Sequential combination of Sonic Hedgehog inhibitors followed by consolidation radiotherapy in locally advanced basal cell carcinoma.

BACKGROUND: Sonic Hedgehog inhibitors (SHHis) are an effective treatment in locally advanced basal cell carcinoma (laBCC), but the use of these drugs is limited by adverse events and relapse at discontinuation in around half of patients. A few cases of patients treated concomitantly by radiotherapy (RT) and SHHis have been reported in the literature, suggesting that the combination results in an improved overall response. Maintaining complete response after stopping treatment is a concern, especially since resuming treatment in the case of relapse does not guarantee a new therapeutic response. The optimal combination and sequence of treatment to improve local control of laBCCs are not yet defined. OBJECTIVE: We hypothesized that consolidation RT after complete response to SHHis could reduce the risk of relapse at discontinuation. METHODS: We present a case series of patients with laBCCs who achieved complete response (CR) after SHHi treatment and were treated with consolidation RT. Patients were evaluated by a skin cancer board. The closure RT technique and dosage were refined by a radiotherapist. RESULTS: Eleven patients were included. SHHis were prescribed for 5 months (range 4-11). Consolidation RT was performed after CR to SHHis and discontinuation. RT was delivered at a median dose of 45 Gy (range 40.5-66) in 10 fractions (range 9-33). With a median follow-up of 23 months, all patients maintained complete clinical response. This strategy was well tolerated with no grade 3 adverse events. CONCLUSION: SHHi treatment followed by RT consolidation after drug discontinuation seems effective and safe. Further studies are needed to develop a precise strategy for the management of laBCCs.

Monomer release from orthodontic retentions: An in vitro study.

INTRODUCTION: The adhesives used to bond orthodontic retentions are low-loaded composite resins with a resinous matrix containing bisphenol A diglycidyl ether dimethacrylate synthesized from bisphenol A (BPA), fluidizers such as triethylene glycol dimethacrylate (TEGDMA) and hydrophilic polymers such as hydroxyethylmethacrylate. BPA disrupts the endocrine balance, and TEGDMA has high risks for human health: eg, allergies and cytotoxicity. The aim of this study was to evaluate in vitro the release of monomers from orthodontic bonded retentions. METHODS: A reproducible model of bonded retentions was carried out using calibrated molds. We analyzed the release of monomers by gas phase chromatography coupled with mass spectrometry. RESULTS: This model allowed us to qualitatively and quantitatively evaluate the in-vitro release of monomers from orthodontic adhesives. The quantitative and qualitative analyses showed no BPA release above the 0.02 ppm detection limit. A greater release of TEGDMA was observed with Transbond LR (31.7 µg/mL) than with Transbond XT (13.12 µg/mL) (both, 3M Unitek, Monrovia, Calif). Other toxic components (iodobenzene, iodobiphenyl, triphenyl stibine, and so on) were also identified. CONCLUSIONS: Toxic and carcinogenic molecules not mentioned in the material safety data sheets were identified.

Release of monomers from orthodontic adhesives.

INTRODUCTION: Most composite resins release both bisphenol A (BPA), which disrupts the endocrine balance, and triethylene glycol dimethacrylate (TEGDMA), which has high risks for human health: eg, allergies and cytotoxicity. The aim of this study was to characterize monomers released from orthodontic adhesives. METHODS: We studied samples of orthodontic adhesives by associating 2 techniques: gas phase chromatography and mass spectrometry. RESULTS: The in-vitro analysis detected significant quantities of BPA, TEGDMA, and other monomers in orthodontic adhesives used in daily practice: Transbond XT, Transbond Supreme LV (both, 3M Unitek, Monrovia, Calif), Blugloo (Ormco, Orange, Calif), and MonoLok 2 (Rocky Mountain Orthodontics, Denver, Colo). CONCLUSIONS: Clinicians should consider that orthodontic adhesives contain BPA, an endocrine disruptor; TEGDMA, an allergic and a cytotoxic compound; and carcinogenic genotoxic compounds. These molecules are not mentioned in the material safety data sheets. Manufacturers should declare all components of dental composites to identify these substances that may result in allergic or undesirable side effects for patients and dental staff.

