Recurrent Oral Squamous Cell Carcinoma Research Articles

Salvage brachytherapy with or without external beam radiotherapy for oral or oropharyngeal squamous cell carcinomas in previously irradiated areas: carcinologic and toxicity outcomes of 25 patients.

PurposeThe aim of this study was to assess outcomes of salvage brachytherapy for oral and oropharyngeal squamous cell carcinoma in previously irradiated areas.Material and methodsThis was a retrospective study with 25 patients, treated between 1997 and 2016 for primary (21 cases) or recurrent (4 cases) oral or oropharyngeal squamous cell carcinomas in previously irradiated areas. Fifteen patients were treated with salvage brachytherapy (BT) alone, while 10 patients additionally received external beam radiotherapy (EBRT). Median BT dose was 45 Gy (range, 15-64 Gy), and a median total cumulative dose was 57 Gy (range, 40-70 Gy). Patient age, tumor stage, radiotherapy dose, and time between first treatment and recurrence were analyzed as prognostic factors.ResultsMedian overall survival (OS) was 16 months. Patients with less advanced (T1) tumors survived significantly longer (27 vs. 14.5 months, p = 0.046). Five patients experienced a local recurrence, and only one of them was treated with a total dose greater than 60 Gy. In multivariate analysis, patients with T1 lesions had a significant higher OS rate compared to patients with larger lesions (HR = 6.25, 95% CI: 1.18-33.1%, p = 0.031). Patients who received more than 60 Gy had a non-significant, 80% increased OS than those treated with a lower dose (p = 0.072). There was four grade 3 acute toxicities, and no grade 3 or more late toxicities.ConclusionsMultimodal treatment, including salvage BT, may offer a curative option for selected patients with an acceptable risk of severe toxicity for the treatment of primary or recurrent tumors in previously irradiated areas.

Increased Expression of SHMT2 Is Associated With Poor Prognosis and Advanced Pathological Grade in Oral Squamous Cell Carcinoma.

This study focused on the expression of mitochondrial serine hydroxymethyltransferase (SHMT2) in oral squamous cell carcinoma (OSCC) and its correlation with clinical traits and the prognosis of OSCC patients. Immunochemical staining and Western blotting were used to quantify the expression of SHMT2 and related immune markers in OSCC. Using OSCC microarrays and The Cancer Genome Atlas (TCGA) database, we evaluated the association between SHMT2 and various clinical traits. We found that increased expression of SHMT2 was detected in OSCC and correlated with advanced pathological grade and recurrence of OSCC. By a multivariate Cox proportional hazard model, high expression of SHMT2 was shown to indicate a negative prognosis. In addition, in the OSCC microenvironment, increasing the expression of SHMT2 was associated with high expression levels of programmed cell death-ligand 1 (PD-L1), CKLF-like MARVEL transmembrane domain containing 6 (CMTM6), V-type immunoglobulin domain-containing suppressor (VISTA), B7-H4, Slug, and CD317. In the future, more effort will be required to investigate the role of SHMT2 in the OSCC microenvironment.

Metformin reduces the increased risk of oral squamous cell carcinoma recurrence in patients with type 2 diabetes mellitus: A cohort study with propensity score analyses

BackgroundTo investigate the impact of type 2 diabetes mellitus (T2DM) and metformin treatment on the prognosis of oral squamous cell carcinoma (OSCC) patients received radical surgical treatment. MethodsEight hundred and fifty-two patients with OSCC between January 2011 and January 2015 were included in the cohort study. Propensity score analysis was used to balance the characteristics of patients with or without T2DM and those of patients with T2DM treated with or without metformin. Five-year OSCC-free survival (OFS) was used to evaluate the prognosis of OSCC patients. ResultsTwo hundred and sixty-nine patients without T2DM and 138 patients with T2DM were selected after the propensity score matching. The 5-year OFS of patients with T2DM was significantly lower than that of those without T2DM, both before (P = 0.019) and after (P = 0.014) the propensity score matching. Forty-four metformin users of OSCC patients with T2DM and 44 patients never users were further compared after the propensity score matching. The 5-year OFS of metformin users was significantly higher than that of metformin never users both before (P = 0.005) and after (P = 0.002) the propensity score matching. ConclusionsT2DM is associated with a higher risk of OSCC recurrence that can be reduced by metformin treatment.

