Recurrent Oral Squamous Cell Carcinoma Research Articles

Clinical outcomes and prognostic factor analysis after salvage surgery for recurrent squamous cell carcinoma of the oral cavity

The purpose of this study was to analyze the oncological outcomes and predictive factors for successful curative salvage surgery after recurrent oral cavity squamous cell carcinoma. A retrospective study was conducted involving 73 patients who received surgery-based salvage treatment. The pattern of failure for primary treatment was local failure in 29 patients, regional failure in 29 patients, and loco-regional failure in 15 patients. The 5-year overall, loco-regional failure-free, and disease-free survival rates were 54.8%, 58.9% and 49.3%, respectively. Patients with an advanced initial N stage, previous treatment with combined modality therapy, loco-regional recurrence, advanced recurrent T stage, a disease-free survival of less than 8 months prior to salvage, and recurrence in a previously treated field had a significantly worse prognosis. Given the potential surgical morbidity, salvage surgery should be undertaken after careful consultation with patients who have factors for a poor prognosis.

Prognostic impact of intra-field heterogeneity in oral squamous cell carcinoma.

Genetic heterogeneity displayed by tumour cells (intratumoural heterogeneity, ITH) represents a diagnostic challenge when assessing tumour mutational profile. In oral squamous cell carcinoma (OSCC), ITH may be found both in tumour cells and in adjacent mucosa. Genetic heterogeneity of the adjacent mucosa can be interpreted as evidence of the field cancerization (field heterogeneity, FH). The aim of the study was to investigate the impact of intratumoural and intrafield heterogeneity on locoregional control. Ten OSCC patients (5 recurrent and 5 nonrecurrent) were studied. Multiple areas were sampled from the bulk of the tumour and the adjacent nonneoplastic mucosa. A panel of 10 tumour-specific OSCC driver genes was analysed for each sample and was used to calculate heterogeneity. Values were compared among recurrent and nonrecurrent OSCC. Mutational analysis highlighted that a single tumour sample has limited accuracy in assessing the genetic profiles of tumours. High values of ITH considering shared mutations between specimens were found in both recurrent and non-recurrent OSCC (p = 0.095). On the contrary, the intrafield genetic heterogeneity was significantly less frequently in the non-recurrent OSCC group (p = 0.032). Heterogeneity within each specimen calculated with variant allele frequency confirmed that there was better discrimination between recurrent and nonrecurrent groups using nonneoplastic adjacent mucosa than tumour tissue (p value 0.0006 and 0.0048 respectively). In agreement with the theory of field cancerization, intrafield genetic heterogeneity correlates with a higher risk of developing loco-regional recurrences and second primaries. In order to reduce the ITH effects, analysis of multiple tumour areas should be encouraged.

Amino Acids Signatures of Distance-Related Surgical Margins of Oral Squamous Cell Carcinoma

