EMT Dynamics in Lymph Node Metastasis of Oral Squamous Cell Carcinoma.

BACKGROUND: Epithelial-mesenchymal transition (EMT) enables tumor cell invasion and metastasis. Many studies have demonstrated the critical role of EMT in lymph node metastasis in oral squamous cell carcinoma (OSCC). During EMT, epithelial cancer cells lose intercellular adhesion and apical-basal polarity and acquire mesenchymal properties such as motility and invasiveness. A significant feature of EMT is cadherin switching, involving the downregulation of E-cadherin and upregulation of N-cadherin. The TGF-ß/SMAD pathway can also induce EMT. We aimed to evaluate EMT markers as predictors of lymph node metastasis in OSCC. METHODS: We performed genetic profiling of 159 primary OSCCs from TCGA and analyzed the expression of EMT markers, including cadherin switch genes (CDH1, CDH2), and TGF-ß/SMAD pathway genes. Samples were divided into advanced (stage III-IV) and early (stage I-II) stage groups. Differential expression analysis was performed, as well as an independent validation study containing fresh OSCC samples. RESULTS: TGF-ß/SMAD pathway genes such as SMAD6 were upregulated in advanced stage tumors. N-cadherin and SNAIL2 were overexpressed in node-positive tumors. Keratins were downregulated in these groups. CONCLUSION: Our findings demonstrate that EMT marker expression correlates with lymph node metastasis in OSCC. Developing therapies targeting regulators such as N-cadherin may prevent metastasis and improve outcomes.

A mucoadhesive patch loaded with freeze-dried liposomes for the local treatment of oral tumors.

Oral cancers affect millions of people globally, with increasing incidences among adults aged 35 and above. Poor drug uptake by lesions in the oral cavity following systemic administration, as well as limited localized treatment modalities for oral tumors, result in poor patient quality of life and high mortality. Here, we describe a solid, dissolvable, bioadhesive alginate patch containing freeze-dried doxorubicin-loaded liposomes as a local treatment for oral tumors located on the tongue. By varying the alginate-to-liposome ratio in the mucoadhesive patch, we could control the degree of bioadhesion to the tongue and the release profile of the drug-loaded liposomes from the matrix. In vitro, exposing squamous cell carcinoma (SCC) to the alginate mucoadhesive patch or tablet resulted in dose-dependent cancer-cell death. In vivo, the efficacy of the local treatment was demonstrated in mice bearing orthotopic SCC tumors in the tongue. The bioadhesive patch, applied directly above the lesion, significantly reduced the tumor size and treatment-associated side effects compared to implanted patches or systemic drug administration. This study demonstrates that local bioadhesive therapies are effective in treating cancers of the oral cavity.

Does fasting during Ramadan increase the risk of the development of sialadenitis?

BACKGROUND: Ramadan is a month within the Islamic lunar calendar when Muslims are required to fast (abstain from food and drink) during the daytime (from sunrise to sunset) for the entire month. Due to the established connection between fasting and dehydration and acute sialadenitis, the aim of this study is to determine if there is a higher frequency of sialadenitis among the Muslim population during Ramadan than during other months of the year. METHODS: We conducted a retrospective study using the medical records of 120 Muslim patients admitted to the emergency room (ER) and diagnosed with acute sialadenitis over a 5-year period at the Baruch Padeh Medical Center, Poriya, and St. Vincent de Paul (French) Hospital, Nazareth, both located in Israel. The study group were Muslim patients, with the aforementioned diagnosis, admitted during Ramadan, while the control group included patients diagnosed with sialadenitis during the rest of the year. We analyzed overall admission frequency as well as descriptive and diagnostic data, including age, sex, gland involved and several blood test results. RESULTS: During the month of Ramadan, the admission of Muslims with a diagnosis of acute sialadenitis was more than double that during the other months of the year - a difference that was found to be statistically significant (p = 0.001). Additionally, we found that Ramadan sialadenitis patients had significantly higher leukocyte numbers at admission (p = 0.0085) and, importantly, a significantly higher level of dehydration (blood urea nitrogen (BUN)/creatinine ratio) than non-Ramadan sialadenitis patients (p = 0.0001). CONCLUSION: There is evidence that fasting in Ramadan may increase the risk for the development of acute sialadenitis. Our results suggest that this may be the result of dehydration.