Effect of Fluorescence Visualization–Guided Surgery on Local Recurrence of Oral Squamous Cell Carcinoma

High local recurrence rates with aggressive disease remain the main concern in oral cancer survival. Use of a translational device using fluorescence visualization (FV) approved by the US Food and Drug Administration and Health Canada, has shown a marked reduction in the 3-year local recurrence rate of high-grade oral lesions in a single-center observational study. To determine whether FV- guided surgery can improve local control rates in the treatment of in situ or T1 to T2 category oral squamous cell carcinoma (OSCC). A multicenter randomized clinical trial was conducted in a surgical setting. A total of 457 patients were enrolled between January 18, 2010, and April 30, 2015. Data analysis of the intention-to-treat population was performed from April 3, 2019, to March 20, 2020. Patients with histologically confirmed high-grade dysplasia/carcinoma in situ or T1 to T2 category OSCC were randomized to receive traditional peroral surgery or FV-guided surgery. Fluorescence visualization during surgery. The primary outcome was local recurrence of OSCC. Secondary outcomes were failure of the first-pass margin, defined as a histologically confirmed positive margin for severe dysplasia or greater histologic change of the main specimen (ie, not the margins taken from the resection bed), regional or distant metastasis, and death due to disease. Of the 457 patients enrolled in the study, 443 patients (264 [59.6%] men; mean [SD] age, 61.5 [13.3] years) completed the randomized treatment: 227 FV-guided and 216 non-FV guided surgery. The median follow-up was 52 (range, 0.29-90.8) months. In total, 45 patients (10.2%) experienced local recurrence. The 3-year local recurrence rate was 9.4% in the FV-guided group and 7.2% in the non-FV group (difference, 2.2%; 95% CI, -3.2% to 7.4%). Other similarities between the FV vs non-FV groups included failure of first-pass margin (68/227 [30.0%]) vs 65/216 [30.1%]), regional failure (39/227 [17.2%] vs 37/216 [17.1%]), disease-specific survival (23/227 [10.1%] vs 19/26 [8.8%]), and overall survival (41/227 [18.1%] vs 38/216 [17.6%]) were also similar between groups. No adverse events were judged to be related to the intervention. In this randomized clinical trial, FV-guided surgery did not improve local control rates in the treatment of patients with in situ or T1 to T2 category oral cancer. Under a controlled environment, FV-guided surgery did not have an evident effect in reduction of local recurrence for localized OSCC. This result suggests that attention be directed to strategies other than improving definitions of nonapparent disease at clinical margins to identify the sources of local recurrence. ClinicalTrial.gov Identifier: NCT01039298.

Overexpression of RRM2 is related to poor prognosis in oral squamous cell carcinoma.

Ribonucleotide reductase M2 (RRM2) is a rate-limiting enzyme involved in DNA repair and synthesis. This study aimed to investigate the expression level, clinicopathological significance, and prognostic value of RRM2 in oral squamous cell carcinoma (OSCC). Human OSCC tissue microarrays were used to detect the expression of RRM2, cancer stem cell (CSC) markers CD44 and aldehyde dehydrogenase 1 (ALDH1), and the epithelial-mesenchymal transition (EMT) marker Slug. The correlation of RRM2 expression with clinicopathological parameters was evaluated. The effects of RRM2 on cell proliferation, migration, and apoptosis were investigated. Compared with normal and dysplastic tissues, the expression of RRM2 in human primary OSCC was significantly increased, and its overexpression was correlated with advanced pathological grade. The overall survival rate of patients with high RRM2 expression was lower than that of patients with low RRM2 expression. The overexpression of RRM2 was significantly associated with OSCC recurrence, and its overexpression was correlated with the CSC markers CD44 and ALDH1 and the EMT marker Slug. The expression of RRM2 promotes the proliferation and migration of human OSCC cells and inhibits apoptosis. Ribonucleotide reductase M2 may be a novel target in the diagnosis, prognosis, and therapy of OSCC.

Sarcomatoid variant of squamous carcinoma in recurrent and second primary tumors of the oral cavity.