Relevance of detection of RAF fusion transcripts in pan-negative melanoma in routine practice.

Pan-negative melanomas account for 30% of melanomas. In case of immunotherapy failure, therapeutic options are limited. Oncogene fusions represent a target of interest in many solid cancers. In melanoma, the frequency of oncogene fusion is not well documented and not routinely investigated. We conducted a single-center retrospective study. The objective was to determine the frequency of oncogene fusion detected by RNA sequencing, in patients with advanced or metastatic pan-negative melanoma. In parallel, an extended molecular alteration search was performed using extended targeted next-generation sequencing. We identified 59 patients with advanced pan-negative melanoma between January 2021 and January 2023. It was a cutaneous melanoma in 71.1% of the cases, a mucous melanoma in 15.2% of the cases. We identified nine patients with a RAF fusion, including seven BRAF gene fusion and two RAF1 fusion. Of the other molecular alterations, NF1 mutation was the most frequent molecular alteration identified. Among the nine patients with RAF fusions, all the patients initially received treatment with anti-PD1 ± anti-CTLA4 immunotherapy. After immunotherapy failure, five patients benefited from second-line targeted therapy (two with BRAF and MEK inhibitors combination, three MEK inhibitors alone). The response rate was 20%. In a population of pan-negative melanoma, we detected 15.2% of RAF fusion. Fusion detection allowed the introduction of a second line of targeted therapy, in the absence of a validated therapeutic option in 55.5% of cases. This study suggests the relevance of detecting RAF fusion in a selected population.

Patterns and sexual dimorphism of non-syndromic hypodontia among a French orthodontic population.

OBJECTIVES: This retrospective study aimed to estimate the prevalence of non-syndromic congenitally missing teeth (CMT) and to explore the frequency of CMT patterns in a French orthodontic population. In addition, the study sought to assess sex-based differences in CMT patterns. DESIGN: Panoramic radiographs of 4569 orthodontic patients between 9 and 21 years-old performed over a 16-year period (2006-2022) were examined to identify non-syndromic tooth agenesis, excluding third molars. A chi-square test or a Fisher exact test were used to determine the difference in the prevalence of tooth agenesis between sex and between arches. RESULTS: Tooth agenesis was observed in 7.3% of the sample (7.9% for females and 6.6% for males). Approximately 86% of the included subjects presented 1 or 2 missing teeth. Single tooth agenesis was significantly more frequent in females than males (p = 0.002, χ2). In total, 23 of the 67 different patterns of CMT observed, were present more than once. 75.5% of male patients and 79.5% of female patients presented one or both missing lateral incisors or second premolars, rarely affected at the same time. This study showed no sex difference in the patterns of tooth agenesis. LIMITATIONS: This study has limitations due to its retrospective nature and our findings apply solely to an orthodontic population from a white ethnic background. CONCLUSIONS: Clinicians should be aware of this particular incisor/premolar phenotype regardless of biological sex. Issues associated with congenitally missing teeth can be managed more effectively with early teenage diagnosis.

Statistical Study Concerning Extraction and Non-Extraction Methods in Orthodontic Treatments.

INTRODUCTION: The need to extract permanent teeth for the correction of dento-maxillary anomalies remains even today a controversy in orthodontic therapy. The purpose of this study was to assess the orthodontist's point of view on the extraction and non-extraction methods used in orthodontic treatments, regarding clinical experience. MATERIAL AND METHODS: A de novo conceived questionnaire was elaborated by means of Google Forms and it comprised 22 questions regarding gender, age, different proprieties and aspects of both extraction and non-extraction methods and the percentage of treated patients who developed an increase in dental sensitivity and caries activity following the therapeutic stripping procedure. RESULTS: 204 orthodontists answered the questionnaire. The respondents chose dental stripping (IPR-interproximal reduction) as the most used non-extraction method in their orthodontic practice with 34,3%, followed by over-expansion and dental stripping 24%. The probability that females will try to avoid dental extractions is 1.888 times higher compared to males. The association is statistically significant (p-value 0.0336). 70,1% of clinicians state that they use dental stripping as a non-extraction method to gain space even when there is NO Bolton discrepancy. In Class III cases, for reducing crowding and correcting the dental relations, 65.2% of doctors opt for dental stripping, while 34.8% do not avoid the extraction of a lower incisor. CONCLUSIONS: Among the non-extraction methods for creating space, the most used by the surveyed orthodontists was dental stripping IPR. Tooth extraction remains a solution used by orthodontists for treating dentomaxillary disharmonies with crowding.

