Oral Oncology

Second primary cancers in patients with oral cavity cancer included in the Korea Central Cancer Registry Publication date: August 2019 Source: Oral Oncology, Volume 95 Author(s): Seung-Ki Min, Sung Weon Choi, Jiwon Lim, Joo Yong Park, Kyu-Won Jung, Young-Joo Won Abstract Objectives The improved survival of patients with oral cavity cancer (OCC) has generated interest in factors affecting survivorship, particularly among second primary cancer (SPC) patients. This study aimed to assess the incidence, patterns, and risk factors for SPC after OCC treatment in the Korean population. Materials and methods Data from 15,261 patients with OCC (ICD-O: C01–C06) identified between 1993 and 2014 were extracted from the Korean Central Cancer Registry. The standardized incidence ratio (SIR) for SPC after index OCC was calculated, and Poisson regression analysis was performed to evaluate the risk factors for SPC among survivors. Results The overall SIR for SPC among OCC survivors was 1.47 (95% confidence interval [CI] 1.39–1.56). SIR differed by sex (male: 1.51 vs. female: 1.37), age at diagnosis (<45 years: 2.47 vs. 45–64 years: 1.68 vs. ≥ 65 years: 1.10), index OCC subsite (floor of mouth: 1.95 vs. gum: 1.30), follow-up duration (6–23 months: 1.64 vs. 24–59 months: 1.51 vs. 60–119 months: 1.48 vs. ≥ 120 months: 1.24), histological OCC type (salivary gland malignancy: 1.77 vs. squamous cell carcinoma: 1.44 vs. others: 1.47), and radiation history (any: 1.94 vs. no radiation: 1.37). The risk factors for SPC development among OCC survivors included younger age at diagnosis and history of radiation therapy. Conclusion OCC survivors have significantly increased risks of SPCs, exhibiting distinctive site distributions and chronological patterns. These patients would benefit from an SPC surveillance protocol.

Intracellular calprotectin (S100A8/A9) controls epithelial differentiation and caspase-mediated cleavage of EGFR in head and neck squamous cell carcinoma Publication date: August 2019 Source: Oral Oncology, Volume 95 Author(s): Prokopios P. Argyris, Zachary Slama, Chris Malz, Ioannis G. Koutlas, Betty Pakzad, Ketan Patel, Deepak Kademani, Ali Khammanivong, Mark C. Herzberg Abstract Objectives Calprotectin (S100A8/A9) appears to function as a tumor suppressor in head and neck squamous cell carcinoma (HNSCC) and expression in the carcinoma cells and patient survival rates are directly related. We seek to characterize the suppressive role of calprotectin in HNSCC. Aims (1) Investigate changes in S100A8/A9 expression as oral carcinogenesis progresses and (2) determine whether intracellular calprotectin can regulate epidermal growth factor receptor (EGFR), a negative prognostic factor, in HNSCC. Materials and methods Using immunohistochemistry (IHC), S100A8/A9 was analyzed in HNSCC specimens (N = 46), including well-differentiated (WD, N = 19), moderately-differentiated (MD, N = 14), poorly-differentiated (PD, N = 5) and non-keratinizing/basaloid (NK/BAS, N = 8), and premalignant epithelial dysplasias (PED, N = 16). Similarly, EGFR was analyzed in HNSCCs (N = 21). To determine whether calprotectin and EGFR expression are mechanistically linked, TR146 HNSCC cells that are S100A8/A9-expressing or silenced (shRNA) were compared for EGFR levels and caspase-3/7 activity using western blotting and immunofluorescence microscopy. Results In normal oral mucosal epithelium, S100A8/A9 stained strongly in the cytoplasm and nucleus of suprabasal cells; basal cells were consistently S100A8/A9 negative. In PED and HNSCC, S100A8/A9 expression was lower than in adjacent normal epithelial tissues (NAT) and declined progressively in WD, MD, PD and NK/BAS HNSCCs. S100A8/A9 and EGFR levels appeared inversely related, which was simulated in vitro when S100A8/A9 was silenced in TR146 cells. Silencing S100A8/A9 significantly reduced caspase-3/7 activity, whereas EGFR levels increased. Conclusions In HNSCC, S100A8/A9 is directly associated with cellular differentiation and appears to promote caspase-3/7-mediated cleavage of EGFR, which could explain why patients with S100A8/A9-high tumors survive longer.