Sarcomatoid variant of oral squamous cell carcinoma (OSCC) is aggressive tumors that frequently recur and metastasize. Our aim was to determine the survival outcomes and factors that predict its incidence in recurrent and second primary tumors (SPT). We retrospectively analyzed the records of SPT and recurrent OSCC cases with sarcomatoid differentiation. The overall survival (OS) and disease-free survival (DFS) were determined by the Kaplan-Meier method. Logistic regression was used to identify the factors associated with SPT and recurrent sarcomatoid OSCC. Recursive partitioning was performed to classify the sample based on the clinicopathological factors of the index tumor. A total of 82 patients were included in the study with a median survival, calculated from the date of diagnosis of recurrence or SPT, of 6months (recurrence-2months, SPT-8months). The 3-year OS for the recurrence group was 19.9% and for SPT group was 29%. Perineural invasion in the index tumor was significantly associated with sarcomatoid differentiation in the recurrent tumor. At one end of the spectrum of the recursive partitioning were the SPTs that had small index tumor sizes and DOI/thickness less than 14.5cm (lowest risk), and at the other end were recurrent diseases that had index tumors of advanced T stage (highest risk). Sarcomatoid variant in the recurrent/SPT OSCC infers a poor prognosis. Recurrent disease that had an index tumor with advanced T stage carries the worst outcomes. Perineural invasion in the index tumor can help predict the presence of sarcomatoid carcinoma in the recurrent or SPT.

Hypermethylated PAX1 and ZNF582 genes in the tissue sample are associated with aggressive progression of oral squamous cell carcinoma.

DNA methylation of paired box gene 1 (PAX1) and zinc finger 582 (ZNF582) is promising cancer biomarkers for oral squamous cell carcinoma detection. This study aims to investigate the correlation between PAX1 or ZNF582 methylation and the progression of oral squamous cell carcinoma (OSCC). A total of 135 OSCC cases from Peking University School and Hospital of Stomatology were enrolled in this study. Tissue specimens were collected from the lesion site and corresponding adjacent normal site. The methylation level of these two genes was evaluated in primary and recurrent OSCC group. Hypermethylation of PAX1 or ZNF582 was observed in lesion sites among primary and recurrent OSCC cases. In the lesion site of primary cases, promoter methylation was observed in T3/T4 (PAX1: P=.02; ZNF582: P=.01), stage III/IV (PAX1: P=.03; ZNF582: P=.01), and bone invasion cases (PAX1: P=.02; ZNF582: P=.047). In the subgroup analysis, the correlation between hypermethylation and OSCC severity remains significant with exposure to smoking/alcohol consumption. Hypermethylated PAX1 and ZNF582 can sufficiently act as biomarkers to reflect the severity or progression of OSCC.

Salvage surgery with second free flap reconstruction for recurrent oral squamous cell carcinoma

PurposeThe purpose of this study was to evaluate the results of the reconstruction using the second free flap following resection of recurrent oral squamous cell carcinoma(OSCC). Patients and methodsA total of 25 patients from 2005 to 2018 who had undergone salvage surgery and reconstruction using the second free flap for recurrent OSCC were included in this study. Medical records were reviewed to obtain demographic data, stages of the primary cancer, region of recurrent OSCC, the period until recurrence, type of the second reconstruction flaps, recipient vessels, survival rate of the flaps and 2- and 5-year survival rates. ResultsThe patients were 13 males and 12 females. The average age was 64.1 years. Of the stages of primary cancer, stage IV patients accounted for the largest number with 13 patients (52.0%). The region of recurrent OSCC was the largest in the mandible with 13 patients, followed by 5 patients in the tongue and 4 patients in the buccal mucosa and maxilla. The mean time interval between the first and second reconstruction was about 34.1 months. Latissimus dorsi free flap and radial forearm free flap used in the second reconstruction were most frequently used in 11 patients (35.5%), followed by fibular composite free flap with 6 patients (19.4%). Facial artery in the recipient arteries of the second reconstruction was most frequently used with 13 cases (43.3%), followed by superior thyroid artery with 8 cases (26.7%) and lingual artery with 7 cases (23.3%). In the second free flap reconstruction, survival rate of the flaps was 96.8%. The 2- and 5-year survival rates in the patients were 70.0% and 62.5%, respectively. ConclusionThe study showed that the second free flap reconstruction with salvage surgery in resectable recurrent OSCC is a safe and reliable method with a high success rate of the flap and improvement of the 5-year survival rate.

