Survival In Oral Cancer Patients Research Articles

Is immediate dental implant in fibula free flap beneficial for implant survival and osteoradionecrosis in jaw reconstruction?

ObjectivesThis study aimed to compare the risk of osteoradionecrosis and implant survival in oral cancer patients undergoing immediate dental implants during jaw reconstruction, termed “Jaw in a Day” (JIAD), with those receiving no implants or delayed implants (non-JIAD). Patients & methodsClinicopathologic data were collected from prospectively enrolled JIAD patients (n = 10, 29 implants) and retrospectively from non-JIAD patients (n = 117, 86 implants). Survival analyses were performed to assess implant survival and osteoradionecrosis-free survival. ResultsOsteoradionecrosis occurred in 0 % of JIAD cases compared to 19.3 % in non-JIAD cases without implants and 71.4 % in non-JIAD cases with delayed implants (p = 0.008). Osteoradionecrosis-free survival was significantly better in the JIAD group than the non-JIAD group (p = 0.0059). Implants in the JIAD group all survived regardless of radiation therapy (29/29, 100 %) and 95.1 % (58/61) of implants survived in delayed implants in non-irradiated fibula without radiotherapy. Meanwhile, only 11 of 25 implants placed in irradiated fibula flaps survived, even when the implants were placed after a median time interval of 624 days after radiotherapy, and none of them were earlier than 360 days. The survival analysis revealed a significant difference (p < 0.0001). ConclusionJIAD appears to offer superior outcomes in terms of implant survival and osteoradionecrosis prevention compared to delayed implant placement. Placing implants in irradiated fibula, even after years, significantly poses high risk of implant failure and osteoradionecrosis. JIAD represents a promising approach for optimal rehabilitation, particularly in oral cancer patients requiring postoperative radiotherapy. Proper positioning and orientation of implants and flaps are crucial for implant survival.

Effect of Preoperative Serum Lactate Dehydrogenase-to-Albumin Ratio on the Survival of Oral Cancer: A Retrospective Study.

Several studies have investigated the relationship between serum lactate dehydrogenase-to-albumin ratio (LAR) and the prognosis of cancers. However, no studies have explored the association between serum LAR and the survival of oral cancer (OC). This study was aimed to determine the association of serum LAR with the overall survival (OS) of OC. One hundred and ninety patients with OC were included in this study between January 2018 and December 2019. Log rank test and Kaplan-Meier method were used to compare the survival rate of OC between the low LAR group and the high LAR group. The association between serum LAR and the survival of OC patients was determined via univariate and multivariate Cox regression analyses. Kaplan-Meier analysis and Log rank test indicated that the OS rate in low LAR group was significantly higher than that in high LAR group (P < 0.05). Univariate cox analysis showed that TNM III-IV stage, serum LDH > 162 U/L, and serum LAR > 3.79 were significantly associated with the OS of OC patients. Multivariate Cox analysis suggested that the TNM III-IV stage (HR, 2.317; 95% CI, 1.423-3.774, P = 0.001) and serum LAR > 3.79 (HR, 5.138; 95% CI, 2.245-11.756, P = 0.000) were independently related with poor OS of OC patients. High serum LAR (>3.79) is an independent predictor of adverse prognosis in OC patients. LAR could be used as a promising marker for predicting the OS of OC patients.

SP110 Could be Used as a Potential Predictive and Therapeutic Biomarker for Oral Cancer.

The morbidity of oral squamous cell carcinoma (OSCC) has been rising year after year, making it a major global health issue. But the molecular pathogenesis of OSCC is currently unclear. To study the potential pathogenesis of OSCC, the differentially expressed genes (DEGs) were screened, and multiple databases were used to perform the tumor stage, expression, prognosis, protein-protein interaction (PPI) networks, modules, and the functional enrichment analysis. Moreover, we have identified SP110 as the key candidate gene and conducted various analyses on it using multiple databases. The research indicated that there were 211 common DEGs, and they were enriched in various GO terms and pathways. Meanwhile, one DEG is significantly related to short disease-free survival, four are associated with overall survival, and 12 DEGs have close ties with tumor staging. Additionally, the SP110 is significantly associated with methylation level, HPV status, tumor staging, gender, race, tumor grade, age, and overall/disease-free survival of oral cancer patients, as well as the immune process. The copy number variation of SP110 significantly affected the abundance of immune infiltration. Therefore, we speculate that SP110 could be used as the diagnostic and therapeutic biomarker for OSCC, and can help to further understand oral carcinogenesis.

