TNF-alpha blockade in Primary Chronic Non-Bacterial Osteomyelitis of the Mandible.

OBJECTIVES: Primary chronic Non-Bacterial Osteomyelitis of the jaw is a rare auto-inflammatory disease of unknown aetiology that bears pathophysiological resemblance to both the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome in adults and chronic recurrent multifocal osteomyelitis (CRMO) in children. Both SAPHO and CRMO respond to TNF-alpha blockade. Previously reported treatment regimens in CNOM including non-steroidal anti-inflammatory drugs, corticosteroids, antibiotics, anti-resorptive therapy, and surgery all bear disappointing results. TNF- α blockade is suggested as a treatment option by some experts but this is not backed by any clinical data.We sought to retrospectively and exhaustively report our experience of anti-TNF alpha therapy in refractory CNOM. METHODS: Fifteen patients with refractory CNOM and high disease burden were referred to our centre. TNF- α blockade was attempted in 10 cases, given its efficacy in neighbouring diseases, its good tolerance profile and failure of previous treatment strategiesWe herein retrospectively report detailed outcomes for all patients having received anti-TNF alpha therapy for this indication in our centre. RESULTS: TNF-α-targeting therapy resulted in a rapid and sustained remission in a majority of patients with CNOM, without serious adverse events. Treatment was tapered and stopped without relapse in some patients despite a refractory course of several years. Male sex seems to be associated with a poorer outcome. CONCLUSION: Our results suggest that blocking TNF-α is efficient and safe in CNOM.

Mandibular revascularization using a humeral periosteal free flap: A technical note.

The vascularized periosteal free flap transposes a non-irradiated soft tissue with neoangiogenesis, bone induction, and osteogenesis qualities. A surgical technique using a humeral periosteal free flap is described for the treatment of recurrent osteoradionecrosis of the lower jaw. The humeral periosteal free flap is a technique associated with low morbidity. The procedure described avoids sacrificing major vessels as seen in other common flap procedures. Hence, this revascularization approach is equivalent to a prevention technique that should be considered early in the development of osteoradionecrosis to avoid further damage and challenging reconstruction.

Geriatric assessment and quality of life for 2 years in older patients with head and neck cancer.

Due to the location and toxicity of treatments, head and neck cancer (HNC) has a major impact on quality of life (QoL). Objective: to assess the effects of geriatric-assessment (GA)-driven interventions on QoL over 2 years in older adults with HNC.EGeSOR was a randomized study of HNC patients aged ≥65, receiving a pretreatment GA, a geriatric intervention and follow-up (intervention) or standard of care (control). The primary endpoint was QoL score using the European Organisation for Research and Treatment of Cancer's (EORTC QLQ-C30) and HNC (QLQ-HN35) QoL questionnaires over 24 months.In total, 475 patients were included (median age: 75.3; women: 31%; oral cancer: 44%). QoL scores improved over 24 months with various trajectories, without significant differences between the groups. A total of 74% of patients (interventional group) did not receive the complete intervention. Cancer characteristics, functional status, and risk of frailty were associated with change in the Global Health Status QoL score.There is a need to develop an alternative model of implementation such as patient-centered health-care pathways. TRIAL REGISTRATION: NCT02025062.

Postoperative infections after sinus lifts and onlay grafts in penicillin allergic patients.