Are the demographics of recurrent oropharyngeal and oral cavity squamous cell carcinoma changing?

e18537 Background: In the current era of human papillomavirus (HPV)-related oropharyngeal cancer and decreasing alcohol and tobacco use, the demographic factors associated with recurrent head and neck cancer may be evolving. We evaluated clinical and demographic factors in a cohort of patients with recurrent and non-recurrent Oral Cavity (OC) and Oropharyngeal Squamous Cell Carcinoma (OPSCC) in order to evaluate which factors are associated with tumor recurrence and how these factors are modified by HPV status. Methods: From a cohort of 3201 patients diagnosed with OC and OPSCC at Kaiser Permanente Northern California between 1/1/2008 and 6/30/2019, 235 recurrent cases were identified. Clinical and demographic factors were extracted from electronic medical records. We calculated frequencies of demographic and clinical factors stratified by recurrence and HPV status, and reported p-values using the chi-square test for independence. Results: HPV-related cases were more likely to be male (84% vs. 64%), younger (80% ≤70 years old vs. 55%), have fewer comorbidities (61% with non-cancer Charlson index < 1 vs. 47%), and higher cancer stage (88% with a stage > 1 vs. 42%) than HPV-unrelated cases. Recurrent HPV-unrelated cases were more likely to be Asian (14% vs. 8%), and from higher income census tracts (75% from tracts with median household income > $60,000 vs. 66%) than recurrent HPV-related cases. Chi-square p-values of < 0.001. Recurrence and HPV status did not appear to be associated with prior smoking and alcohol abuse. Conclusions: Our cohort verifies that HPV-related OPSCC patients are more likely to be younger, male, and with lower Charlson scores, while recurrent HPV-unrelated OC and OPSCC may be more common among Asians and individuals from higher-income census tracts. This may have important implications for future clinical trial design and surveillance for recurrence. [Table: see text]

Survival for oropharyngeal and oral cavity cancer patients based on time to recurrence and HPV status.

e18544 Background: It is unknown whether patients with recurrent oral cavity (OC) or oropharyngeal squamous cell carcinoma (OPSCC) have improved survival if the recurrence occurs beyond one year. We analyzed a cohort of recurrent OC/OPSCC patients to study survival outcomes stratified by time to recurrence and human papillomavirus (HPV) status. Methods: From a cohort of 3201 OC/OPSCC patients initially diagnosed between 1/1/2008 and 6/30/2019, 235 recurrent cases were identified. Time from the end of treatment until first recurrence was ascertained by chart review. HPV status was determined by HPV testing or based on anatomical site. Overall survival (OS) rates and median OS time after diagnosis of recurrence was evaluated across the time-to-recurrence and HPV groups using the Kaplan-Meier method. Differences in the survival curves tested for using the log-rank test. Results: 130 (56%) of the recurrent tumors recurred <1 year after end of treatment, and 104 (44%) ≥1 year. Patients with HPV-related tumors that recurred beyond one year had the best survival, with two-year OS at 0.62 (95% CI: 0.42-0.76), while patients with non-HPV related tumors that recurred <1 year had the worst survival, two-year OS of 0.38 (95% CI: 0.28-0.48). HPV-related tumors that recurred <1 year had roughly similar survival (two-year OS of 0.45, 95% CI: 0.30-0.59) to non-HPV-related tumors that recurred < 1 year (two-year OS of 0.51, 95% CI: 0.38-0.62). The log-rank test for difference in survival across time-to-recurrence and HPV groups was significant at p=0.03. Conclusions: In our cohort, patients with HPV-related head and neck cancer with recurrence ≥1 year had improved survival compared to all other recurrent head and neck cancer patients. In addition, our findings suggest that patients with HPV-related head and neck squamous cell carcinoma who recur prior to 12 months have long-term survival similar to patients with HPV-unrelated cancers. This has important implications for clinicians treating patients with recurrent head and neck cancer and may help guide the design of future clinical trials. [Table: see text]

The role of routine surveillance imaging in detecting oral cavity cancer recurrence in asymptomatic patients.