Oral mucositis in head and neck cancer: Evidence-based management and review of clinical trial data Publication date: August 2019 Source: Oral Oncology, Volume 95 Author(s): Adriana Blakaj, Marcelo Bonomi, Mauricio E. Gamez, Dukagjin M. Blakaj Abstract Oral Mucositis (OM) continues to be an oncologic challenge in the context of antineoplastic therapy for head and neck cancer (HNC) treatment. It is a dose-limiting toxicity of chemotherapy and radiation treatment and negatively impacts quality of life and cancer treatment efficacy. Significant effort in the field of OM has been made to help alleviate its symptoms and its subsequent clinical and economic impact. Despite these advances, the treatment of oral mucositis remains difficult and focuses on palliative measures. There are, however, many promising new biological targets currently undergoing investigation to ameliorate or help prevent the toxicity of OM in HNC. Some of these targets undergoing investigation in phase 2 and 3 clinical trials are further highlighted along with the pathobiology of OM, clinical course, prevention, and management measures.

Priorities of human papillomavirus-associated oropharyngeal cancer patients at diagnosis and after treatment Publication date: August 2019 Source: Oral Oncology, Volume 95 Author(s): Melina J. Windon, Carole Fakhry, Farhoud Faraji, Tanya Troy, Christine G. Gourin, Ana P. Kiess, Wayne Koch, David W. Eisele, Gypsyamber D'Souza Abstract Introduction Little is known regarding how human papillomavirus-positive oropharyngeal cancer (HPV-OPC) patient goals change with treatment. This study evaluates whether patient ranking of non-oncologic priorities relative to cure and survival shift after treatment as compared to priorities at diagnosis. Materials and Methods This is a prospective study of HPV-OPC patient survey responses at diagnosis and after treatment. The relative importance of 12 treatment-related priorities was ranked on an ordinal scale (1 as highest). Median rank (MR) was compared using Wilcoxon matched-pairs signed-rank tests. Prevalence of high concern for 11 treatment-related issues was compared using paired t-test. The effect of patient characteristics on change in priority rank and concern was evaluated using linear regression. Results Among 37 patients, patient priorities were generally unchanged after treatment compared with at diagnosis, with cure and survival persistently ranked top priority. Having a moist mouth uniquely rose in importance after treatment. Patient characteristics largely did not affect change in priority rank. Concerns decreased after treatment, except concern regarding recurrence. Discussion Treatment-related priorities are largely similar at diagnosis and after treatment regardless of patient characteristics. The treatment experience does not result in a shift of priorities from cure and survival to non-oncologic domains over cure and survival. The rise in importance of moist mouth implies that xerostomia may have been underappreciated as a sequelae of treatment. A decrease in most treatment-related concerns is encouraging, whereas the persistence of specific areas of concern may inform patient counseling.

A three-gene expression signature associated with positive surgical margins in tongue squamous cell carcinomas: Predicting surgical resectability from tumour biology? Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Zuzana Saidak, Caroline Pascual, Jebrane Bouaoud, Louise Galmiche, Florian Clatot, Stéphanie Dakpé, Cyril Page, Antoine Galmiche Abstract Objectives Achieving complete tumour resection is one of the main goals of surgery for head and neck squamous cell carcinoma (HNSCC) tumours. Whether biological characteristics of tumours contribute to the surgical resectability and the presence of positive surgical margins (SM) after resection of HNSCC is unclear. We aimed to address this issue. Materials and methods We used data from The Cancer Genome Atlas (TCGA) to relate the SM status of 356 HNSCC tumours covering five major primary locations (tongue, larynx, tonsils, floor of mouth and buccal mucosa) with data from multiple omics approaches (transcriptomic, genomic and proteomic analyses). Results We identified three differentially expressed genes whose expression was significantly associated with the presence of positive SM in tongue tumours (n = 144). The three genes (CCDC66, ZRANB2 and VCPKMT) displayed significantly higher mRNA levels in tongue tumours with positive SM compared to tumours with negative SM. The corresponding gene expression signature identified tongue tumours with a positive SM with high sensitivity and specificity (85% and 76%, respectively, Area Under the Curve (AUC) = 0.84). Tongue tumours with this signature were characterised by a high grade, elevated proliferation levels and a tumour stroma with fewer fibroblasts and endothelial cells. Conclusion Positive SM were found to be strikingly associated with tumour biology in tongue tumours. These findings offer interesting perspectives for biomarker identification and precision surgery in these tumours.