INTRODUCTION: The primary objective of this retrospective study was to determine whether patients treated with clindamycin due to a reported allergy to penicillin have an increased risk of postsurgical infections after sinus lifts and onlay grafts. MATERIAL AND METHODS: A retrospective cohort study was performed on patients who underwent bone reconstruction procedures between October 2018 and December 2020. Data from all patients operated at the Pitié Salpêtrière University Hospital for sinus lifts or onlay grafts were collected. All surgical procedures studied were performed under preoperative and postoperative antibiotic prophylaxis with either amoxicillin (+/- clavulanic acid) or clindamycin for patients with reported penicillin allergy. Bone graft-associated infections as well as graft failures were recorded. RESULTS: In this study, 111 patients received bone reconstructions (89 sinus lifts and 148 onlay grafts). In the sinus lifts group, infections occurred in 5 of 89 sites (5.6 %). The infection rate was 28.5 % (7 graft sites) and only 3.9 % (82 graft sites) for clindamycin and for amoxicillin, respectively. In the onlay graft group, infections occurred in 25 of 148 sites (16.8 %). The infection rate was 56 % and only 12 % for clindamycin (18 graft sites) and for amoxicillin, respectively (130 graft sites). Non-Penicillin treated patients had a higher risk of infection with an odd ratio of 7.8 (95 % CI 1.1-54.8, P = 0.04) and 4.8 (95 % CI 1.9-12.3, P = 0.001) compared with patients receiving amoxicillin for onlay grafts and sinus lifts. CONCLUSION: Penicillin allergy and clindamycin use after sinus lift and onlay graft procedures were associated with a higher rate of infection and may be a risk factor for complications related to bone reconstruction surgery.

Extensive head and neck skin cancers: Carcinologic surgery as a cornerstone of treatment.

BACKGROUND AND OBJECTIVE: The prevalence of extensive skin cancers increases with the aging of the population. Surgical management is the gold standard of curative treatment while morbidity is not negligible. There are few data in the literature concerning extensive head and neck cutaneous cancers. The aim of this article is to report our experience of curative management of head and neck extensive skin cancers. METHOD: In this single-center retrospective observational study, we report a series of 17 patients with extensive skin facial cancers treated by surgery between 2013 and 2022 in the maxillofacial surgery department of the Pitié-Salpêtrière Hospital. We collected clinical, therapeutic, histological, and carcinologic data. RESULTS: The median age of the patients was 66 years [35-94]. There were 9 male and 8 women. Scalp (39 %) and cheek (22 %) locations were the most frequent ones. The most frequent histological types were squamous cell carcinoma (61 %) and basal cell carcinoma (17 %). Three patients received neoadjuvant treatment. The surgical treatment consisted mainly of carcinological resection followed by one-stage reconstruction by free flap for 5 (30 %) patients and without reconstruction for primary for 12 (70 %) patients, of whom 8 benefited from secondary reconstruction. Five patients received adjuvant radiotherapy or radio-chemotherapy. With a median follow-up of 40 months (2-72), the median overall survival was 40 months (12-72). CONCLUSION: We know that extensive skin cancers of the face have a good prognosis on condition that the carcinological and reconstructive requirements are respected. Surgery remains the cornerstone of treatment while the improvement of adjuvant therapies, in particular the rise of immunotherapies or other targeted therapies, may allow to limit recurrences.

Epidemiology of facial skin cancers managed in a French ambulatory surgical center.

INTRODUCTION: Approximately 80,000 cases of skin cancer are diagnosed annually in France. The management of these cancers can occur in both university hospital centers and ambulatory surgery centers. Limited data exist regarding the epidemiology of cutaneous cancers treated through ambulatory surgery centers. The objective of our study is to describe the epidemiological characteristics of cutaneous cancers managed in a tertiary ambulatory surgery center. METHODS: This is a retrospective, single-center observational study. The included patients were those who underwent surgical excision of one or more skin cancers within the maxillofacial department of a tertiary ambulatory surgery center. Clinical, therapeutic, histopathological, and follow-up data (additional surgery if margins were not clear, progression, recurrence, second cancer…) were collected. RESULTS: Among the n = 1931 patients operated for a head and neck skin tumor from September 2018 to July 2022, n = 426 (22 %) were diagnosed with cancer upon histological analysis. The median age was 76 years (31-100), with a male-to-female ratio of 1/1. The most frequent locations were the nose (23 %) and cheek (20 %). Ten percent of patients had dual-site skin cancer at initial diagnosis. The most common histological types were basal cell carcinoma (77 %) and squamous cell carcinoma (18 %). Surgical treatment primarily consisted of "excision-reconstruction with local flap" (51 %) or "excision-suture" (34 %). Resection margins were mostly clear (65 %), and only six patients (2 %) experienced local recurrence or progression during follow-up. CONCLUSIONS: Skin cancers are prevalent in ambulatory practice. Surgical treatment allows for effective control of the cancer. Photoprotection, particularly in immunocompromised patients, remains crucial for prevention.