e18561 Background: The optimal surveillance approach for patients who were definitively treated for oral squamous cell carcinoma (OSCC) is unclear, but it includes physical exams (PE) and surveillance imaging (SI) studies at intervals that vary amongst institutions. At our institution, patients are seen in office and underwent PE monthly for the first 3-6 months then every 3 months thereafter. SI is performed every 3 months during the first 2 years, every 6 months till year 4, and yearly thereafter. Concerning symptoms or findings resulting from PE or SI may trigger further tests including biopsies as deemed necessary by treating team. In this study, we investigated value of SI in detecting recurrence of OSCC. Methods: Retrospective chart review was performed for the patients who were diagnosed with OSCC from 2014 to 2017 at our institution. Eligible patients included those who underwent definitive treatment (surgery, chemotherapy, radiation) of OSCC with curative intent. Patients without evidence of disease on post treatment imaging were included. Results: Two hundred OSCC patients were treated definitively. 138 (69%) patients had local disease and 62 (31%) patients had regional disease. 183 patients (%) had no clinical evidence of disease on post treatment baseline imaging. Patients who had residual disease on post-to scab were excluded from further analysis. The median follow-up was 29 months. 2-year overall survival was 87.4%. 82 patients underwent biopsy for suspicious findings and 44 patients had confirmed recurrence. 37 (84.1%) of the recurrences occurred in the first two years. 28 (63.6%) of recurrences were local, 13 (29.5%) were regional and 3 (6.8%) were metastases. 31 (70.6%) of patients with disease recurrence presented with clinical symptoms or had suspicious findings on PE. 13 (29.4%) of the recurrences were detected by SI alone (PPV=54.2 %) in asymptomatic patients most of which (92.3%) occurred within first 2 years. Conclusions: Majority of OSCC recurrence were detected due to clinical symptoms or positive findings on PE. However, 29.4% of recurrences were detected by SI alone in asymptomatic patients suggesting a role for SI for the first 2 years post-treatment of OSCC. Larger prospective studies are needed to determine the optimal frequency of SI.

Oral Squamous Cell Carcinoma and the Cutting Edge of Nanotechnology

Introduction: Cancer is a group of diseases characterized by uncontrolled cellular growth or proliferation. Oral squamous cell carcinoma (OSCC) is a group of cancers mainly affecting the buccal cavity and associated area, with high rate of mortality and morbidity. Chronic consumption of alcohol, both smoking and smokeless tobacco, and betel quid are considered as the prominent determinants for the initiation and development of OSCC. The current treatment strategy of OSCC is associated with the common side effects of non-specific anticancer drug delivery. In addition, the treatment also deals with the recurrence of OSCC after completion of the therapy, which is responsible for its high mortality rate. Nanotechnology is an emerging discipline in drug delivery, disease diagnosis, and imaging. Nanoparticles are a group of colloidal carriers with approximately 1-1000 nm size range. Nanoparticles, due to large surface area to volume ratio, display different physicochemical characteristics favorable for their use in chemotherapy. The nanoparticles with options for modifications in theirsizes, surface charges, drug payload, and drug bioavailability can be used as a drug delivery system. The dynamic and flexible nature of nanoparticles can be employed to both active and passive targeting of cancer cells combating the usual side effects as well as other complexities associated with the conventional chemotherapy. Conclusions: The nanoparticles can be regarded as the future of drug delivery in cancer therapy.

Immunoexpression of p53 and ki-67 correlated with clinicopathological parameters in predicting recurrence of oral squamous cell carcinoma