Does increasing the incidence of extracapsular dissection for benign tumors of the parotid correlate with an increased need for revision surgery? Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Konstantinos Mantsopoulos, Sarina K. Mueller, Miguel Goncalves, Mirco Schapher, Michael Koch, Heinrich Iro Abstract Objectives The aim of this study was to investigate the hypothesis of whether extracapsular dissection (ED) of the parotid gland increases the need for revision surgery for benign tumours in comparison to traditional surgical modalities. A further aim of this study was to evaluate and compare the functional outcome of revision procedures after primary ED with other modalities involving the parotid gland in our department. Materials and methods All patients who underwent revision parotid surgery after a primary surgical procedure at a tertiary care hospital (University of Erlangen-Nürnberg) between 2000 and 2016 were included in our study. Data concerning the indication for revision surgery as well as the functional postsurgical outcome were obtained. Results 2465 cases formed our study sample. In total, revision surgery was necessary in 30/2465 cases (1.2%). 1532 patients underwent primary ED, with 17 cases requiring revision (1.1%), whereas 933 cases were managed by means of other facial nerve dissecting surgical modalities, with the indication for revision surgery in 13 cases (1.4%). Our analysis did not reveal a statistically significantly higher need for revision surgery or a higher rate of facial nerve palsies after revision surgery in the group of patients after primary ED. Conclusion The argument in favour of a greater need for revision surgery after primary parenchyma-sparing modalities was not sustained from our data. Due to the low revision rate and the acceptable functional results after revision surgery, we believe that extracapsular dissection is justified in cases where a benign lesion is suspected preoperatively.

Multifocality of papillary thyroid carcinoma as a risk factor for disease recurrence Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Woo Ri Choi, Jong-Lyel Roh, Gyungyup Gong, Kyung-Ja Cho, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim Abstract Objectives Tumor multifocality or bilaterality is associated with increased risk of papillary thyroid carcinoma (PTC) recurrence. However, its prognostic value in clinical outcomes remains controversial. This study aimed to evaluate the association of multifocality or bilaterality with recurrence and survival after total thyroidectomy. Methods This was a retrospective study of 2390 consecutive patients with pathologically confirmed PTC who underwent total thyroidectomy. Multifocality and bilaterality were decided based on the final pathology results, that is, if there were two or more tumor foci and bilateral location, respectively. Primary outcomes were recurrence-free survival (RFS). Cox proportional hazards regression analyses were used to assess the associations of multifocality, bilaterality, and other clinicopathological factors with RFS. Results Multifocal and bilateral PTC were found in 892 (37.3%) and 593 (24.8%) patients, respectively. Multivariate analyses showed that multifocality, lymphovascular invasion, N category, and number of positive lymph node (>5) were significant independent variables predictive of RFS (all P < 0.05). Multifocality was associated with adjusted hazard ratios for RFS of 1.93 (95% confidence interval = 1.33–2.80; P = 0.001). In a subset analysis, the prognostic value of multifocality was found to be significant in those patients with PTC > 1 cm, but not in papillary thyroid microcarcinoma. Conclusions Tumor multifocality is an independent risk factor of PTC recurrence after total thyroidectomy. This indicate a more progressive state of disease, being included in risk stratification.

Prospective clinical trial to evaluate safety and feasibility of using a single port flexible robotic system for transoral head and neck surgery Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Jason Y.K. Chan, Raymond K. Tsang, F. Christopher Holsinger, Michael C.F. Tong, Cherrie W.K. Ng, Philip W.Y. Chiu, Simon S.M. Ng, Eddy W.Y. Wong Abstract Introduction The aim of this study was to determine the clinical safety and feasibility of a novel single-port flexible robot for Transoral Robotic Surgery (TORS). Materials and methods This was a prospective phase II / IDEAL stage 2 clinical trial of both benign and malignant lesions of the head and neck. The primary endpoint included conversion rates and perioperative complications within 30 days following surgery. The study was registered on www.ClinicalTrials.gov (NCT03010813). The Fisher's exact test and Mann-Whitney U test were used to compare categorical, and non-parametric data for the trial. A p value <0.05 was considered to be statistically significant. Statistical analysis was performed with SPSS 20.0 (IBM Corp., Armonk, New York) Results Twenty-one patients safely underwent TORS with the da Vinci SP (Intuitive Surgical Inc., Sunnyvale, CA) demonstrating the feasibility of access to the nasopharynx, oropharynx, larynx and hypopharynx. There were no conversions of the robotic surgical system. There were no serious adverse events or adverse events related to the use of the robot at 30-day follow-up for all patients. Conclusions In a prospective Phase II clinical trial, a novel single-port flexible robotic system appears safe and feasible to use for transoral endoscopic head and neck surgery to access the nasopharynx, oropharynx, larynx and hypopharynx.

