Prevalence of free flap failure in mandibular osteoradionecrosis reconstruction: a systematic review and meta-analysis.

Our study aimed to estimate the prevalence of total free flap failure following free flap reconstruction for mandibular osteoradionecrosis (mORN) and assess the impact of potential moderators on this outcome. A comprehensive systematic literature search was independently conducted by two reviewers using the Medline, Scopus, Web of Science and Cochrane Library databases. Quality assessment of the selected studies was performed, and prevalence estimates with 95% confidence intervals (CI) were calculated. Outlier and influential analyses were conducted, and meta-regression analyses was employed to investigate the effects of continuous variables on the estimated prevalence. Ultimately, forty-six eligible studies (involving 1292 participants and 1344 free flaps) were included in our meta-analysis. The findings of our study revealed a prevalence of 3.1% (95% CI 1.3-5.4%) for total free flap failure after reconstruction for mORN. No study was identified as critically influential, and meta-regression analysis did not pinpoint any potential sources of heterogeneity. These findings provide valuable insights for researchers and serve as a foundation for future investigations into the management of mandibular osteoradionecrosis and the prevention of free flap failure in this context.

Irradiation Induced Biochemical Changes in Human Mandibular Bone: A Raman Spectroscopic Study.

Understanding the biochemical changes in irradiated human mandible after radiotherapy of cancer patients is critical for oral rehabilitation. The underlying mechanism for radiation-associated changes in the bone at the molecular level could lead to implant failure and osteoradionecrosis. The study aimed to assess the chemical composition and bone quality in irradiated human mandibular bone using Raman spectroscopy. A total of 33 bone biopsies from 16 control and 17 irradiated patients were included to quantify different biochemical parameters from the Raman spectra. The differences in bone mineral and matrix band intensities between control and irradiated groups were analyzed using unpaired Student's t-test with statistical significance at p < 0.05. Findings suggest that the intensity of the phosphate band is significantly decreased and the carbonate band is significantly increased in the irradiated group. Further, the mineral crystallinity and carbonate to phosphate ratio are increased. The mineral to matrix ratio is decreased in the irradiated group. Principal component analysis (PCA) based on the local radiation dose and biopsy time interval of irradiated samples did not show any specific classification between irradiation sub-groups. Irradiation disrupted the interaction and bonding between the organic matrix and hydroxyapatite minerals affecting the bone biochemical properties. However, the normal clinical appearance of irradiated bone would have been accompanied by underlying biochemical and microscopical changes which might result in radiation-induced delayed complications.

Empirical modeling of the percent depth dose for megavoltage photon beams.

INTRODUCTION: This study presents an empirical method to model the high-energy photon beam percent depth dose (PDD) curve by using the home-generated buildup function and tail function (buildup-tail function) in radiation therapy. The modeling parameters n and µ of buildup-tail function can be used to characterize the Collimator Scatter Factor (Sc) either in a square field or in the different individual upper jaw and lower jaw setting separately for individual monitor unit check. METHODS AND MATERIALS: The PDD curves for four high-energy photon beams were modeled by the buildup and tail function in this study. The buildup function was a quadratic function in the form of [Formula: see text] with the main parameter of d (depth in water) and n, while the tail function was in the form of e-µd and was composed by an exponential function with the main parameter of d and µ. The PDD was the product of buildup and tail function, PDD = [Formula: see text]. The PDD of four-photon energies was characterized by the buildup-tail function by adjusting the parameters n and µ. The Sc of 6 MV and 10 MV can then be expressed simply by the modeling parameters n and µ. RESULTS: The main parameters n increases in buildup-tail function when photon energy increased. The physical meaning of the parameter n expresses the beam hardening of photon energy in PDD. The fitting results of parameters n in the buildup function are 0.17, 0.208, 0.495, 1.2 of four-photon energies, 4 MV, 6 MV, 10 MV, 18 MV, respectively. The parameter µ can be treated as attenuation coefficient in tail function and decreases when photon energy increased. The fitting results of parameters µ in the tail function are 0.065, 0.0515, 0.0458, 0.0422 of four-photon energies, 4 MV, 6 MV, 10 MV, 18 MV, respectively. The values of n and µ obtained from the fitted buildup-tail function were applied into an analytical formula of Sc = nE(S)0.63µE to get the collimator to scatter factor Sc for 6 and 10 MV photon beam, while nE, µE, S denotes n, µ at photon energy E of field size S, respectively. The calculated Sc were compared with the measured data and showed agreement at different field sizes to within ±1.5%. CONCLUSIONS: We proposed a model incorporating a two-parameter formula which can improve the fitting accuracy to be better than 1.5% maximum error for describing the PDD in different photon energies used in clinical setting. This model can be used to parameterize the Sc factors for some clinical requirements. The modeling parameters n and µ can be used to predict the Sc in either square field or individual jaws opening asymmetrically for treatment monitor unit double-check in dose calculation. The technique developed in this study can also be used for systematic or random errors in the QA program, thus improves the clinical dose computation accuracy for patient treatment.