A Radiomics Approach to Identify Immunologically Active Tumor in Patients with Head and Neck Squamous Cell Carcinomas.

BACKGROUND: We recently developed a gene-expression-based HOT score to identify the hot/cold phenotype of head and neck squamous cell carcinomas (HNSCCs), which is associated with the response to immunotherapy. Our goal was to determine whether radiomic profiling from computed tomography (CT) scans can distinguish hot and cold HNSCC. METHOD: We included 113 patients from The Cancer Genome Atlas (TCGA) and 20 patients from the Groupe Hospitalier Pitié-Salpêtrière (GHPS) with HNSCC, all with available pre-treatment CT scans. The hot/cold phenotype was computed for all patients using the HOT score. The IBEX software (version 4.11.9, accessed on 30 march 2020) was used to extract radiomic features from the delineated tumor region in both datasets, and the intraclass correlation coefficient (ICC) was computed to select robust features. Machine learning classifier models were trained and tested in the TCGA dataset and validated using the area under the receiver operator characteristic curve (AUC) in the GHPS cohort. RESULTS: A total of 144 radiomic features with an ICC >0.9 was selected. An XGBoost model including these selected features showed the best performance prediction of the hot/cold phenotype with AUC = 0.86 in the GHPS validation dataset. CONCLUSIONS AND RELEVANCE: We identified a relevant radiomic model to capture the overall hot/cold phenotype of HNSCC. This non-invasive approach could help with the identification of patients with HNSCC who may benefit from immunotherapy.

Reliability of gene-expression profiling from tumor biopsy for refining neoadjuvant strategies in patients with head and neck squamous cell carcinoma.

While recent clinical trials evaluating neoadjuvant immune checkpoint inhibitors showed promising results in a subset of patients with head and neck squamous cell carcinomas (HNSCC), there is a need for the identification of robust biomarkers in tumor biopsies to improve patient selection. This context suggests unravelling transcriptomic heterogeneity between untreated paired samples from same patient with HNSCC. Based on previous studies and the analysis of publicly available gene expression profiles of paired tumor biopsies and surgical resection specimens, we discuss the reliability of tumor biopsy to capture the overall activation of targetable biological pathways in patients with HNSCC. Further studies investigating intratumor transcriptomic heterogeneity as well as the effect of sampling methods on gene expression are needed in patients with HNSCC, in order to develop innovative and relevant biomarker-driven neoadjuvant strategies.

Datasets for gene expression profiles of head and neck squamous cell carcinoma and lung cancer treated or not by PD1/PD-L1 inhibitors.

Identification of tumors harboring an overall active immune phenotype may help for selecting patients with advanced head and neck squamous cell carcinomas (HNSCC) and non-small cell lung cancer (NSCLC) who may benefit from immunotherapies. In this context, we generated targeted gene expression profiles in three and two independent cohorts of patients with HNSCC or NSCLC respectively, treated or not by PD-1/PD-L1 inhibitors. Notably, we generated two datasets including 102 and 82 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors. Clinical information, including detailed survival raw data, is available for each patient, allowing to test association between gene expression data and patient survival (overall and progression-free survival). Moreover, we also generated gene expression datasets of 27 paired HNSCC samples from diagnostic biopsies and versus surgically resected specimens as well as 33 paired HNSCC samples at initial diagnosis (untreated) and at recurrence. Those datasets may allow to test the stability of a given biomarker across paired samples.

Immunologically active phenotype by gene expression profiling is associated with clinical benefit from PD-1/PD-L1 inhibitors in real-world head and neck and lung cancer patients.