Purpose: Histological assessment of the resected margins is the gold standard for determining the status of surgical margin of oral squamous cell carcinoma (OSCC). However, histological evaluation has significant deficiencies, such as the limitation of the thichness of slide, and other reasons, resulting the higher local recurrence (LR) although the margin status was negative. Many studies have demonstrated metabolic reprogramming in cancer or precancerous cells. Therefore, we aimed to identify a panel of metabolic molecular markers for evaluating the surgical margins of OSCC during the surgery. Experimental Design: A total of 28 cases (each case including Tumor, Margin-1, Margin-2and Margin-3 four sections) were enrolled in the study. 8 of the 28 cases were used for developing markers (Development group), and another 20 cases (Validation group) were used to validate the results of the Development group. Gas chromatography-mass spectrometry (GC-MS) untargeted analysis was used to evaluate the metabolic perturbation of the distance related surgical margins from development group. The acquired MS data of development group samples were further subjected to multivariate data analysis, and the significantly altered metabolites were identii¬ed. UHPLC-MS/MS targeted quantitative analysis was used to validate the results of the development group. Meanwhile, another 60 OSCC patients with dysplastic surgical margins were used to further validate the results of the development group by immunohistochemical exam key enzyme (asparagine synthetase, ASNS) expression, and correlate with clinicopathological parameters and clinical outcomes. Results: In development group, a panel of 10 amino acids was found to discriminate negative margin and another panel of 9 amino acids was found to discern the dysplastic margin. It was further determined 9 amino acids for negative margin biomarkers and 6 amino acids for dysplastic margin biomarkers from above markers (development group) by UHPLC-MS/MS targeted quantitative analysis in validation group. Individual amino acid biomarker for the ability to detect negative margin or dysplastic margin based on ROC curves, displayed good sensitivity and specificity. Moreover, the combination of the panel amino acids can significantly improve sensitivity and specificity of the diagnostic accuracy by multiple linear regressive analysis. Among them, aspartic acid and asparagine were found to be high in dysplastic margin and tumor tissues, so, we examined asparagine synthetase (aspartic acid metabolic key enzyme) expression in 60 OSCC samples with dysplastic margins by IHC analysis, which showed that ASNS positive expression in dysplastic surgical margins was correlated with tumor recurrence and local relapse-free survival (RFS). Conclusions: We developed a panel of amino acid markers to supplement the evaluation of negative and dysplastic margins, ASNS expression level was a predictor of tumor recurrence and poor prognosis in OSCC with dysplastic surgical margins. In conclusion, amino acids signatures of distance-related surgical margins of OSCC has positive clinical significance. Funding: This study was supported by Jiangsu Province’s Key Provincial Youth Talents Program (Grant No. QNRC2016841); Nanjing Municipal Key Medical Laboratory Constructional Project Funding (Since 2012); Center of Nanjing Clinical Medicine Tumor (Since 2014). Declaration of Interest: The authors have declared that no competing interests exist. Ethical Approval: This study was approved by the medical ethics committee of Stomatological Hospital, Medical School of Nanjing University, and carried out according to the recommendations of the Declaration of Helsinki.

Overexpression of AKR1B10 predicts tumor recurrence and short survival in oral squamous cell carcinoma patients.

Aldo-keto reductase family 1 member B10 (AKR1B10) is an enzyme implicated in physiological xenobiotic detoxification and also in pathological carcinogenesis. Overexpression of AKR1B10 has been reported in oral squamous cell carcinoma (OSCC), but its correlation with clinical prognosis is controversial. The aim of this study was to investigate and clarify the role of AKR1B10 in OSCC carcinogenesis. Tumor tissue specimens were surgically obtained from 107 patients with OSCC. The expression of AKR1B10 was analyzed by immunohistochemistry to explore the relationship between the level of AKR1B10 and clinicopathological features of OSCC patients. Kaplan-Meier survival and Cox proportional hazard analysis were used to determine the prognostic value of AKR1B10 in OSCC. High expression of AKR1B10 was found to be associated with tumor size (P=0.043), perineural invasion (P=0.012), and recurrence (P=0.001) in OSCC. Cox model analysis revealed that high expression of AKR1B10 is significantly associated with poor overall and disease-free survival in OSCC patients. With the combination of clinicopathological factors in analysis, we found that the expression level of AKR1B10 was a practical indicator that could categorize OSCC patients into different risk groups. High expression of AKR1B10 was associated with a reduced survival in patients with well and moderately differentiated OSCC and even a high incidence of tumor recurrence in the patients with late-stage (III and IV) disease. We validated and expanded data on the expression of AKR1B10 in OSCC, suggesting that it is a valuable biomarker for prognostic prediction of recurrence and survival in OSCC.

Time to recurrence and patient survival in recurrent oral squamous cell carcinoma

ObjectivesTumour relapse remains one of the major problems in managing oral squamous cell carcinoma (OSCC) with mortality rates of up to 92%. Early recurrences have a worse prognosis than late relapses. However, few has been written about the influence of clinicopathological parameters on the timing of recurrence and the patient survival. Materials and methodsRetrospective chart review of 159 patients with an OSCC recurrent disease. Exclusion criteria were neoadjuvant chemoradiotherapy, follow-up <6 weeks, perioperative death, second primaries and inadequate information on clinicopathological parameters. Statistical analysis was performed using univariate and multivariate analysis. ResultsA significant correlation was found in the χ2-analysis between the timing of recurrence and the margin status (p = 0.020), lymph node ratio (p = 0.030) and grading (p = 0.003) of the primary tumour. In the multivariate survival analysis, the timing of recurrence (p < 0.001), margin status of the primary tumour (p = 0.023), presence of extracapsular spread in the primary tumour (p = 0.003) and performance of a salvage treatment (p < 0.001) were shown to be independent risk factors for overall survival. ConclusionFor patients with a recurrent OSCC, the time to recurrence, margin status, extracapsular spread and the performance of a salvage treatment are independent prognostic factors for overall survival. Furthermore, a significant association exists between the moment of recurrence and the lymph node ratio, the margin status and grading of the primary tumour. This knowledge can allow for the development of individualised surveillance programs and like this, an earlier diagnosis and better second treatment chance in the case of a recurrence.

Combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the initiation and recurrence of oral squamous cell carcinomas by repressing SOX2.

Treatment of oral squamous cell carcinoma (OSCC) remains a challenge because of the lack of effective early treatment strategies and high incidence of relapse. Here, we showed that combined 4SC-202 (a novel selective class I HDAC inhibitor) and INK128 (a selective mTORC1/C2 inhibitor) treatment exhibited synergistic effects on inhibiting cell growth, sphere-forming ability, subcutaneous tumor formation and ALDH1+ cancer stem cells (CSCs) in OSCC. The initiation of OSCC was significantly inhibited by combined treatment in 4NQO-induced rat model. In addition, upregulated SOX2 was associated with advanced and metastatic tumors in OSCC patients and was responsible for the drug-resistance property of OSCC cells. The inhibitory effect of combined treatment on cell viability and ALDH1+ CSCs were attenuated by SOX2 verexpression. Furthermore, combined treatment can effectively overcome chemoresistance and inhibit the growth of recurrent OSCC in vitro and in vivo. Mechanistically, 4SC-202 and INK128 repressed SOX2 expression through miR-429/miR-1181-mediated mRNA degradation and preventing cap-dependent mRNA translation, respectively. These results suggest that combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the carcinogenesis and recurrence of OSCC by repressing SOX2.

KLF4 expression in the surgical cut margin is associated with disease relapse of oral squamous cell carcinoma

The presence of cancer stem-like cells (CSCs) in the majority of tumors is one of the factors responsible for disease relapse in oral squamous cell carcinoma (OSCC). In this study, we investigated the role of octamer-binding transcription factor 4 (OCT4) and Kruppel-like factor 4 (KLF4) in OSCC progression and disease relapse. In this study, 102 patients with OSCC were included. The expression of β-catenin and CSC markers (KLF4 and OCT4) in surgical cut margin and tumor were investigated through Western blot analysis, immunohistochemistry, and quantitative polymerase chain reaction analysis. The χ2 test was used to evaluate the association of β-catenin, OCT4, and KLF4 expression with clinicopathologic characteristics. Kaplan-Meier and Cox regression analyses were performed to correlate different clinical factors with the prognoses of patients with OSCC. We observed increased expression of OCT4, KLF4, and β-catenin in the cut margins (CMs) in recurrent OSCC. The χ2 test exhibited recurrence as one of the key factors associated with high expression of these markers. Kaplan-Meier and COX regression analyses demonstrated that increased expression of KLF4 in the CM region of recurrent patients was independently associated with a poor prognosis. Our findings indicated that expression of KLF4 can be used for monitoring disease progression and may serve as prognostic marker to predict recurrence.

Salvage of Recurrence after Surgery and Adjuvant Therapy: A Multi-institutional Study.