Background: Prognosis of oral squamous cell carcinoma (OSCC) can be predicted by evaluating both clinicopathological parameters and molecular markers. Understanding the reasons of recurrence is important to increase the morbidity and mortality of the patient.
 Objectives: The objectives are to study the immunoexpression of p53 and Ki-67 in recurrent and non recurrent OSCC. And correlate the clinicopathological parameters among non-recurrent and recurrent OSCC to predict the prognosis of OSCC.
 Methods: Clinicopathological and immunoexpression of p53 and Ki-67 at the histologically negative margin (HNM) and invasive tumor front (ITF) were assessed in 50 cases of non-recurrent and recurrent OSCC. Overall survival and disease free survival was estimated. Statistical tests like Mann Whitney U test, t Test, Pearson correlation coefficient, Kaplan Meier curve and Log Rank test were used.
 Results: The Labelling Index (LI) of p53 and Ki-67 was marginally higher in recurrent than in non-recurrent OSCC cases. When compared with clinicopathologic parameters, non-recurrent OSCC cases showed no significance with p53 LI in margin and ITF except for site, muscle invasion, pattern of invasion (POI) and muscle invasion, whereas in recurrent OSCC cases p53 LI in HNM and ITF did not show any statistical significance except for duration. In both groups, OS and DFS was higher in patients with lesser LI while higher in the greater LI but more number of deaths occurred in this category respectively.
 Conclusion: To conclude p53 and Ki-67 positivity in the HNM and ITF of non-recurrent and recurrent OSCC was seen and thus can be an important marker for identification of high and low risk individuals.

A Phase 2 Trial of Chemoradiation Therapy Using Weekly Docetaxel for High-Risk Postoperative Oral Squamous Cell Carcinoma Patients

To evaluate the efficacy and safety of postoperative concurrent chemoradiation therapy using weekly docetaxel in patients with high-risk oral squamous cell carcinoma (OSCC). This is a prospective single-arm study from a single institute in Shanghai Ninth People's Hospital, Shanghai, China. Patients with locally stage III to IV OSCC who underwent radical surgery with at least 1 high-risk feature were enrolled for the study. High-risk features evaluated included (1) pathologically confirmed positive or close margins in the primary site or extracapsular nodal extension; (2) histologic involvement of ≥2 regional lymph nodes; and (3) locoregional recurrent OSCC (after initial surgery alone) treated with salvage surgery with curative intent. Docetaxel was administered at a dose of 20 mg/m2 concurrently with postoperative radiation therapy (total dose 60-66 Gy). The primary outcome was 2-year disease-free survival (DFS). Secondary endpoints included 2-year locoregional progress-free survival, 2-year overall survival (OS), and toxicities. From March 2016 to February 2018, 91 patients (59 males, 32 females) were recruited. Median age was 59 years (range, 26-70). All patients were included in final analysis. Fifty-eight patients (63.7%) completed the 6 planned cycles of docetaxel, and all patients completed postoperative radiation therapy. With a median follow-up of 24 months, the 2-year DFS and OS were 75.3% (95% confidence interval, 65.7%-84.2%) and 82.4% (95% confidence interval, 73.0%-89.6%), respectively. Patterns of failure were 13 local recurrences, 2 regional lymph nodes recurrences, and 8 distant failures. Seven patients (7.7%) were recorded as having grade 3 oral cavity mucositis. Two patients had grade3hypersensitivity reaction. No other grade 3 or higher adverse events, including hematologic toxicities, were observed. The addition of low-dose weekly docetaxel with concurrent radiation therapy is a tolerable regimen with favorable DFS and OS in patients with high-risk, resected OSCC.

RP11-874J12.4 promotes oral squamous cell carcinoma tumorigenesis via the miR-19a-5p/EBF1 axis.

Oral squamous cell carcinoma (OSCC) ranks as the fifth most frequent cancer worldwide, and the recurrence and migration of OSCC still pose large threats to patients. Long non-coding RNAs (lncRNAs) have recently emerged as crucial players in cancer development, and it is of great significance to understand the regulatory nexus of lncRNAs in OSCC. Here, we identified a novel lncRNA, RP11-874J12.4, which is ectopically expressed in OSCC and facilitates OSCC. RP11-874J12.4 directly binds to and regulates miR-19a-5p. Interestingly, RP11-874J12.4 and miR-19a-5p form a negative regulatory loop that inhibits the expression of miR-19a-5p in OSCC. The expression of an oncogenic transcription factor, EBF1, is unleashed in OSCC due to the low expression of miR-19a-5p, which promotes the growth and migration of OSCC. Our data illustrate a regulatory axis of RP11-874J12.4/miR-19a-5P/EBF1 and an inhibitory loop with RP11-874J12.4 and miR-19a-5p. These data provide insights into the tumorigenesis of OSCC and the novel drug targets for OSCC.