Preoperative Serum Selenium Concentrations and Disease-Specific Survival in Patients With Oral Cancer: A Long-Term Follow-Up Study

BackgroundSerum selenium (Se) concentration has been reported to be associated with the incidence of oral cancer. The association between serum Se and long-term survival in oral cancer patients is still unclear. PurposeThe purpose of this study is to measure the association between serum Se and disease-specific survival (DSS). Study design, setting, and sampleThis was a single-center, prospective cohort study conducted at the First Affiliated Hospital of Fujian Medical University (Fujian province, China) from September 2011 to December 2018. The inclusion criteria were patients with newly diagnosed primary oral cancer confirmed by histology. The exclusion criteria were patients with recurrent oral cancer or metastatic cancer. Predictor VariableThe predictor variable is the preoperative serum Se concentration measured using inductively coupled plasma-mass spectrometry (ICP-MS). Outcome VariablesThe primary outcome variable is DSS calculated from the date of diagnosis to date of death due to oral cancer or end of follow-up, whichever occurred first. CovariatesThe covariates were age, sex, occupation, education level, BMI, surgery therapy, adjuvant therapy, TNM stage, pathological grading. AnalysesKaplan-Meier survival analysis, Cox proportional hazards regression and restricted cubic spline regression were utilized. P-value < 0.05 was significant. ResultsThe sample was composed of 235 subjects with a median age of 59 years (ranged from 20 to 80 years) and 142 (60.43%) were male. The median follow-up was 54.90 months (interquartile range: 35.47). Se levels were associated with DSS (unadjusted HR=0.70, 95% CI: 0.54-0.91) suggesting that higher levels of Se are associated with longer or improved DSS. After adjustment of age, sex, occupation, education level, residence, TNM stage, pathological grading, surgery therapy, radiotherapy and chemotherapy, patients with higher serum Se had a better DSS (aHR=0.67, 95% CI: 0.49-0.92). Of note, we found that the association between serum Se and DSS was observed only in patients with radiotherapy (aHR= 0.49, 95% CI: 0.33-0.73). And the protective effect of radiotherapy on survival was only observed in patients with higher Se concentrations (aHR=0.36, 95% CI: 0.20-0.63). Additionally, there was a multiplicative interaction between Se and radiotherapy on the prognosis of oral cancer patients (Pinteraction<0.01). Conclusion and RelevanceOur findings suggest that a high Se concentration might contribute to better DSS among oral cancer patients, and the effect may partly depend on radiotherapy treatment. Given these findings, additional research should focus on the role of Se in DSS among oral cancer patients and the interaction with radiotherapy.

Enabling multi-modal imaging and photoimmunotherapy of oral cancer spheroids through an EGFR-targeted antibody conjugate

SignificanceDelineating tumor margins during surgery and eliminating residual disease is a major challenge in the treatment of oral cancers. The dual function antibody conjugate (DFAC) developed in this study can enable 3D-imaging and destroy residual microscopic disease by photoimmunotherapy in a single intra-operative setting. ApproachDFAC was synthesized by routine carbodiimide crosslinker chemistry. Multi-modal imaging (Photoacoustic and fluorescence imaging) and photoimmunotherapy was performed on oral cancer spheroids. ResultsPhotoacoustic imaging could detect tumor spheroids, even of the smallest size (0.01 mm3), while fluorescence imaging could detect only larger spheroids with volumes greater than 0.049 mm3 and treated with a higher DFAC concentration. Photoimmunotherapy showed a spheroid size dependent response, with smaller spheroids of volumes 0.018 mm3 and lower showing no recurrence. ConclusionsThe complementary imaging and treatment capabilities of DFAC could help in minimizing healthy tissue resection and enhance recurrence free survival in oral cancer patients.