To determine the oncologic outcomes of patients undergoing salvage surgery for recurrent oral cavity squamous cell carcinoma (OCSCC) and oropharyngeal squamous cell carcinoma (OPSCC) after initial treatment with surgery and adjuvant therapy. Retrospective case series with chart review. Five academic tertiary care centers. Patients included those with OCSCC and OPSCC who were initially treated with surgery and adjuvant therapy between 2000 and 2015 and underwent salvage surgery for local and/or regional recurrence. A total of 102 patients were included (76% OCSCC, 24% OPSCC). Five-year overall survival was 31% (95% CI, 21%-41%) and was significantly improved among patients with human papillomavirus-associated oropharyngeal tumors (hazard ratio [HR], 0.34; 95% CI, 0.11-0.98) and significantly worse for those with postoperative positive margins (HR, 2.65; 95% CI, 1.43-4.93). Adjuvant (chemo)reirradiation was not associated with disease control or survival regardless of margin status. Combined locoregional recurrence was significantly correlated with a positive margin resection (HR, 5.75; 95% CI, 1.94-17.01). Twenty-five patients (25%) underwent a second salvage surgical procedure, of whom 8 achieved long-term disease control. Patients presenting with resectable recurrence after initial therapy with surgery and adjuvant therapy have a reasonable salvage rate when a negative margin resection can be attained. Patients with postoperative positive margins have poor survival outcomes that are not significantly improved with adjuvant (chemo)reirradiation. Those with combined locoregional recurrence are at particularly high risk for postoperative positive margins. The functional consequences of salvage surgery and its effect on quality of life are critical in decision making and require further investigation.

MCM 2 a novel marker in predicting recurrence and prognosis at negative surgical margins of oral squamous cell carcinoma

ObjectivesThe treatment failure in Oral carcinoma patients is mainly due to recurrence leading to a poor prognosis. Genetically transformed cells in the adjacent mucosal area thought to be the reason for local recurrences and an invasive tumour front area is known to host the aggressive tumour cells. Hence, the study conducted to quantify and compare proliferative markers Ki-67 and MCM 2 antigens at the margins and invasive tumour front to predict recurrence and prognosis in Oral squamous cell carcinomas. Materials and methodThe study involved paraffin tissue sections of 30 cases of recurrent, and 30 cases of non recurrent Oral squamous cell carcinomas were subjected to Immunohistochemical analysis at negative surgical margins and invasive tumour front (ITF). The mean labelling index (Li) of MCM 2 (Minichromosome Maintenance Protein 2) and Ki-67 was compared among the groups with ‘t’ test to predict the recurrence and overall survival by Kaplan-meier curve and Log-rank test survival estimate. ResultsThe Li of Ki-67 and MCM 2 were higher at negative margin and ITF of recurrent group compared to non recurrent OSCC group with statistically significant difference (P < 0.05) only with MCM 2. Li of MCM 2 at margin and ITF was a better predictor of overall survival than Ki-67. The overall survival was significantly lower in 43.95 months with Li of MCM 2 more than 48.2 at margin. ConclusionMCM 2 is a novel marker at negative margins in predicting the recurrence and survival of Oral squamous cell carcinoma.

Metabolic tumor volume and total lesion glycolysis predict tumor progression and survival after salvage surgery for recurrent oral cavity squamous cell carcinoma.

This study evaluated the prognostic role of Fluorine 18-fluorodeoxyglucose positron emission tomography/CT (18 F-FDG PET/CT) parameters quantitatively measured in patients with recurrent oral cavity cancer. Cox proportional hazards regression analyses were used to assess the associations between quantitative 18 F-FDG PET/CT parameters and other clinicopathological factors and progression-free survival (PFS) and overall survival (OS). All of the 18 F-FDG PET parameters (SUVmax , SUVmean , SUVpeak , metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) were significantly associated with poor PFS and OS outcomes after salvage treatment (P < .01). In multivariate analyses, Karnofsky performance score, recurrence site, MTV, and TLG were independent variables predictive of both PFS and OS (P < .05). High MTV (>8.8 mL) or TLG (>29.4 g) values at recurrent lesions were associated with >5-fold increased risk for tumor progression and mortality after salvage surgery. The PET parameters of MTV and TLG measured at recurrent lesions may predict tumor progression and survival after salvage treatment. This study examined the role of 18 F-FDG PET/CT at recurrent staging for predicting tumor progression and survival in 71 consecutive patients with recurrent oral cavity squamous cell carcinomas. Of 18 F-FDG parameters, metabolic tumor volume and total lesion glycolysis were independent factors predictive of tumor progression and survival after salvage treatment.