The Face of War: Maxillofacial Patients in the Syrian Civil War.

The type of the armed conflict on the Syrian battle field acquired several types of injuries; including injuries that were caused by explosive, shrapnel and blast injuries.In the current study, the authors conducted an overview of maxillofacial patients, who mainly suffered from ballistic injuries in term of injuries, reconstruction, and management.Overall, 53 maxillofacial Syrian patients were treated. The most prominent injury was soft tissue lacerations (21/97) and in terms of hard tissue injuries, the most prominent site was the mandible (N = 19) while the ramus and the body presented the most common sub-sites of injury. Hard tissue injuries were treated either by close or open reduction to obtain primary stabilization.From the psychological aspect, most of the patients suffered from guilt for leaving the combat area, those patients were mostly males in their 20s or 30s. On the other hand, older patients suffered mainly from depression, stress, and fear of returning to their home land.To conclude, the Syrian civil war has several characteristics that defer from other combats. Thus, the management of Syrian patients has to be tailored accordingly.

The efficiency of extended postoperative antibiotic prophylaxis in orthognathic surgery: A prospective, randomized, double-blind, placebo-controlled clinical trial.

Postoperative antibiotics are commonly administered in orthognathic surgery, despite the fact that there is no consensus regarding their efficacy. The objective of this study was to investigate the effectiveness of postoperative antibiotics in orthognathic surgery by conducting a prospective, randomized, double-blind, placebo-controlled trial. Patients were randomly allocated into one of two study groups: the intervention group (treated with 1 g of intravenous (IV) amoxicillin-clavulanate TID) or the placebo group (treated with 50 mL of IV 0.9% NaCl TID). The infection rate was assessed using clinical and laboratory parameters. The intervention group included 38 patients, with 40 patients in the placebo group. Baseline and surgical characteristics were comparable between both groups. Mean postoperative C-reactive protein (CRP) and temperature were similar for both groups. Serous discharge was observed in two patients (both in the placebo group), and one of them required surgical intervention. Overall, infection rate was similar in both groups (p-value > 0.1). To conclude, administration of postoperative antibiotics in healthy, young patients undergoing orthognathic surgery did not show a significant advantage in reducing surgical infection rate.

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

PURPOSE: Recurrent 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 METHODS: Molecular 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. RESULTS: The 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. CONCLUSIONS: In 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.

Tobacco and alcohol-induced epigenetic changes in oral carcinoma.

PURPOSE OF REVIEW: The present review aims to describe the epigenetic alterations observed in oral cancer linked to the exposure to alcohol and/or tobacco. RECENT FINDINGS: Recent findings emphasize the importance of epigenetics in oral cancer progression and in how risk factors (as tobacco and alcohol) affect the basal epigenetic profiles. Deeper techniques and detailed approaches allowed the perception that individual CG changes and even subtle changes may represent important epigenetic alterations resulting in expression changes and other carcinogenic consequences. New classes of epigenetic alterations including noncoding RNAs have been gaining attention. SUMMARY: Many epigenetic alterations have been described in oral carcinoma progression induced by tobacco and/or alcohol, including: promoter hypermethylation in genes with tumor suppressive activity, global (genome-wide) hypomethylation, change in methylation patterns throughout the genes, alteration in noncoding RNAs, and histones modifications. These changes represent progress in the knowledge of how these risk factors act in a molecular level. There is an urgent need for large independent studies to move these potential makers further and validate them to identify risk assessment, early diagnostic markers, and therapeutic targets, as well as to be the base for prevention and intervention strategies.

The Possible Role of Human Papillomavirus Infection in the prognosis of Oral Squamous Cell Carcinoma in a Northern Israel Population.