Comparative Evaluation of Dental Enamel Microhardness Following Various Methods of Interproximal Reduction: A Vickers Hardness Tester Investigation.

Interproximal enamel reduction, also known as stripping, is a common orthodontic procedure that reduces the mesiodistal diameter of teeth, allowing for a balance of available space in dental arches. The aim of this study was to assess the enamel surface microhardness resulting from the application of currently available methods for interproximal reduction. Forty-two extracted human permanent teeth were divided into six different groups, each subjected to a therapeutic stripping procedure using various methods (i.e., diamond burs, abrasive strips of 90 µm, 60 µm, 40 µm, and 15 µm, and abrasive discs). Stripping was performed by a single individual in accordance with the manufacturers' recommendations for the various systems used. One of the proximal faces of the tooth underwent IPR, while the other side remained untreated for control. The hardness of the enamel surface was measured using a Vickers hardness tester. The control group achieved the hardest enamel surface (354.4 ± 41.02 HV1), while the lowest was observed for enamel surfaces treated with 90 µm abrasive strips (213.7 ± 118.6). The only statistically significant difference was identified in comparisons between the values measured for the control group and those obtained after stripping with diamond burs (p = 0.0159). Enamel microhardness varied depending on the stripping instrument used, but no statistically significant differences were found (p > 0.05). Optimal microhardness values, close to those of healthy enamel, were achieved after mechanical treatment with 15 µm abrasive strips and abrasive discs. Dental stripping is a safe therapeutic procedure that has a relatively minor influence on the microhardness of surface enamel.

An Effective Primary Treatment Using Radiotherapy in Patients with Eyelid Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare type of neuroendocrine tumor. Palpebral localization represents 2.5% of MCCs. Surgery is not always possible due to the localization or comorbidities of elderly patients. We hypothesized that radiotherapy (RT) alone could be a curative treatment in patients contraindicated for oncological surgery. METHODS: We performed a retrospective monocentric study of patients with localized eyelid MCC treated with curative intent using curative radiotherapy. RESULTS: Overall, 11 patients with histologically confirmed eyelid MCC were treated with curative radiotherapy. The median age was 77 years old (range: 53-94). Curative RT was decided mainly due to difficult localization and significant co-morbidities. The median lesion dose was 57 Gy (range: 47-70). Most patients had adjuvant lymph nodes irradiation with a median dose of 50 Gy (n = 9; 82%). The median follow-up was 62 months (6-152 months). None of the seven deaths were MCC-related. None of our patients relapsed during follow-up. Side effects related to radiotherapy were mild (no grade ≥ 2) and rare (n = 3, 21%). CONCLUSION: Our data suggest that curative radiotherapy is an effective and safe treatment for Merkel cell carcinoma of the eyelid and periocular region. Radiotherapy alone allows limiting the aesthetic and functional sequelae in elderly and comorbid patients who are contraindicated for oncological surgery.

Description of supportive care and feasibility of physical exercise program to improve quality of life in advanced melanoma patients.

Physical activity is the first-line treatment of cancer-related fatigue. It has shown benefits on patient's quality of life (QoL) when practiced during and after treatment. New treatments have drastically changed the prognosis of melanoma. Still, few data are available about research program of supportive care in advanced melanoma. The primary outcome was to assess the feasibility of setting up a prospective study evaluating the benefits of Adapted Physical Activity (APA) on the QoL of patients with advanced melanoma. Feasibility was defined with a combination of five criteria including completion of questionnaire, recruitment, participant retention, patient adhesion to supportive care, and absence of adverse event. Between September 2019 and March 2021, 271 melanoma patients were questioned. Around 60% of stage IV melanoma patients were interested in support care. Patient retention at 3 months was sufficient. Only one patient could not be evaluated after 3 months of enrolment because of deterioration of the general state. Adhesion to exercise and sessions was good. Supervised APA program appeared to be safe and well tolerated as no adverse events or discontinuations were reported. Setting up a prospective research program evaluating the benefits of physical activity in advanced melanoma patients seems feasible. With melanoma becoming a chronic disease, supportive care may reduce fatigue, improve QoL and help maintain a healthy lifestyle. Data supporting its benefits on this survivor population are needed.