Prognostic value of intratumour and intra field heterogeneity rate in predicting second events in oral squamous cell carcinoma

Event Abstract Back to Event prognostic value of intratumour and intra field heterogeneity rate in predicting second events in oral squamous cell carcinoma Andrea Gabusi1*, Davide Bartolomeo Gissi1, Roberto Rossi1 and Luca Morandi1 1 University of Bologna, Department of Biomedical and Neuro-Muscular Sciences - Section of Oral Science, Italy Aim. Improvements in sequencing technologies have revealed that genetic differences among neoplastic cells may reflect clonal expansion and thereby the coexistence of multiple subclones in a single tumour. Prognostic implications of intratumour heterogeneity are not fully understood. Aim of this project was to investigate if the degree of intratumour heterogeneity was related to tumour progression in oral squamous cell carcinoma (OSCC). Materials and Methods. Patients operated for OSCC and attending regular follow up for disease relapse at the Unit of Oral Medicine and Maxillofacial Surgery S.Orsola Hospital, University of Bologna were recruited for the study in order to include both recurrent and non recurrent OSCC. Inclusion criteria: diagnosis of primary tumor of T2-T4 according to the p-TNM classification of tumours, absence of nodal involvement, history of non-smokers, absence of lichenoid inflammation in tumour microenvironment, surgical margin of resection free from neoplasia, Follow up ≥ 3 years after surgical resection. Multiple samples were obtained from each tumour and from related adjacent non neoplastic mucosa. Next generation sequencing for mutational analysis was applied for 10 OSCC tumour specific genes: KRAS ,NRAS, HRAS, BRAF, PIK3CA, TP53, NOTCH1, PTEN , CDKN2A, EGFR. The degree of ITH for OSCC somatic mutations was derived by calculating the heterogeneity rates (HR) of all affected genes and dividing that sum by the number of affected genes not shared by all tumor regions. These values were used to compare the ITH in the group of recurrent and non recurrent OSCCs. Results. HR values between groups were then statistically compared using the non parametric U-Mann-Whitney test for independent samples (IBM® SPSS Software v.21). P value in primary tumours scored 0,095 and did not reach significativity indicating the absence of a statistical difference in the degree of intratumor heterogeneity among the groups of recurrent and non recurrent OSCC.By contrast, U-Mann-Whitney test performed on samples from non neoplastic adjacent mucosa disclosed that non recurrent OSCC tends to exhibit statistically lower values of HR if compared to recurrent OSCCs ( p= 0,032). Discussion. According to our results , in primary tumours, no particular degree of heterogeneity was able to distinguish OSCC with aggressive local behaviors. Genetic instability in tumours may produce heterogeneous subclones but not all subclones may reflect aggressive behaviors. On the other hand, ITH analysis of non neoplastic adjacent mucosa disclosed that non recurrent OSCC tends to exhibit statistically lower values of HR if compared to recurrent OSCCs ( p= 0,032). Fields of less aggressive OSCCs are thus more homogeneous. A prognostic implication of genetic heterogeneity of pre neoplastic field is here documented for the first time.

Loss of CDKN2A and CDKN2B expression is associated with disease recurrence in oral cancer.

Background:Loco-regional recurrence is one of the major reasons for poor prognosis of oral squamous cell carcinoma (OSCC). However, till date, no feasible molecular marker is available to predict the risk of recurrence in OSCC patients.Aim:To evaluate the cell cycle regulatory genes expression and its association with the risk of recurrence in oral cancer patients.Materials and Methods:Transcript level expressions of 47 cell cycle regulatory genes were analyzed in 73 OSCC tumors from buccal mucosa and tongue, 26 adjacent normal samples using real-time polymerase chain reaction. TaqMan low-density array data were analyzed using the DataAssist™ v 3.01. Significantly altered genes within the tumor samples and samples showing recurrence (re-appearance of disease during the follow-up in cases having complete response to initial treatment assessed after 3 months of the treatment) were identified. Further, Kyoto Encyclopedia of Genes and Genomes pathway analysis and The Cancer Genome Atlas (TCGA) online data analysis portal were used to analyze interacting protein and pathways significantly associated with the altered gene.Results:CCNA1, CCNB2, CCND2, CCNE1, CCNF, CDC2, CDK6, CHEK1, and TGFA found to significantly alter in the tumor sample of oral cancer patients, and down-expression of CDKN2A and CDKN2B found to associate with the recurrence of disease in oral cancer patients. TCGA data also showed the loss of CDKN2A and CDKN2B significantly associated with recurrence in head and neck cancer patients.Conclusion:CDKN2A and CDKN2B expression analysis can be used as the prognostic marker for the oral cancer patients. The present method of data analysis helps overcome the limitations and complications of high throughput techniques and thereby increases the opportunity of employing molecular markers in routine clinical management of OSCC.