BACKGROUND: Several types of human papillomavirus (HPV) have been found to be associated with oral squamous cell carcinoma (OSCC). Still, the significance of HPV infection and its relationship to patient prognosis remains an important matter of debate. OBJECTIVES: To investigate the incidence of HPV infection in OSCC patients in northern Israel populations to determine its role in the etiology and prognosis of OSCC. METHODS: OSCC tissues were gathered from the pathology departments at Rambam and Padeh medical centers in northern Israel. HPV DNA typing and immunohistochemistry for p16INK4A antibodies were conducted to evaluate their incidence in OSCC tissues. Statistical analysis regarding its expression in the different sub-populations (Jews, Arabs, Druze) was conducted using chi-square and Fisher's exact tests. RESULTS: The study included 82 patients: 53 men and 29 woman; median age 62.1 years; 54 Jews, 25 Arabs, and 3 Druze. The overall incidence of HPV expression was 45% (n=37). The median age of HPV-positive patients was 53 years vs. 65.8 in the negative group (P < 0.001). The 5 year overall survival of HPV-positive patients was not significantly higher than HPV-negative patients. A significant association was found between P16 expression and overall survival (log-rank P = 0.001). CONCLUSIONS: HPV infection in OSCC was not found to be significant in this study; however, P16 expression in the tumor tissue was found to be a positive prognostic factor for better survival.

Clinical significance of preoperative imaging in oral squamous cell carcinoma compared with lymph node status: a comparative retrospective study.

OBJECTIVE: The accuracy and sensitivity of commonly used imaging modalities in evaluating oral cavity cancer was evaluated by comparing the preoperative radiologic findings and the postoperative pathology report. STUDY DESIGN: Patients with oral squamous cell carcinoma, who had undergone at least 1 imaging test 2 weeks before surgery were included. Radiologic findings were compared with the dissected neck findings to assess the lymph node status. Sensitivity and specificity of the imaging modalities were calculated by using the χ2 test. RESULTS: Sensitivities for detecting metastatic neck lymph nodes at a threshold of 1 cm were 48% (P = .02) and 43.8% (P = .3) for computed tomography (CT) and magnetic resonance imaging respectively. Specificities were 76.3% and 70%, respectively. As for the 1.5 cm threshold, sensitivities were 36% (P = .002) and 31.3% (P = .5), respectively, and specificities were 91.5% and 76.7%, respectively. PET-CT was the most sensitive modality in the present study, with a P value of .02. CONCLUSIONS: The different studied imaging modalities used for preoperative neck staging are not sensitive enough and would lead to underdiagnoses of a significant proportion of patients. Thus, prophylactic neck dissection for occult neck disease is of extreme importance and remains the gold standard for oral cancer treatment.

Mucoadhesive alginate pastes with embedded liposomes for local oral drug delivery.

Oral cancers are extremely common among adults with increasing incidences due to human papillomavirus, while treatment modalities are limited. This study aims to develop a new oral mucoadhesive delivery system based on the combination of alginate and liposomes. The polymer provides adhesion properties and induces local release of the drug-loaded carriers, while the liposomes protect the drug from degradation and improve its absorption into the cells. Three hybrid alginate/liposomes delivery systems were investigated: a hybrid paste, which presented excellent adhesive capabilities, yet fast burst release of 90% after 2h; a hybrid hydrogel, demonstrating controllable release rates of 5%, 30% or 60% after 2h but poor mucoadhesive properties. These findings led to the development of a hybrid cross-linked paste. Polymer retention studies demonstrated that 80% of the crosslinked paste was retained on tongue tissue compared to 50% retention of the non-cross-linked pastes, verifying its superior mucoadhesion. The hybrid cross-linked paste presented controllable release rate of 20% after 2h. Alginate paste incorporating doxorubicin loaded liposomes presented similar release rates and were highly effective in promoting cancer cell death. Thus, our innovative formulation, including both desired characteristics of mucoadhesion and sustained liposomes release, is an important milestone in the development of a new potential treatment for oral cancer.

[GLOBAL INCIDENCE AND RISK FACTORS OF ORAL CANCER].