Surrogates of immunologic cell death (ICD) and chemoradiotherapy outcomes in head and neck squamous cell carcinoma (HNSCC) Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Panagiota Economopoulou, George Koutsodontis, Areti Strati, Efthymios Kirodimos, Evangelos Giotakis, Pavlos Maragoudakis, Constantine Prikas, Nikolaos Papadimitriou, Christos Perisanidis, Eleni Gagari, Ioannis Kotsantis, Elena Vagia, Maria Anastasiou, Maria Gkotzamanidou, George Kavourakis, Evi Lianidou, Amanda Psyrri Abstract Objectives Chemoradiation can induce immunogenic (ICD) or tolerogenic cell death. ICD relies on the generation of damage-associated molecular patterns which can stimulate toll-like receptors (TLRs). We sought to determine whether we can predict responses to chemoradiation by measuring surrogate biomarkers of ICD in a cohort of patients with locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). Materials and Methods In a cohort of 113 LA HNSCC pts we evaluated expression of TLR4, TLR7 and TLR9 in the EpCAM + circulating tumor cell (CTC) fraction at baseline and after cisplatin chemoradiation. We also quantified changes in chemokines CXCL10, CXCL16 and IL-2R in the serum. Results Seventy three patients had evaluable specimens. Among cases with biomarker assessment at baseline and post treatment, 36.8% had an increase in CXCL10 levels (p = 0.022), 73.7% had an increase in CXCL16 levels (p = 0.002) and 63.8% had an increase in IL2Ra levels (p = 0.032) with treatment. 52.0% of evaluable cases at baseline and post-treatment had an increase in TLR4 levels (p = 0.996), 42.9% had an increase in TLR7 levels (p = 0.042) and 27.7% had increase in TLR9 levels (p = 0.011) with treatment. CXCL10 levels at baseline were significantly associated with PFS and OS (p = 0.010 and p = 0.032, respectively). Conclusions Our results suggest that chemoradiation leads to quantifiable effects in surrogate markers of ICD. These effects may inform trials combining chemoradiation with immune checkpoint inhibitors. In addition, CXCL10 has prognostic effect in pts treated with chemoradiation.

Sex disparities in salivary malignancies: Does female sex impact oncological outcome? Publication date: July 2019 Source: Oral Oncology, Volume 94 Author(s): Ximena Mimica, Marlena McGill, Ashley Hay, Daniella Karassawa Zanoni, Jatin P. Shah, Richard J. Wong, Alan L. Ho, Marc A. Cohen, Snehal G. Patel, Ian Ganly Abstract Objective Previous population-based studies in salivary gland carcinomas have described a relationship between female sex and superior oncological outcome. Patients and methods Our institutional database of 884 surgically treated patients with salivary gland malignancies from 1985 to 2015 was analyzed for the impact of sex on oncological outcomes. Histologies were classified in three risk groups, low, intermediate and high. Survival outcomes were determined using the Kaplan-Meier method. Hazard ratios for male sex were determined using the Cox proportional hazards model. Results Eight hundred sixty-seven patients were identified; median age was 59 years, and 51% had a minor salivary gland malignancy. Female patients were younger (58 versus 60 years; p = 0.040) and had a lower incidence of high-risk histologies (25% versus 40%, p < 0.001) and T3-T4 tumors compared to men (23% versus 31%, p < 0.001). With a median follow-up of 57 months, female patients had a superior 5-year disease-specific survival (DSS) (90% versus 79%; p < 0.001). The unadjusted hazard ratio showed male patients had a 2.15-fold increased risk of death (HR 2.15; 95% CI, 1.50–3.06, p < 0.001). After adjusting for Charlson comorbidity index, tobacco use, histological risk group, and overall pathological stage, males still had a statistically significant increased risk of death (HR 1.48; 95% CI 1.05–2.17; p = 0.047). Subgroup analysis showed DSS for females was significantly better in the high-risk histological group (5-year 68% versus 49%, p = 0.007). Conclusion Our study shows that sex has an impact on cancer-specific survival and that female sex favors improved survival.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
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6948891480

alsfakia@gmail.com