Downregulation of lncRNA CASC2 promotes the postoperative local recurrence of early oral squamous cell carcinoma.

LncRNA CASC2 plays a role as tumor suppressor gene in different types of human malignancies, while its involvement in oral squamous cell carcinoma (OSCC) is unknown. The present study aimed to investigate the involvement of lncRNA CASC2 in OSCC. In this study, the expression of lncRNA CASC2 in tumor tissues, adjacent healthy tissues, and plasma of 122 OSCC patients as well as in plasma of 52 healthy controls was detected by RT-qPCR. Diagnostic value of lncRNA CASC2 for OSCC was evaluated by ROC curve analysis. Patients were followed up for 5years to record recurrence. LncRNA CASC2 expression vectors were transfected into cells of human OSCC cell lines, and the effects on cancer cell proliferation and miRNA-21 expression were analyzed by CCK-8 assay and RT-qPCR, respectively. We found that CASC2 was significantly downregulated in OSCC patients than in healthy controls. Downregulation of CASC2 distinguished OSCC patients from healthy controls. Local recurrence was observed in 26 out of 122 patients and no distant recurrence was observed during follow-up. Compared with pretreatment levels, plasma levels of CASC2 were significantly increased in patients with local recurrence than in patients without recurrence. Transfection of CASC2 expression vectors led to significantly inhibited tumor cell proliferation and reduced miRNA-21 expression levels. We, therefore, conclude that downregulation of lncRNA CASC2 may participate in the postoperative local recurrence of early OSCC through miRNA-21.

A Retrospective Analysis of the Clinicopathologic Risk Factors for Recurrence in Early Stage Oral Cancer

Objective: Oral squamous cell carcinoma (OSCC) is a life-threatening disease that can cause significant morbidity and mortality. OSCC recurrence occurs frequently, with the rates varying between 12% and 40%, depending on tumor stage. Our aim was to determine association between select clinicopathologic factors and the risk of local recurrence in early-stage OSCC.

Intratumoral Heterogeneity in Recurrent Metastatic Squamous Cell Carcinoma of the Oral Cavity: New Perspectives Afforded by Multiregion DNA Sequencing and mtDNA Analysis

Improvements in sequencing technologies have shown that genetic differences among neoplastic cells can reflect clonal expansion. Intratumor heterogeneity (ITH) has been suggested to explain differences in prognosis and treatment response, indicating that personalized medicine is the goal of the future. This study evaluated ITH in 5 patients with recurrent metastatic oral squamous cell carcinoma (OSCC) and tracked the evolution from non-neoplastic tissue to neoplastic events developing after primary tumor formation. Representative regions were macrodissected from specimens obtained from patients with OSCC of the tongue (n=4) and floor of the mouth (n=1). ITH and tumor evolution were explored by analyzing DNA mutations disclosed by next-generation sequencing of specific driver genes combined with changes in the mtDNA D-loop hypervariable region. Phylogenetic trees were generated employing MAFFT tool with UPGMA/Jukes-Cantor serving as the substitute model. High levels of heterogeneity were observed within and among tumors. ITH emerged as metastatic and recurrent events progressed, but the evolutionary patterns differed. In some patients, specific subclones persisted during tumor relapse. Neighboring tissue also was heterogeneous at the premalignant level. A multiregion approach yielded more representative data than did single samples when tumors were subjected to molecular investigation. Persistent mutations that might be targeted by individualized medicine were thus exposed. Mitochondrial DNA is a useful adjunct tool when studying the phylogenetic evolution of subclones. The clinical implications of "field" heterogeneity should be studied in depth.