INTRODUCTION: Cancer of the oral cavity (Oral cancer) is the 11th most common malignancy in the world. Despite the general global trend of a slight decrease in the incidence of oral cancer, tongue cancer incidence is increasing. The incidence and mortality caused by this tumor show variability according to the geographic location in which it is diagnosed. However, in the last decade an increase was observed in the percentage of young patients, especially patients with tongue cancer. The main risk factors of head and neck cancer worldwide are smoking and alcohol, as well as DNA oncogenic viruses and habits, such as betel nut. METHODS: Data were collected from worldwide databases, such as Survival Epidemiology and End Result (SEER), The National Center of Health Statistics (NCHS) and GLOBCAN (2012) IARC. RESULTS: In 2012, 369,200 new cases of oral cancer were reported worldwide, with two-thirds of the tumors diagnosed in developing countries. These tumors are responsible for approximately 145,328 deaths worldwide per year. The highest incidence of these cancers is mainly reported in South and Southeast Asia and some countries in southern Europe. Prevalence and clinical pattern of OSCC varies greatly, depending on geographical location while diagnosed. DISCUSSION: As described in our review, the incidence of and mortality due to oral tumors pose a significant health problem in many aspects all around the world, and differences exist in the behavior of these tumors. We witnessed more cases of anterior tongue cancers mainly affecting the young age patient group. Several countries in Europe showed a significant increase in oral cancer prevalence, such as in Germany. Studies have reported an alarming lack of awareness about oral cancer, its symptoms, causes, and these gaps in knowledge need to be addressed by further public education, possibly targeted to high-risk groups. With the awareness to risk factors, primary prevention through the elimination of tobacco consumption, moderation of alcohol intake and chemoprevention are urgently needed.

Maxillofacial Injuries Related to the Syrian War in the Civilian Population.

PURPOSE: Injured Syrian patients are commonly transferred to local hospitals and field clinics immediately after being injured. Since February 2011, more than 2,000 injured Syrian patients have been transferred to and treated in northern Israeli medical centers. The aim of the present study was to evaluate the epidemiology and general nature of the injuries, with special attention to maxillofacial (MF) injuries. PATIENTS AND METHODS: The medical files of all injured Syrian patients who were treated in 2 major medical centers in northern Israel from December 2012 through December 2015 were reviewed. Computerized data were collected and analyzed based on the cause of injury, anatomic location, Injury Severity Score (ISS) at admission, hospitalization duration, and duration in the intensive care unit. RESULTS: The study cohort included 227 patients (204 male [90%], 23 female [10%]; mean age, 24.5 ± 11 yr). The median calculated ISS was 20.6 ± 13.9. The mean interval from injury to recorded admission time was 86.37 hours. Fifty patients had MF injuries (22%). Of these, 45 were adults (44 men, 6 women). Patients' age ranged from 16 to 27.3 years. The mean interval from injury to time of admission was 24 hours and the mean ISS on admission was 24.5 ± 12.7, which was significantly higher than the overall ISS (median, 24.5 vs 16; P = .005). CONCLUSION: Several features observed in the present study had a direct effect on treatment quality and success. Those features included delay from injury to hospital admission; lack of body armor protection, including helmets, which explained the high prevalence of MF injuries; and the multiple sites of injury.

Indications for Elective Tracheostomy in Reconstructive Surgery in Patients With Oral Cancer.

BACKGROUND: Oral cancer surgery carries a high risk of upper airway obstruction; yet optimal airway management approach remains controversial. AIM OF STUDY: The purpose of the present study was to evaluate the use of tracheostomy in oncological patients undergoing oral cancer surgery with intra oral flap reconstruction. METHODS: The study cohort included 75 patients with oral cancer, who underwent major intraoral resections and reconstruction with vascularized flaps. RESULTS: Thirty-six percent of the patients received elective tracheostomy (27 patients). Mean hospital stay of the patients with tracheostomy was 28.4 ±â€Š12.5 days compared with 9.7 ±â€Š2.1 days in the nontracheostomy patients. A scoring system rendered from this study suggests that patients with a total scoring at or above 8 should be considered for elective tracheostomy. CONCLUSIONS: With appropriate postoperative monitoring, selected patients can be managed without routine elective tracheostomy, yet, patients with comorbidities, mostly elderly patients, which undergo surgical resection and reconstruction in high-risk areas that can result in a bulky flap that pose danger to the postoperative airway, should receive elective tracheostomy.

The Possible Role of Dental Implants in the Etiology and Prognosis of Osteomyelitis: A Retrospective Study.