Clinical response under MEK inhibitor alone in metastatic melanoma with a novel fusion involving the RAF1 gene.

Currently, in the absence of BRAFV600 mutation, the management of advanced melanomas is based on immunotherapies, but only half of the patients are responders. RAF1 (also named CRAF) fusions occur in 1-2.1% of wild-type melanomas. Preclinical data suggest that the presence of RAF fusion may be sensitive to MEK inhibitors. We report the case of a patient with an advanced melanoma harboring an EFCC1-RAF1 fusion who showed a clinical benefit from and a partial response to a MEK inhibitor.

Oral mucosal melanoma - A systematic review.

Oral mucosal melanoma (OMM) is the subject of few studies, resulting in a lack of understanding. The aim of this study is to review the current literature on OMM. The term searched was "oral mucosal melanoma" between 01/01/2000 and 03/15/2021 in the PubMed Database (MEDLINE). Patients presenting with OMM and treated in our center between January 2009 and January 2020 were included in a case series. Demographics, location, risk factors, genetic mutations, treatment performed, and overall survival (OS) rates were evaluated. The PubMed database search yielded a total of 513 results, thirty-eight articles were finally included, which amounted to 2230 cases of OMM. 13 patients were included in the case series. A male-to-female ratio of 1.28:1.00 was found with a mean age at first diagnosis of 58.2 years old. Hard palate (1060 cases) and then gingiva (794 cases) were the two main locations. No risk factors could be identified. OMM were staged III or IV at diagnosis. Mutations were described as such: KIT in 14.6% of cases, BRAF in 7%, and NRAS in 5.6%. Treatment protocols varied but radical surgery was the cornerstone treatment associated with adjuvant therapies. Immunotherapy has not been evaluated for OMM. OS rates were 43.4% at 3 years, 33.1% at 5 year and 15.4% at 10 years. OMM show distinct features from cutaneous melanoma (CM): typical locations, no identified risk factors, different mutations profile, worse prognosis with advanced stage at diagnosis. Targeted therapies are still underused compared to CM.

Lipid Metabolism and Resistance to Anticancer Treatment.

Metabolic reprogramming is crucial to respond to cancer cell requirements during tumor development. In the last decade, metabolic alterations have been shown to modulate cancer cells' sensitivity to chemotherapeutic agents including conventional and targeted therapies. Recently, it became apparent that changes in lipid metabolism represent important mediators of resistance to anticancer agents. In this review, we highlight changes in lipid metabolism associated with therapy resistance, their significance and how dysregulated lipid metabolism could be exploited to overcome anticancer drug resistance.

Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study.

Despite significant progress in melanoma survival, therapeutic options are still needed in case of progression under immune checkpoint inhibitors (ICI), and resistance to targeted therapies (TT) in BRAF-mutated melanomas. This study aimed to assess the safety of combined ICI and TT as a rescue line in real-life clinical practice. We conducted a study within the prospective French multicentric MelBase cohort, including patients treated with a combination of anti-PD1 (pembrolizumab/nivolumab) and BRAF inhibitor (BRAFi: dabrafenib/vemurafenib) and/or MEK inhibitors (MEKi: trametinib/cobimetinib) for BRAF mutated or wild-type advanced melanoma. Fifty-nine patients were included: 30% received the triple combination, 34% an anti-PD1 and BRAFi, and 36% an anti-PD1 and MEKi. Grade 3-4 adverse events occurred in 12% of patients. Permanent discontinuation or dose reduction of one of the treatments for toxicity was reported in 14% and 7% of patients, respectively. In the BRAF wild-type subgroup, treatment with MEKi and anti-PD1 induced a tumor control rate of 83% and median progression-free survival of 7.1 months. The combination of anti-PD1 and BRAFi and/or MEKi was a safe rescue line for advanced melanoma patients previously treated with ICI/TT. The benefit of these combinations, specifically anti-PD1 and MEKi in BRAF wild-type melanoma patients, needs to be prospectively studied.