A 4-gene signature from histologically normal surgical margins predicts local recurrence in patients with oral carcinoma: clinical validation

Prognostic biomarkers for recurrence of Oral Squamous Cell Carcinoma (OSCC) are urgently needed. We aimed to independently validate a 4-gene expression signature (MMP1, COL4A1, P4HA2, THBS2) predictive of OSCC recurrence risk. Gene expression was measured using Nanostring nCounter® in 245 histologically normal surgical resection margins from 62 patients. Association between risk scores for individual patients and recurrence was assessed by Kaplan-Meier analysis. Signature performance was quantified by concordance index (CI), hazard ratio (HR) and the area under receiver operating characteristics (AUC). Risk scores for recurrence were significantly higher than recurrence-free patients (p = 9.58e-7, Welch’s t-test). A solid performance of the 4-gene signature was determined: CI = 0.64, HR = 3.38 (p = 1.4E-4; log-rank test), AUC = 0.71. We showed that three margins per patient are sufficient to preserve predictive performance (CI = 0.65; HR = 2.92; p = 2.94e-3; AUC = 0.71). Association between the predicted risk scores and recurrence was assessed and showed HR = 2.44 (p = 9.6E-3; log-rank test, N = 62). Signature performance analysis was repeated using an optimized threshold (70th percentile of risks), resulting in HR = 3.38 (p = 1.4E-4; log-rank test, N = 62). The 4-gene signature was validated as predictive of recurrence risk in an independent cohort of patients with resected OSCC and histologically negative margins, and is potentially applicable for clinical decision making on adjuvant treatment and disease monitoring.

LncRNA SNHG17 promotes the progression of oral squamous cell carcinoma by modulating miR-375/PAX6 axis.

The prognosis of patients with recurrent and/or metastatic oral squamous cell carcinoma (OSCC) remains poor, and its incidence is especially high in developing countries. Multiple long non-coding RNAs (lncRNAs) are recently identified as crucial oncogenic factors or tumor suppressors. This study aimed to probe into the role of lncRNA small nucleolar RNA host gene 17 (SNHG17) on the progression of OSCC. The expression level of SNHG17 in OSCC samples was tested using quantitative real-time polymerase chain reaction (qRT-PCR). Human OSCC cell lines CAL-27 and Tca8113 were used in in vitro studies. Cell counting kit-8 (CCK-8) and BrdU assays were used to assess the effect of SNHG17 on OSCC cell proliferation. Flow cytometry was used to study the effect of SNHG17 on OSCC cell apoptosis. Transwell assay was conducted to detect the effect of SNHG17 on migration and invasion. Moreover, luciferase reporter assay was employed to confirm targeting relationship between miR-375 and SNHG17. Additionally, Western blot was used to observe the regulatory function of SNHG17 on PAX6. SNHG17 expression in OSCC clinical samples was significantly increased and was correlated with unfavorable pathological indexes. Its overexpression remarkably accelerated proliferation and metastasis of OSCC cells, while reduced apoptosis. Accordingly, knockdown of SNHG17 suppressed the malignant phenotypes of OSCC cells. Overexpression of SNHG17 significantly reduced the expression of miR-375 by sponging it, but enhanced the expression of PAX6. SNHG17 is a sponge of tumor suppressor miR-375 in OSCC, enhances the expression of PAX6 indirectly, and functions as an oncogenic lncRNA.

Immunoexpression of p53 in histologically negative surgical margins adjacent to oral squamous cell carcinoma:A preliminary study

The prognostic significance of genetic changes occurring in the histologically negative surgical margins (HNMs) has been focus of various studies recently. Since p53 is the most frequently observed genetic alteration found in oral squamous cell carcinoma (OSCC), we hypothesized that a similar variation might be evident in HNMs as well. Literature is scarce regarding comparison of expression of p53 in the tumor tissue and its adjacent HNMs; hence, the aim of the present study was to study p53 immunoexpression in OSCC and its HNMs. We included 12 paraffin-embedded tissue blocks of OSCC having tumor tissue and HNMs. The samples were subjected to immunohistochemical staining using primary mouse monoclonal antibody against p53, and the stained slides were evaluated for staining intensity and percentage of expression. Descriptive analysis and Chi-square test were applied. The expression of p53 was observed in 66% of HNMs and 91.6% of tumor tissue. The three cases which showed local recurrence demonstrated the expression of p53 in HNM. Hence, molecular analysis of p53 in surgical margins might potentially predict local recurrence of OSCC.