A hospital-based study of survival in oral cancer patients of Tata Memorial Hospital, Mumbai.

Oral cancer represents a significant global public health concern, with the death rate for lip and oral cavity malignancies experiencing a 1.40-fold increase worldwide in the past three decades. This retrospective study aimed to comprehensively understand overall survival (OS) and the influence of sociodemographic and clinical factors on patients diagnosed with oral cavity cancer. The study focused on oral cancer patients enrolled in 2016 and treated at Tata Memorial Hospital, Mumbai, with a follow-up period extending to 5 years until 2021. Utilising the Kaplan-Meier technique and log-rank test, we examined OS and variations based on sociodemographic factors, while the Cox proportional hazard model allowed us to investigate the simultaneous impact of multiple factors on OS. A total of 1,895 eligible participants were included. The overall 5-year survival rate was 65%. After adjusting for age, gender, education, primary site, tumour grade, TNM staging, treatment intention, status and modality, we found in our study oral cancer patients aged more than 60 years (HR = 1.37, 95% CI: 1.01-1.85, p-value 0.03), patients who had poorly differentiated carcinoma (HR = 2.44, 95% CI: 1.56-3.81, p-value < 0.001), belonged to stage IV as per TNM staging (HR = 2.44, 95% CI: 1.65-3.61, p-value < 0.001), patient who have received partial treatment (HR = 2.44, 95% CI: 1.65-3.61, p-value < 0.001) and only chemotherapy (HR = 3.56, 95% CI: 2.43-5.23, p-value < 0.001) found to have a higher hazard of dying while literate (HR = 0.73, 95% CI: 0.56-0.95, p-value 0.02) are protective. The retrospective nature of the study posed constraints in exploring additional variable associations. Overall early detection, appropriate treatment, and regular follow-up are critical for improving the survival rate of patients with oral cavity cancer. This research proposes that improving the socioeconomic status and promoting proactive treatment-seeking behaviour is crucial for enhancing the survival of oral cancer patients. Cancer hospitals, in collaboration with the wider public healthcare system in India, which includes clinicians and policymakers, should consider these suggestions to enhance cancer treatment and control in low-middle-income countries.

Site-specific radiation dosage and implant survival in oral cancer patients: A cohort study.

We assessed the radiation dosages (Dmean) on implant regions to identify the threshold for implant loss in patients with an intraoral malignancy treated with dental implants to support a mandibular denture during ablative surgery before volumetric-modulated arc therapy (VMAT). Data was collected prospectively from 28 patients treated surgically for an intraoral malignancy, followed by postoperative radiotherapy (VMAT) and analyzed retrospectively. Patients received 2 implants in the native mandible during ablative surgery. Implant-specific Dmean values were retrieved from the patients' files. Radiographic bone loss was measured 1 year after implant placement and during the last follow-up appointment. Implant survival was analyzed with the Kaplan-Meier method. Univariate logistic regression and Cox-regression analyses were performed to investigate the effect of increasing implant-specific radiation dosages on implant loss. Five out of 56 placed implants were lost during follow-up (median 36.0 months, IQR 39.0). Radiographically, peri-implant bone loss occurred in implants with a Dmean > 40 Gy. Implant loss occurred only in implants with a Dmean > 50 Gy. An implant-specific Dmean higher than 50 Gy is related to more peri-implant bone loss and, eventually, implant loss.

TMEM16A enhances the activity of the Cdc42-NWASP signaling pathway to promote invasion and metastasis in oral squamous cell carcinoma