Orthodontic reduction of a displaced alveolar fracture: a case study.

A 42-year-old woman had sustained a severe dental trauma with an alveolar fracture after an epileptic attack. A tooth block 31, 32, 33 and 34 was dislocated about 7 mm in buccal direction. Panoramic X-rays and CT-scan disclosed the alveolar fracture without total disjunction of the fragment. An orthodontic appliance was used to reduce the fracture with gentle forces during a 5-month period. Normal function was established and the teeth remained vital.

Implementation of orthodontic extraction for pre-implant soft tissue management: A systematic review.

OBJECTIVE: This systematic review aims to define the recommendations allowing an optimized clinical implementation for orthodontic extraction as a pre-implant soft tissue management procedure. MATERIALS AND METHODS: A digital search was performed in the Cochrane Library, PubMed, Scopus, and DOSS databases; a pre-screening was conducted according to the title and summary of the articles. After a complete reading, only the articles meeting all of our inclusion criteria were selected, and a second search, this time manual, was performed within their references. The selected articles were then analysed according to twelve parameters. RESULTS: Thirty-nine articles were included. Despite low statistical evidence in the available literature, some principal guidelines, which seem generally accepted by the scientific community, could be highlighted based on this analysis. However, no ideal clinical protocol could be established. CONCLUSIONS: Orthodontic extraction is an efficient procedure for pre-implant soft tissue management, however, further studies are needed to establish full clinical recommendations and optimize its clinical implementation.

[Orthodontic failures in Class II cases]. / Les échecs orthodontiques dans le traitement des classes II∗.

In Class II treatment, as with all malformations, therapeutic failure can impact some or all of our treatment aims, whether occlusal, functional or esthetic. Using clinical cases, we will first define the concept of failure and the limits of what is acceptable in these different areas. We will then attempt to determine the main causes underlying our failures in order to better avoid them. An analysis of the literature and of the clinical cases demonstrates that our failures are most often caused by a misevaluation of the amount and direction of residual growth, poor control of the vertical dimension, inadequate management of functional problems, an inadequate position of the maxillary and mandibular incisors. In addition to these major treatment errors, one also encounters insufficient patient cooperation, which needs to be assessed and maintained in order to limit the number of failures and treatment drop-outs.

[Orthognathic mandibular osteotomy and condyle positioning: update and innovation]. / Ostéotomie mandibulaire orthognathique et positionnement condylien : point et innovation.

The temporomandibular joints function in synergy with the dental occlusion within the manducatory system. Orthodontists and surgeons must take into account the condylar position since any problem related to positioning of the condyle could result in occlusal disorders including relapse and the risk of occurrence, decompensation or worsening of temporomandibular dysfunction. We wanted to answer three questions: What is the position of the condyle following orthognathic surgery? What benefit is there in repositioning the condyle? What means are available to check condylar position? Finally, in the light of the answers, we describe an innovative occlusal and condylar positioning device for mandibular osteotomies based on computer-assisted surgical planning techniques. It consists of a three-dimensional, printed guide enabling surgeons to position the condyles as desired. It is accurate, simple, reproducible, independent of operator experience as well as rapid and economical.

Amelogenesis imperfecta and nephrocalcinosis: a new case of this rare syndrome.

This article describes a new case of a rare syndrome including enamel agenesis of the primary and permanent dentition, delayed or absent eruption of the permanent dentition, coronal intra-alveolar resorption and gingival enlargement. Renal symptoms include medullary nephrocalcinosis without any apparent cause, and evolution to a renal failure. The early diagnosis provided by the oral symptoms leads to a better renal prognosis. As a consequence, pediatric dentists should be aware of this pathology.