PURPOSE: The aim of this study was to describe the clinical outcome of osteomyelitis of the mandible or maxilla following dental implants. A detailed treatment protocol is also proposed. MATERIALS AND METHODS: Electronic data of all the patients who were treated between October 2009 and November 2014, in three maxillofacial surgical departments, were reviewed. Computed databases were searched for the diagnosis of osteomyelitis of the mandible or maxillas (ICD9 code 526.2), and medical files were analyzed. Treatment outcome was considered successful if only primary treatment (debridement and antibiotic therapy) was applied. Statistical analysis was performed to compare treatment outcomes in the different etiologic groups. RESULTS: The cohort included 29 men and 25 women, with histologically and clinically proven osteomyelitis. The mean age was 59 years (range, 24 to 70 years). Forty patients had complete remission, as opposed to 14 patients who failed the primary treatment and required a more aggressive surgical intervention (11 had segmental mandibulectomy, 2 patients had marginal mandibulectomy, and 1 patient had maxillectomy). Most failures were in the dental implantation group. A previous dental implant was an independent factor for primary treatment failure and the need for aggressive surgical intervention (P = .0001). CONCLUSION: The results of this retrospective study suggest that a previous dental implant is an independent predictive factor of failure in primary treatment in osteomyelitis of the mandible or maxilla. Also, dental implant-induced osteomyelitis is a rare pathology, but it presents an aggressive subtype of osteomyelitis, and requires a broader and more comprehensive management.

Level IIB Neck Dissection in Oral Squamous Cell Carcinoma: Science or Myth?

Selective neck dissection enables us to reduce the morbidity of neck dissection while maintaining the same oncological results, mainly in clinically negative neck N0. The most common morbidity associated with selective neck dissection is spinal accessory nerve dysfunction and related shoulder disability, which are encountered during dissection of level IIB.The aim of authors' study is to evaluate the incidence of sublevel IIB lymphatic metastasis in clinically N0 oral squamous cell carcinoma (OSCC) patients.The study group comprised 48 men (68%) and 22 women (32%). The median number of the lymph nodes removed from level IIB was 6.5. All the investigated necks were clinically classified as N0, of which 14 (20%) turned out to have an occult nodal metastasis, including only 1 patient (1.42%) of level IIB occult metastasis, which originated from the primary tumor located in the tongue and also metastasized to level IIA. The most associated morbidity was shoulder pain and dysfunction, which presented in 60% of the patients.Also, an electronic search was conducted to find relevant studies investigating the prevalence of level IIB metastasis in OSCC. Ten studies were included for full text review, including the current study. The overall incidence of level IIB metastasis is 4% (17 patients); of these 17 patients, only 4 patients had isolated level IIB nodal metastases (2%).To conclude, neck dissecting, including dissecting level IIB, remains the keystone of treating OSCC. Its prognostic and therapeutic value exceeds its associated morbidity; therefore, dissecting level IIB is recommended in treating OSCC in clinically N0 patients.

The Role of Fine Needle Aspiration in the Diagnosis of Parotid Gland Tumors: Correlation With Preoperative Computerized Tomography Tumor Size.

The role of fine needle aspiration cytology (FNAC) in the diagnosis of parotid gland masses is still controversial, regarding its sensitivity and specificity that vary between 41% and 100% and between 86% and 100% respectively.The aim of this study was to identify the specificity and sensitivity of FNAC of parotid gland tumors in relation to the tumor size as characterized preoperatively by computer tomography. The medical files of 79 patients whom were referred to the MaxilloFacila Surgery Department, Rambam medical center, over a 10.5-year period (2000-2010) were analyzed retrospectively.The extensity of the operation was determined by the location of the tumor as presented in computed tomography (CT) radiography, and preoperative FNAC examination.The majority of the masses were located in the superficial lobe (88.52%), and only 11.48% of the patients were located in the deep lobe (8:1 ratio). FNAC results were nondiagnostic in 7 patients (8.86%), 62 patients were diagnosed as inflammatory and benign lesion in (78.48%), malignant tumors were diagnosed in 10 patients (12.65%).The sensitivity in our study was 90%, the specificity was 98%, positive predictive value was 90%, negative predictive value was 98%, and diagnostic accuracy was 88%. The positive predictive value was 90%, the negative predictive value was 98%.Analyzing the effect of the preoperative CT size upon the accuracy of the FNAC diagnosis, we found that lesion with preoperative CT size greater than 24 mm has a more accurate FNAC result (P = 0.034).