ObjectiveTo explore the relationship between TMEM16A and metastasis and development in oral squamous cell carcinoma (OSCC). Study DesignDatabases GEPIA and UALCAN were employed to analyze the relationship between the expression of TMEM16A and the survival of oral cancer patients. TMEM16A was knocked down and overexpressed in CAL27 and SCC-4 cells, respectively, and the malignant behavior, and the expression of key proteins were detected. The Cdc42-NWASP pathway was inhibited, and the effects of TMEM16A and Cdc42-NWASP pathway on promoting the malignant behavior of cancer cells were verified. The xenograft tumor model was constructed, and tumor growth, cell proliferation index, apoptosis and Cdc42-NWASP signal pathway activity were detected. ResultsThe expression of TMEM16A in oral cancer tissues was significantly higher than that in adjacent tissues, and the patients with high expression of TMEM16A had shorter survival time. Overexpression of TMTM16A can significantly promote the occurrence of cancer and reduce the apoptosis of cancer cells, while the activity of Cdc42 pathway was higher. Knocking down TMEM16A or inhibiting Cdc42-NWASP pathway can reverse the above results. ConclusionThe activation of Cdc42-NWASP pathway by TMEM16A high expression is closely related to OSCC, which may become a new therapeutic target to prevent OSCC metastasis.

The Impact and Prognostic Significance of Extra-Nodal Extension in Clinically N0 Oral Cancer: A Prospective Clinical Study.

Oral cavity squamous cell carcinoma (OCSCC) demonstrates a high propensity to metastasize to regional lymph nodes. Despite technological and scientific advances, identification of pathological adverse features preoperatively remains elusive. This study intended to identify the true occurrence of extra-nodal extension (ENE) in clinically and radiologically N0 OCSCC patients and to investigate its impact and prognostic significance. A prospective, single-centre, non-randomized study was conducted at a tertiary cancer centre in South India to include all untreated operable patients of OCSCC without clinical, radiological, or cytological evidence of nodal metastasis (cN0). All the patients underwent tumor resection surgery with neck dissection and received adjuvant therapy when indicated. Patients were followed up and neck dissection specimens were histopathologically analyzed. The primary outcome was to assess the presence of ENE in cN0 OCSCC patients and its extent. The secondary outcomes were 2-year disease-free survival (DFS) and tumor characteristics. A total of 237 patients with operable OCSCC were evaluated. Out of these, 80 patients who were clinically and radiologically N0 were included in the study and they underwent tumor resection surgery and neck dissection. The final histopathological evaluation revealed that 21.25% of patients (n = 17) had metastatic neck disease and 7.5% of patients (n = 6) had ENE, and all were reported as microscopic ENE. Within the node-positive group, the 2-year DFS for patients with and without ENE were 50% and 90.9%, respectively (p = 0.0362). The results suggest that ENE remains a strong predictor of adverse outcomes, recurrence, and survival in oral cancer patients.

Application and Performance of Artificial Intelligence (AI) in Oral Cancer Diagnosis and Prediction Using Histopathological Images: A Systematic Review.

Oral cancer (OC) is one of the most common forms of head and neck cancer and continues to have the lowest survival rates worldwide, even with advancements in research and therapy. The prognosis of OC has not significantly improved in recent years, presenting a persistent challenge in the biomedical field. In the field of oncology, artificial intelligence (AI) has seen rapid development, with notable successes being reported in recent times. This systematic review aimed to critically appraise the available evidence regarding the utilization of AI in the diagnosis, classification, and prediction of oral cancer (OC) using histopathological images. An electronic search of several databases, including PubMed, Scopus, Embase, the Cochrane Library, Web of Science, Google Scholar, and the Saudi Digital Library, was conducted for articles published between January 2000 and January 2023. Nineteen articles that met the inclusion criteria were then subjected to critical analysis utilizing QUADAS-2, and the certainty of the evidence was assessed using the GRADE approach. AI models have been widely applied in diagnosing oral cancer, differentiating normal and malignant regions, predicting the survival of OC patients, and grading OC. The AI models used in these studies displayed an accuracy in a range from 89.47% to 100%, sensitivity from 97.76% to 99.26%, and specificity ranging from 92% to 99.42%. The models' abilities to diagnose, classify, and predict the occurrence of OC outperform existing clinical approaches. This demonstrates the potential for AI to deliver a superior level of precision and accuracy, helping pathologists significantly improve their diagnostic outcomes and reduce the probability of errors. Considering these advantages, regulatory bodies and policymakers should expedite the process of approval and marketing of these products for application in clinical scenarios.

Predicting Overall Survival Using Machine Learning Algorithms in Oral Cavity Squamous Cell Carcinoma.