Downregulation of DHRS9 is associated with poor prognosis in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) has a high potential for local invasion and nodal metastasis. Therefore, early detection and elucidation of the detailed molecular mechanisms underlying OSCC are essential. Dehydrogenase/reductase member 9 (DHRS9) is downregulated in recurrent OSCC. Although DHRS9 is reported to act as a tumour suppressor in several malignancies, its expression in OSCC cells is unknown. In this study, we examined DHRS9 expression immunohistochemically in specimens from a sample of 98 OSCC patients. Reduced DHRS9 expression was observed in 68 of 98 patients (69.4%) with OSCC. A significant association was found between low DHRS9 expression and local progression (T factor) (p=0.0135). Furthermore, patients with low DHRS9 expression had a significantly poorer prognosis than those with high DHRS9 expression (p=0.0443). In multivariate analysis using the Cox proportional hazards model, decreased DHRS9 expression strongly correlated with worse prognosis. The study findings suggest that DHRS9 might be a useful diagnostic and prognostic marker for OSCC.

Clinical and genetic signatures of local recurrence in oral squamous cell carcinoma

PurposeRecurrent and metastatic Oral Squamous Cell Carcinoma (OSCC) is often incurable. There are large gaps in the understanding of the clinical course, biology and genetic biomarkers of OSCC which could help us identify patients with high-risk of recurrence who may benefit from intensified therapy or novel targeted therapy trials.The purpose of this study was to identify significant clinical, pathological and genomic risk factors for local recurrence in OSCC. Patients and methodsMolecular data sets and clinicopathological characteristics of 159 head and neck carcinoma patients were obtained from The Cancer Genome Atlas (TCGA) data portal and analyzed using the Genome Data Analysis Center and cBioPortal to find significant risk factors for tumor recurrence. ResultsThe local recurrence rate was 24%. OSCC originating from the buccal mucosa composed 13% of all the tumors in the recurrent group, making it a statistically significant risk of recurrence (P value = 0.03). Likewise, positive surgical margins, pathological T staging, and alcohol consumption were found to be significantly associated with recurrence (P value < 0.05).Genetic profiling revealed the top 5 mutated genes (using the MutSigCV analysis). Only one of these genes, CASP8 was the only gene that was significantly altered only in the recurrent group (Q value = 8.7 × 10−11). The fingerprint of 5 mutated genes was found in 97% of the patients in the recurrence group. Moreover, copy number alterations in cytoband 5p15.33, which involved amplification in telomerase reverse-transcriptase (TERT) gene, was found to be significant only in the recurrent group. ConclusionsIn the current study, we found several clinical and genetic characteristics that could define patients with high-risk of OSCC recurrence. This provides a means of identifying patients that may benefit from intensified therapy or novel targeted therapy trials.

What Factors Are Associated With Regional Recurrence After Operative Treatment of Oral Squamous Cell Carcinoma?

A considerable proportion of oral squamous cell carcinoma (OSCC) recurrences involve the neck, which has a substantial impact on prognosis and is poorly understood.The purpose of this study was to analyze clinical and pathologic characteristics of regional recurrence of OSCC and identify possible risk factors. A single-center retrospective cohort study was designed to address the study purpose. All patients who were treated surgically for primary OSCC with or without adjuvant therapy between 2010 and 2015 were considered for inclusion with respect to predefined criteria, and demographic, clinical, and pathologic variables were collected. The lymph node status after primary OSCC treatment (pN) was defined as the predictor variable, and the occurrence of regional recurrence served as the primary outcome variable. Further variables of special interest were the histologic differentiation (G status) of the primary OSCC and the values of the lymph node ratio and log odds of positive lymph nodes. Descriptive, inferential, and appropriate time-dependent (Kaplan-Meier analysis, Cox regression model) statistics were computed. The level of statistical significance was set at P≤.05. The study sample was composed of 171 patients (70 women and 101 men; average age, 62.4years). Neck failure occurred in 18 patients (11%) either in combination with local recurrence (15patients) or in isolation (3 patients).Poor histologic differentiation of the primary tumor was identified as an independent risk factor for regional recurrence. Most neck recurrences manifested in previously unaddressed levels (IV and V). Regional recurrence of OSCC might be associated with specific clinicopathologic parameters of the primary tumor. The importance of these parameters for OSCC prognosis assessment and recurrence prediction should be elucidated in further studies.