INTRODUCTION: Identification of tumours harbouring an overall active immune phenotype may help for selecting patients with advanced head and neck squamous cell carcinomas (HNSCC) and non-small cell lung cancer (NSCLC) who may benefit from immunotherapies. Our objective was to develop a reliable and stable scoring system to identify those immunologically active tumours. METHODS: Using gene expression profiles of 421 HNSCC, we developed a score to identify immunologically active tumours. Validation of the 'HOT' score was done in 40 HNSCC and 992 NSCLC. Stability of the 'HOT' score was tested in paired HNSCC samples from diagnostic biopsies versus surgically resected specimens, untreated versus recurrent samples, and pre-versus post-cetuximab samples in a total of 76 patients. The association between the 'HOT' score with overall survival (OS) and progression-free survival (PFS) was tested in 184 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors. RESULTS: A 27-gene expression based 'HOT' score was correlated with: (i) PD-L1 and IDO1 expression, (ii) TCD8 infiltrate and (iii) activation of the IFN-γ pathway. The HOT score concordance when comparing diagnostic biopsies and surgically resected specimens was higher than in untreated samples versus recurrent or pre-versus post-cetuximab samples. In 102 and 82 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors, the HOT score was associated with an improved OS and PFS in multivariate analysis. CONCLUSION: The 'HOT' score is a simple and robust approach to identify real-world patients with HNSCC and NSCLC immunologically active tumours who may benefit from PD-1/PD-L1 inhibitors.

Effectiveness of Geriatric Assessment-Driven Interventions on Survival and Functional and Nutritional Status in Older Patients with Head and Neck Cancer: A Randomized Controlled Trial (EGeSOR).

This study assesses the efficacy of Geriatric Assessment (GA)-driven interventions and follow-up on six-month mortality, functional, and nutritional status in older patients with head and neck cancer (HNC). HNC patients aged 65 years or over were included between November 2013 and September 2018 by 15 Ear, Nose, and Throat (ENT) and maxillofacial surgery departments at 13 centers in France. The study was of an open-label, multicenter, randomized, controlled, and parallel-group design, with independent outcome assessments. The patients were randomized 1:1 to benefit from GA-driven interventions and follow-up versus standard of care. The interventions consisted in a pre-therapeutic GA, a standardized geriatric intervention, and follow-up, tailored to the cancer-treatment plan for 24 months. The primary outcome was a composite criterion including six-month mortality, functional impairment (fall in the Activities of Daily Living (ADL) score ≥2), and weight loss ≥10%. Among the patients included (n = 499), 475 were randomized to the experimental (n = 238) or control arm (n = 237). The median age was 75.3 years [70.4-81.9]; 69.5% were men, and the principal tumor site was oral cavity (43.9%). There were no statistically significant differences regarding the primary endpoint (n = 98 events; 41.0% in the experimental arm versus 90 (38.0%); p = 0.53), or for each criterion (i.e., death (31 (13%) versus 27 (11.4%); p = 0.48), weight loss of ≥10% (69 (29%) versus 65 (27.4%); p = 0.73) and fall in ADL score ≥2 (9 (3.8%) versus 13 (5.5%); p = 0.35)). In older patients with HNC, GA-driven interventions and follow-up failed to improve six-month overall survival, functional, and nutritional status.

A Retrospective Study of 23 Cases: Are Lichenoid Lesions of the Labial Mucosa Induced?

Background Lichen planus (LP) is a pathology that affects the skin and the mucosa. The lips are rarely involved but represent a diagnostic challenge in those cases. Oral lichenoid lesions (OLL) are defined as lesions that resemble oral lichen planus (OLP) but do not fully meet the clinical and/or histologic criteria for OLP. This study aimed to present our case series and to study the correlation between the location of the lesion and the dental factor (resin composite, amalgams, crowns, abrasive teeth, and mandibular crossbite) that could cause the lesion. Methods We conducted a retrospective observational study of 23 patients with LP/OLL of the lips treated in the Department of Oral Mucosal Pathology of the Department of Stomatology and Maxillofacial Surgery of the Pitié-Salpêtrière Hospital in Paris between January 2017 and February 2021. We noted the location of the lesion (upper, lower, or both lips), medical history, treatments, smoking habits, and the aspect of the teeth facing the lesion. Patients received a local corticoid treatment and were monitored via follow-up. Results Sixteen patients had lesions on the upper lip, two on the lower lip, and five on both lips, and most patients (n = 14, 60.1%) had a dental factor facing the lesion (e.g., abrasive teeth, resin composites, dental crowns, and mandibular crossbite). Six patients received clobetasol propionate, and 15 patients received a preparation combining betamethasone and benzocaine (Orabase, ConvaTec, Deeside, UK). Fourteen patients returned for post-treatment follow-up consultations approximately two months after treatment. Seven patients saw clinical improvement, five had partial improvement, and two had no improvement. Conclusions Lesions of the labial mucosa appear to be a rare condition in LP/OLL. The difference between LP and OLL can be difficult, even with histological analysis. Its pathogenesis remains unknown, although some studies found evidence of lichenoid reactions of the lips in contact with dental composite restorations. In our study, 14 of our patients had a dental factor facing the lesions. However, our study failed to show a correlation between the presence of an inducing factor and the lesion. In a future study, the potential effect of dental inducing factor removal could be studied. This topic requires further investigations, particularly regarding the inducing factor and the optimal therapeutic approach.