Machine learning (ML) models are often modelled to predict cancer prognosis but rarely consider spatial factors in a region. Hence this study explored machine learning algorithms utilising Local Government Areas (LGAs) in Queensland, Australia to spatially predict 3- and 5-year prognosis of oral cancer patients and provide clinical interpretability of the predicted outcome made by the ML model. Data from a total of 3,841 oral cancer patients were retrieved from the Queensland Cancer Registry (QCR). Synthesizing minority oversampling technique together with edited nearest neighbours (SMOTE-ENN) was used to pre-process unbalanced datasets. Five ML models: logistic regression, random forest classifier, XGBoost, Gaussian Naïve Bayes and Voting Classifier were trained. Predictive features were age, sex, LGAs, tumour site and differentiation. Outcomes were 3- and 5-year overall survival of patients. Model performances on test set were evaluated using area under the curve and F1 scores. SHapley Additive exPlanations (SHAP) method was applied to the best performing model for model interpretation of the predicted outcome. The Voting Classifier was the best performing model with F1 score of 0.58 and 0.64 for 3- and 5-year overall survival, respectively. Age was the most important feature in the Voting Classifier in 3- and 5-year prognosis prediction. LGAs at diagnosis was the top 3 predictive feature for both 3- and 5-year models. The Voting Classifier demonstrated the best overall performance in classifying both 3- and 5-year overall survival of oral cancer patients in Queensland. SHAP method provided clinical understanding of the predictive features of the Voting Classifier.

Meta-signature guided investigation of miRNA candidates as potential biomarkers of oral cancer.

This study aimed to experimentally validate dysregulated expression of miRNA candidates selected through updated meta-analysis of most commonly deregulated miRNAs in oral cancer and to explore their diagnostic and prognostic potential. Five miRNAs (miR-31-3p, miR-135b-5p, miR-18a-5p, miR-30a-5p and miR-139-5p) from updated meta-signature were selected for validation by qRT-PCR method in 35 oral cancer clinical specimens and adjacent non-cancerous tissue. Updated meta-analysis has identified 13most commonly deregulated miRNAs in oral cancer. Seven miRNAs were consistently up-regulated (miR-21-5p, miR-31-3p, miR-135b-5p, miR-31-5p, miR-424-5p, miR-18a-5p and miR-21-3p), while five were down-regulated (miR-139-5p, miR-30a-3p, miR-375-3p, miR-376c-3p and miR-30a-5p). Increased expression of miR-31-3p and miR-135b-5p, and decreased expression of miR-139-5p and miR-30a-5p were confirmed in oral cancer compared to adjacent non-cancerous tissue. A three miRNAs combination (miR-31-3p, miR-139-5p and miR-30a-5p) gave the most promising diagnostic potential for discriminating oral cancer from non-cancerous tissue (AUC: 0.780 [95% CI: 0.673-0.886], p<0.0005, sensitivity 94.3%, specificity 51.4%). High expression of miR-135b-5p, miR-18a-5p and miR-30a-5p was associated with poor survival (p=0.003, p=0.048, p=0.016 respectively). miR-31-3p, miR-139-5p and miR-30a-5p panel was confirmed as a potential diagnostic biomarker when distinguishing oral cancer from non-cancerous tissue. miR-135b-5p, miR-18a-5p and miR-30a-5p might serve as potential biomarkers of poor survival of oral cancer patients.

Preoperative circulating fibrinogen to albumin ratio in predicting 5-year prognosis of oral cancer radical surgery.

Accurate prediction of oral cancer (OC) prognosis before surgery is the key to treatment. The prognosis of OC is mainly based on the Tumor-Node-Metastasis (TNM) staging system, but TNM staging cannot accurately predict clinical prognosis. Current research results show that systemic inflammatory and nutritional markers can influence the postoperative prognosis and outcome of malignant tumors. The objectives of this research are to explore the preoperative blood fibrinogen and albumin in OC patients and to determine the predictive validity of the fibrinogen to albumin ratio (FAR) over 5 years of follow-up. This retrospective cohort study queried The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University database and identified 157 cases of OC operations performed between 2014 and 2016. Survival curves were presented by the Kaplan-Meier method. Univariate and multivariate analyses were used to assess clinical value for patients with radical surgery. The FAR revealed a good prediction for 5-year cancer-specific survival (CSS). The optimal cut-off value for FAR was 0.072. Multivariate logistic regression analyses revealed that FAR was an independent risk factor for survival. Increased FAR (>0.072) is negatively associated with the CSS of patients (log-rank test, p<0.01). The preoperative FAR may provide a significant predictor of cancer-specific survival in oral cancer patients undergoing radical surgery.