PO-382 Differentially methylated sites in histologically negative surgical margins of oral squamous cell carcinoma patients

Introduction Oral squamous cell carcinoma (OSCC) is the most common malignant tumour of the head and neck. The presence of microscopic tumour in surgical margins contributes to increased local recurrence rates and decreased overall survival. However, from 10% to 30% of patients with negative histological margins present locoregional recurrences. Many studies have suggested the presence of epigenetic changes prior to the onset cancer phenotype in the mucosa adjacent to the primary tumour. Thus, the aim of this study was to evaluate the hypermethylation profile of negative surgical margins from patients with OSCC as a prognostic factor for tumour recurrence. Material and methods The methylation profile of 32 cryopreserved histologically negative surgical margins samples was performed using the Illumina Infinium MethylationEPIC BeadChip platform. The patients were divided into the following two groups: a) 16 who developed local recurrence and b) 16 who did not developed local recurrence. The generated data were analysed with RStudio software using the ChAMP (Chip Analysis Methylation Pipeline) package. Results and discussions The majority of patients were male (68.8%), had initial disease (71.9%) and were tobacco users (71%). All samples presented less than 1% of failed probes, so they were all included in the subsequent analyses. Probes that anneal at more than one site in the genome, probes with Single Nucleotide Polymorphisms (SNPs) and/or failed in more than one sample were excluded, leaving 7 80 437 probes for comparison. In the comparative analysis between the groups, 908 CpG sites differentially methylated were identified using p Conclusion Our results demonstrated that patients with negative histological margins have a differentially methylated signature, which is important for the identification of individuals at high risk of developing local recurrence of OSCC, decreasing morbidity and improving survival rates.

Only Time Can Tell. Overlapping Features of Osteoradionecrosis and Recurrent Oral Squamous Cell Carcinoma

Osteoradionecrosis (ORN) is a debilitating complication of chemoradiation therapy for head and neck cancer. ORN is difficult to differentiate from recurrent or progressive cancer, as they may share clinical and imaging characteristics. It is crucial, however, to distinguish between these two conditions, because management is quite different and outcomes depend on timely intervention. We performed a retrospective chart review with the goal of identifying potential clinical and radiological factors helpful in differentiating ORN from recurrent cancer. This retrospective case series examined 10 patients (pts) treated for oral squamous cell carcinoma in the last 2 years who were clinically suspected to have ORN based on physical exam, CT and/or PET imaging. Clinical details, tobacco and alcohol history, cumulative dose of radiation, chemotherapy, radiological appearance, histopathology, final diagnosis, treatment received and outcome were collected. Of the 10 patients, 9 had locally advanced disease at presentation. Six pts were male, and 4 female. Median age was 66 years (range 22-90). Five were ultimately diagnosed with ORN (cohort A) and the rest had progressive/recurrent disease (cohort B). In both cohorts, 3 pts had mandibular involvement, and 2 maxillary. Predominant symptoms were trismus (2 pts each in A and B), oral pain (4 pts each in A and B), spontaneous teeth loss (1 pt each in A and B), and exposed bone or fistula formation (2 pts each in A and B). Median cumulative radiation dose was 6000 cGy in cohort A and 6600 cGy in cohort B. The radiation technique (SBRT, IMRT) did not appear to be associated with either outcome. Time interval between RT and suspicion of ORN was longer in cohort A (13.8 months vs. 7 months). Radiologic features were also similar in cohort A and B, with soft tissue thickening and enhancement being seen in the majority of both ORN and cancer cases. Sclerosis was noted in 1 pt in A, and 2 pts in B. Median Standardized uptake value in the bone suspected to have ORN was 6.95 in cohort A and 6.3 in cohort B. Two pts in cohort B had initial biopsies that were negative for malignancy, but were positive on subsequent biopsies. All 5 pts with ORN are alive with stable or improving clinical status but all 5 pts with recurrent cancer have expired. ORN and recurrent cancer share common clinical and radiologic features. ORN symptoms occurring within a year of completion of radiation should prompt additional work up to rule out recurrence. While biopsy demonstrating malignancy can clearly help differentiate between the 2, a negative result does not rule out recurrence due to sampling issues. Repeated biopsies should be considered in pts who fail to improve with supportive care. It should be noted however that pts can have concurrent ORN and cancer and prioritization of management should be based on a discussion amongst multidisciplinary teams.