Unmet Needs and Perspectives in Oral Cancer Prevention.

Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation.

Maxillofacial free flap surgery outcomes in critical care: a single-center investigation looking for clues to improvement.

BACKGROUND: Maxillofacial surgery for free flap reconstructions is associated with many complications due to technical complexity and comorbidity of patients. With a focus on critical care, the authors studied the impact of complications to highlight predictors of poor postoperative outcomes in order to implement optimization protocols. METHODS: This case-control study analyzed the relationship between perioperative variables and postoperative medical and surgical complications of patients who underwent head and neck surgery using fibular and forearm free flaps. The primary objective was the incidence of prolonged intensive care unit (ICU) length of stay (LOS). Secondary objectives were the incidence of ICU readmissions, postoperative infections, and 1-year mortality. A univariable logistic regression model was used. A study of mortality was performed with survival analysis. Regarding our primary objective, we performed a Benjamini-Hochberg procedure and a multivariable Poisson regression with defined variables of interest. RESULTS: The data of 118 hospital stays were included. Prolonged ICU LOS was observed in 47% of cases and was associated with chronic obstructive pulmonary disease, pneumopathies, intraoperative blood transfusion, and surgical duration. Medical and surgical complications were associated with prolonged ICU LOS. After the Benjamini-Hochberg procedure, infectious complications, complications, major complications, total number of pneumopathies, and operative time remained significant. At least one complication was experienced by 71% of patients during the hospitalization, and 33% of patients suffered from major complications. Infectious complications were the most common (40% of patients) and were mainly caused by pneumonia (25% of patients); these complications were associated with low preoperative hemoglobin level, intraoperative blood transfusion, accumulation of reversible cardiovascular risk factors, chronic alcohol consumption, and duration of surgery. Pneumonia was specifically associated with chronic obstructive pulmonary disease. The ICU readmission rate was 10% and was associated with lower preoperative hemoglobin level, pneumopathies, surgical duration, and use of a fibular flap. The 1-year mortality was 12%, and the survival analysis showed no association with prolonged ICU LOS. Poisson regression showed that ICU LOS was prolonged by smoking history, lower preoperative hemoglobin level, intraoperative blood transfusion, major complication, and pneumopathies. CONCLUSIONS: Practices such as blood management and respiratory prehabilitation could be beneficial and should be evaluated as a part of global improvement strategies.

Identification of a Gene-Expression-Based Surrogate of Genomic Instability during Oral Carcinogenesis.

BACKGROUND: Our goal was to identify a gene-expression-based surrogate of genomic instability (GI) associated with the transformation of oral potentially malignant disorder (OPMD) into oral squamous cell carcinoma (OSCC). METHODS: GI was defined as the fraction of genome altered (FGA). Training sets included the CCLE and TCGA databases. The relevance of the enrichment score of the top correlated genes, referred to as the GIN score, was evaluated in eight independent public datasets from the GEO repository, including a cohort of patients with OPMD with available outcome. RESULTS: A set of 20 genes correlated with FGA in head and neck SCC were identified. A significant correlation was found between the 20-gene based GIN score and FGA in 95 esophagus SCC (r = 0.59) and 501 lung SCC (r = 0.63), and in 33 OPMD/OSCC (r = 0.38). A significantly increased GIN score was observed at different stages of oral carcinogenesis (normal-dysplasia -OSCC) in five independent datasets. The GIN score was higher in 10 OPMD that transformed into oral cancer compared to 10 nontransforming OPMD (p = 0.0288), and was associated with oral-cancer-free survival in 86 patients with OPMD (p = 0.0081). CONCLUSIONS: The GIN score is a gene-expression surrogate of GI, and is associated with oral carcinogenesis and OPMD malignant transformation.