Clinical Significance and the Role of Guanylate-Binding Protein 5 in Oral Squamous Cell Carcinoma.

Simple SummaryThe survival rate of oral squamous cell carcinoma (OSCC) patients has not been improved in the past few decades, likely as a result of a lack of therapeutic targets. Through next generation sequencing for tumor tissues of OSCC patients, the gene expression level of guanylate binding protein 5(GBP5) was significantly elevated in tumor tissues compared with adjacent normal tissues and associated with poor prognosis in OSCC patients. Moreover, we found that GBP5 modulated cell cycle, invasion/migration, and cancer stemness in OSCC cells. Our study indicated that GBP5 might be a potential biomarker and therapeutic target for OSCC patients.Guanylate binding protein 5 (GBP5) is the interferon (IFN)-inducible subfamily of guanosine triphosphatases (GTPases) and is involved in pathogen defense. However, the role played by GBP5 in cancer development, especially in oral squamous cell carcinoma (OSCC), is still unknown. Herein, next-generation sequencing analysis showed that the gene expression levels of GBP5 were significantly higher in OSCC tissues compared with those found in corresponding tumor adjacent normal tissues (CTAN) from two pairs of OSCC patients. Higher gene expression levels of GBP5 were also found in tumor tissues of 23 buccal mucosal squamous cell carcinoma (BMSCC)/14 tongue squamous cell carcinoma (TSCC) patients and 30 oral cancer patients from The Cancer Genome Atlas (TCGA) database compared with those in CTAN tissues. Immunohistochemical results showed that protein expression levels of GBP5 were also higher in the tumor tissues of 353 OSCC patients including 117 BMSCC, 187 TSCC, and 49 lip squamous cell carcinoma patients. Moreover, TCGA database analysis indicated that high gene expression levels of GBP5 were associated with poor overall survival in oral cancer patients with moderate/poor cell differentiation, and associated with poor disease-free survival in oral cancer patients with moderate/poor cell differentiation and lymph node metastasis. Furthermore, GBP5-knockdowned cells exhibited decreased cell growth, arrest at G1 phase, and decreased invasion/migration. The gene expression of markers for epithelial−mesenchymal transition and cancer stemness was also reduced in GBP5-silenced oral cancer cells. Taken together, GBP5 might be a potential biomarker and therapeutic target for OSCC patients, especially for those with poor cell differentiation and lymph node metastasis.

MicroRNA-133 Targets Phosphodiesterase 1C in Drosophila and Human Oral Cancer Cells to Regulate Epithelial-Mesenchymal Transition.

Non-coding microRNAs (miRNAs) have been proposed to play diverse roles in cancer biology, including epithelial-mesenchymal transition (EMT) crucial for cancer progression. Previous comparative studies revealed distinct expression profiles of miRNAs relevant to tumorigenesis and progression of oral cancer. With putative targets of these miRNAs mostly validated in vitro, it remains unclear whether similar miRNA-target relationships exist in vivo. In this study, we employed a hybrid approach, utilizing both Drosophila melanogaster and human oral cancer cells, to validate projected miRNA-target relationships relevant to EMT. Notably, overexpression of dme-miR-133 resulted in significant tissue growth in Drosophila larval wing discs. The RT-PCR analysis successfully validated a subset of its putative targets, including Pde1c. Subsequent experiments performed in oral cancer cells confirmed conserved targeting of human PDE1C by hsa-miR-133. Furthermore, the elevated level of miR-133 and its targeting of PDE1C was positively correlated with enhanced migrative ability of oral cancer cells treated with LPS, along with the molecular signature of a facilitated EMT process induced by LPS and TGF-β. The analysis on the RNAseq data also revealed a negative correlation between the expression level of hsa-miR-133 and the survival of oral cancer patients. Taken together, our mammal-to-Drosophila-to-mammal approach successfully validates targeting of PDE1C by miR-133 both in vivo and in vitro, underlying the promoted EMT phenotypes and potentially influencing the prognosis of oral cancer patients. This hybrid approach will further aid to widen our scope in investigation of intractable human malignancies, including oral cancer.

