%/7% (P < 0.001) respectively. The combined assessment of tumor and nodal SUV-max, genetic markers, and pathological node status may refine the prognostic stratification of OCSCC patients.

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.