Defining biomarkers in oral cancer according to smoking and drinking status.

Introduction: Oral Squamous Cell Carcinomas (OSCC) are mostly related to tobacco consumption eventually associated to alcohol (Smoker/Drinker patients: SD), but 25-30% of the patients have no identified risk factors (Non-Smoker/Non-Drinker patients: NSND). We hypothesized that these patients have distinguishable immune profiles that could be useful for prognosis. Materials and Methods: Cells present in immune tumor microenvironment (TME) and blood from 87 OSCC HPV-negative patients were analyzed using a multiparameter flow cytometry assay, in a prospective case-control study. Cytokine levels in tumor supernatants and blood were determined by a cytometric bead array (CBA) assay. Results: Normal gingiva and blood from healthy donors (HD) were used as controls. A significant increase of granulocytes (p<0.05 for blood), of monocytes-macrophages (p<0.01 for blood) and of CD4+ T cells expressing CD45RO and CCR6 (p<0.001 for blood; p<0.0001 for TME) as well as higher levels of IL-6 (p<0.01 for sera, p<0.05 for tumor supernatant) were observed in SD patients as compared to NSND OSCC patients and HD. High percentages of CD4+ T cells expressing CD45RO and CCR6 cells in tumor tissue (p=0.05) and blood (p=0.05) of SD OSCC patients were also associated with a poorer prognosis while a high percentage of regulatory T cells (Treg) in tumor tissue was associated with a more favorable prognostic factor (p=0.05). Also, a higher percentage of blood CD8+ T lymphocytes among CD45+ cells in NSND patients was associated with a better disease-free survival (p=0.004). Conclusion: Granulocytes, monocytes-macrophages, and CD4+ T cells expressing CD45RO and CCR6 in blood and TME as well as serum IL-6 can therefore distinguish OSCC SD and NSND patients. Quantifying the proportion of CD4+ T cells expressing CD45RO and CCR6 and of Treg in SD patients and CD8+ T cells in NSND patients could help defining the prognostic of OSCC patients.

Early changes in the immune microenvironment of oral potentially malignant disorders reveal an unexpected association of M2 macrophages with oral cancer free survival.

Understanding the dynamics of the immune microenvironment is critical to the development of immuno-based strategies for the prevention of oral potentially malignant disorders transformation to oral squamous cell carcinoma (OSCC). We used laser capture microdissection and RNA-sequencing to profile the expression of 13 matched pairs of epithelial versus stromal compartments from normal mucosa, hyperplasia, dysplasia, and invasive tumors in the 4-nitroquinolein (4-NQO) murine model of oral carcinogenesis. Genes differentially expressed at each step of transformation were defined. Immune cell deconvolution and enrichment scores of various biological processes including immune-related ones were computed. Immunohistochemistry was also performed to characterize the immune infiltrates by T-cells (T-cells CD3+, helper CD4+, cytotoxic CD8+, regulatory FoxP3+), B-cells (B220+), and macrophages (M1 iNOS+, M2 CD163+) at each histological step. Enrichment of three independent M2 macrophages signatures were computed in 86 oral leukoplakia with available clinical outcome. Most gene expression changes were observed in the stromal compartment and related to immune biological processes. Immune cell deconvolution identified infiltration by the macrophage population as the most important quantitatively especially at the stage of dysplasia. In 86 patients with oral leukoplakia, three M2 macrophages signatures were independently associated with improved oral cancer-free survival. This study provides a better understanding of the dynamics of the immune microenvironment during oral carcinogenesis and highlights an unexpected association of M2 macrophages gene expression signatures with oral cancer free survival in patients with oral leukoplakia.