Comparison of machine learning algorithms for the prediction of five-year survival in oral squamous cell carcinoma.

Machine learning analyses of cancer outcomes for oral cancer remain sparse compared to other types of cancer like breast or lung. The purpose of the present study was to compare the performance of machine learning algorithms in the prediction of global, recurrence-free five-year survival in oral cancer patients based on clinical and histopathological data. Data were gathered retrospectively from 416 patients with oral squamous cell carcinoma. The data set was divided into training and test data set (75:25 split). Training performance of five machine learning algorithms (Logistic regression, K-nearest neighbours, Naïve Bayes, Decision tree and Random forest classifiers) for prediction was assessed by k-fold cross-validation. Variables used in the machine learning models were age, sex, pain symptoms, grade of lesion, lymphovascular invasion, extracapsular extension, perineural invasion, bone invasion and type of treatment. Variable importance was assessed and model performance on the testing data was assessed using receiver operating characteristic curves, accuracy, sensitivity, specificity and F1 score. The best performing model was the Decision tree classifier, followed by the Logistic Regression model (accuracy 76% and 60%, respectively). The Naïve Bayes model did not display any predictive value with 0% specificity. Machine learning presents a promising and accessible toolset for improving prediction of oral cancer outcomes. Our findings add to a growing body of evidence that Decision tree models are useful in models in predicting OSCC outcomes. We would advise that future similar studies explore a variety of machine learning models including Logistic regression to help evaluate model performance.

Targeting the endothelin axis as a therapeutic strategy for oral cancer metastasis and pain

Metastasis reduces survival in oral cancer patients and pain is their greatest complaint. We have shown previously that oral cancer metastasis and pain are controlled by the endothelin axis, which is a pathway comprised of the endothelin A and B receptors (ETAR and ETBR). In this study we focus on individual genes of the pathway, demonstrating that the endothelin axis genes are methylated and dysregulated in cancer tissue. Based on these findings in patients, we hypothesize that ETAR and ETBR play dichotomous roles in oral carcinogenesis and pain, such that ETAR activation and silenced ETBR expression result in increased carcinogenesis and pain. We test a treatment strategy that targets the dichotomous functions of the two receptors by inhibiting ETAR with macitentan, an ETAR antagonist approved for treatment of pulmonary hypertension, and re-expressing the ETBR gene with adenovirus transduction, and determine the treatment effect on cancer invasion (i.e., metastasis), proliferation and pain in vitro and in vivo. We demonstrate that combination treatment of macitentan and ETBR gene therapy inhibits invasion, but not proliferation, in cell culture and in a mouse model of tongue cancer. Furthermore, the treatment combination produces an antinociceptive effect through inhibition of endothelin-1 mediated neuronal activation, revealing the analgesic potential of macitentan. Our treatment approach targets a pathway shown to be dysregulated in oral cancer patients, using gene therapy and repurposing an available drug to effectively treat both oral cancer metastasis and pain in a preclinical model.

Polymorphic variants of drug-metabolizing enzymes alter the risk and survival of oral cancer patients