Non-SMC Condensin I Complex Subunit H (NCAPH) Is Associated with Lymphangiogenesis and Drug Resistance in Oral Squamous Cell Carcinoma

Background: Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth most common malignancy. OSCC has strong invasive ability, and its malignant potential is closely associated with local expansion and lymph node metastasis. Furthermore, local or nodal recurrence worsens OSCC prognosis. In our previous cDNA microarray analysis, non-structural maintenance of chromosome (SMC) condensin I complex subunit H (NCAPH) was identified as an upregulated gene in recurrent OSCC. Although NCAPH has several functions in tumors, its role in OSCC is unknown. Methods: In this study, we examined NCAPH expression in OSCC and performed a functional analysis of human OSCC cells. Results: NCAPH expression was higher in OSCC than in normal oral mucosa. In immunohistochemistry using 142 OSCC specimens, the immunostaining of NCAPH was strongly associated with nodal metastasis and lymphatic infiltration. In multivariate analysis using the Cox proportional hazards model, NCAPH expression was an independent poor prognostic indicator for OSCC. Moreover, NCAPH promoted the migration and adhesion of endothelial cells to OSCC cells and promoted the resistance to platinum anticancer drugs. Conclusions: Our present findings suggest that NCAPH is a novel diagnostic and therapeutic target in OSCC.

Alpha DaRT: Revolutionary Alpha-Emitters Brachytherapy

Diffusing Alpha-emitters Radiation Therapy (‘Alpha DaRT’) is a revolutionary new cancer treatment modality, which enables – for the first time - the treatment of solid tumors by alpha particles. The basic idea is to insert into the tumor an array of implantable seeds, whose surface is embedded with a low activity of radium 224. Each seed continuously emits into the tumor, by recoil, a chain of short-lived alpha emitting atoms (progeny of radium) which spread by diffusion and convection over several mm around it, creating a continuous “kill region” of high alpha-particle dose. After many years of basic work on the technology and associated physics, as well as an extensive campaign of preclinical studies in mice, Alpha DaRT has recently entered clinical trials, in the framework of a new company, Alpha TAU Medical Ltd. The first trial, in Rabin Medical Center (Israel), focuses on recurrent skin and oral cavity squamous cell carcinoma, and tumor size < 5 centimeters in the longest diameter. So far, 15 of the enrolled patients have completed follow-up. Tumor locations included the chin, ear, tongue, lip, nose, forehead, scalp and parotid skin areas. Treatment was delivered based on a CT-simulation pre-treatment plan. DaRT seeds were inserted under local anesthesia using a specially designed applicator. The seeds (1 cm long and 0.7 mm in diameter) each carrying an activity of 2 μCi 224Ra were placed 5-6 millimeters from each other, based on a DaRT-specific dosimetry model. The total 224Ra activity administered was ∼5 μCi per gram of tumor. Two to four weeks after implantation the seeds were removed, and six weeks after treatment CT was performed to assess the effect of treatment. Blood tests and urinalysis were performed during the treatment. The number of DaRT seeds inserted into the tumor was in the range of 7-169 seeds, and treatment duration was 14 to 26 days. Initial efficacy results for a single application of DaRT seeds, for 15 subjects who have reached the study endpoint, are highly promising: eleven subjects (11/15, 73%) had a Complete Response to the treatment and four (4/15, 27%) had Partial Response (substantial reduction in tumor volume). The treatment was shown to be safe for both the patient and medical staff. Local side effects of the treatment were minimal, amounting to erythema, swelling and mild to moderate pain in the insertion area, which resolved either by the time the seeds were removed or shortly after. Radioactivity measurements of 212Pb in the blood were consistent with a biokinetic model of DaRT, which predicts negligible dose levels to distant organs. No clinically significant abnormal blood or urine lab results, or clinically significant changes in vital signs were observed. Based on the successful outcomes of the first clinical trial, clinical protocols are in preparation for various indications with leading research centers worldwide, including cutaneous and mucosal neoplasia, neoadjuvant and recurrent rectal cancer, recurrent prostate cancer, inoperable breast cancer, recurrent gynecological cancer, sarcoma and pancreatic cancer.