The present study investigated the prevalence of CYP2D6*4, CYP3A5*3 and SULT1A1*2, using PCR-RFLP, in normal and oral cancer (OC) patients that were stratified by OC subtype and gender. The risk of cancer, 5-year cumulative survival and hazard's ratio (HR) with respect to risk factors and clinical factors were estimated using Fisher's exact test, Kaplan-Meier analysis, and Cox proportional hazards models. CYP2D6*4 'GA' lowered the risk of buccal mucosa cancer (BMC) in males (OR = 0.37), whereas, 'G' allele of CYP3A5*3 increased risk of tongue cancer (TC) (OR = 1.67). SULT1A1*2 'GA' increased the risk of TC (OR = 2.36) and BMC (OR = 3.25) in females. The 5-year survival of the patients depended on factors like age, lymphovascular spread (LVS), perinodal spread (PNS), recurrence, tobacco, and alcohol. CYP3A5*3 'AG' and 'GG' had decreased the hazard ratio (HR) for BMC females when inflammatory infiltrate alone or along with other covariates, LVS, PNI, PNS, metastasis, recurrence, and relapse was adjusted. Similarly, CYP3A5*3 'AG' decreased the risk of death (HR = 0.05) when the grade was adjusted. SULT1A1*2 'GA' had decreased HR for TC males (HR = 0.08) after adjusting for inflammatory infiltrate, LVS, perineural invasion (PNI), PNS, metastasis, recurrence, and relapse. Further, our bioinformatics study revealed the presence of a CpG island within the CYP2D6 and a CTCF binding site upstream of CYP2D6. Interestingly, three CpG islands and two CTCF binding sites were also identified near the SULT1A1. In conclusion, the SNPs altered risk and survival of BMC and TC differentially in a gender specified manner, that varied with clinical and risk factors.

5-year cumulative survival of oral cancer patients with FAS and FASL SNPs

IntroductionFAS binds to FASL to initiate extrinsic apoptosis which plays a key role in maintaining cellular homeostasis. Disruption of apoptosis leads to tumorigenesis. MethodsWe investigated the association of FAS -1377 G/A, FAS -670 A/G and FASL -844 T/C SNPs with survival of oral cancer (OC) patients, stratified by gender and cancer sub-type into buccal mucosa cancer (BMC) and tongue cancer (TC). 5-year cumulative survival and hazards ratio (HR) with respect to risk and clinical factors were estimated using Kaplan–Meier analysis and Cox proportional hazards models. ResultsThe survival of the patients differed amongst both genders in TC and BMC. Survival depended on risk and clinical factors. Male TC patients with FAS -1377 ‘GA’ survived significantly (P = 0.038) better than BMC patients, with mean survival time of 45.24 ± 2.93 months. TC females with metastasis and FAS -670 ‘AA’ or ‘AG’ had longer survival than TC males. BMC males with FASL -844 ‘TC’ (25.11 ± 6.71 months) or ‘CC’ (22.63 ± 3.57 months) and with PNS showed better survival than wild type ‘TT’ (7.9 ± 1.27 months). FAS -1377 ‘AA’ (HR = 47.14) and FASL -844 ‘CC’ variant (HR = 10.87) showed significantly increased risk of death (HR) in TC males, when LVS and PNI were also adjusted. Interpretation & ConclusionsThese SNPs altered the survival and risk of death (HR) of BMC and TC differentially, that varied with clinical and risk factors.

The impact of comorbidities on survival in oral cancer patients: a population-based, case-control study

Background Comorbidities have shown to highly influence the outcome and risk of death of head and neck cancer patients. The purpose of this study was to examine the comorbidities among oral cavity squamous cell carcinoma (OSCC) patients, and to investigate the impact of comorbidities on overall survival (OS) and recurrence free survival (RFS). Methods Patients diagnosed with OSCC in Eastern Denmark in the period 2000–2014 and treated with curative intend were included. Patients data were linked to the Danish National Patients Register to identify comorbidities based on the Charlson Comorbidity Index (CCI) at the time of diagnosis and five years after diagnosis. Each patient was age-and sex-matched in a 1:10 ratio with an age and sex matched reference group. Results A total of 1,183 patients and 11,830 controls were included. Overall this study found comorbidities to be more common among OSCC compared to the reference group both at the time of diagnosis and five years after. The 5-year OS among patients with a CCI score of zero, one, two, and three or above was 60%, 44%, 41%, and 40%, respectively. Similarly, the multivariate cox-regression analysis showed that patients with increasing CCI score also had an increasing risk of death compared to patients with no comorbidities. Conclusion OSCC patients had significantly higher comorbidity burden at diagnosis and risk of developing additional comorbidities after diagnosis compared to the reference population. Survival outcomes decreased significantly with higher CCI.