Refining the mandibular osteoradionecrosis rat model by in vivo longitudinal µCT analysis.

Osteoradionecrosis (ORN) is one of the most feared side effects of radiotherapy following cancers of the upper aero-digestive tract and leading to severe functional defects in patients. Today, our lack of knowledge about the physiopathology restricts the development of new treatments. In this study, we refined the ORN rat model and quantitatively studied the progression of the disease. We tested the impact of radiation doses from 20 to 40 Gy, delivered with incident 4MV X-ray beams on the left mandible of the inbred Lewis Rat. We used micro-computed tomography (µCT) to obtain in vivo images for longitudinal bone imaging and ex vivo images after animal perfusion with barium sulphate contrast agent for vessel imaging. We compared quantification methods by analyzing 3D images and 2D measurements to determine the most appropriate and precise method according to the degree of damage. We defined 25 Gy as the minimum irradiation dose combined with the median molar extraction necessary to develop non-regenerative bone necrosis. µCT image analyses were correlated with clinical and histological analyses. This refined model and accurate methods for bone and vessel quantification will improve our knowledge of the progression of ORN pathology and allow us to test the efficacy of new regenerative medicine procedures.

[Impact of neck dissection in N2-3 oropharyngeal squamous cell carcinomas treated with definitive chemoradiotherapy: An observational real-life study]. / Impact du curage ganglionnaire cervical dans la prise en charge par chimioradiothérapie exclusive des cancers de l'oropharynx de stade N2-3 : étude observationnelle en vie réelle.

PURPOSE: The purpose of this study was to assess the efficacy in terms of neck failure of an initial neck dissection before definitive chemoradiotherapy in N2-3 oropharyngeal squamous cell carcinomas, as well as the dosimetric impact and the acute and delayed morbidity of this approach. MATERIALS AND METHODS: All patients consecutively treated between 2009 and 2018 with definitive chemoradiotherapy using intensity-modulated conformal radiotherapy (IMRT) for a histologically proven N2-3 oropharyngeal squamous cell carcinomas were retrospectively included. The therapeutic approach consisted of induction chemotherapy, followed by cisplatine-based chemoradiotherapy preceded or not by neck dissection. Neck dissection was discussed on a case-by-case basis in a dedicated multidisciplinary tumour board for patients with a dissociated response to induction chemotherapy, defined as a better response on the primary than on the node. Chemoradiotherapy without neck dissection was systematically performed in case of a major lymph node response to induction chemotherapy (decrease in size of 90% or more). Intensity-modulated radiotherapy using a simultaneous-integrated boost delivered 70Gy in 35 fractions on macroscopic tumour volumes, 63Gy on intermediate-risk levels or extra-nodal extension and 54Gy on prophylactic lymph node areas. RESULTS: Two groups were constituted: 47 patients without an initial neck dissection (62.7%), and 28 patients with a neck dissection prior to definitive chemoradiotherapy (37.3%). Initial patient characteristics were not statistically different between the two groups. The median follow-up was 60.1months (range: 3.2-119months). Incidence of neck failure was higher in patients without neck dissection (P=0.015). The neck failure rate at 5years was 19.8% (95% confidence interval: 7.4-30.6%; P=0.015) without neck dissection versus 0% following neck dissection. All lymph node failures occurred in the planned target volume at 70Gy. Upfront neck dissection suggested a decrease in the mean dose received by the homolateral parotid gland (P=0.01), mandible (P=0.02), and thyroid gland (P=0.02). Acute toxicity of chemoradiotherapy after neck dissection suggested a reduction in grade≥3 adverse events (P=0.04), early discontinuation of concomitant chemotherapy (P=0.009) and feeding tube-dependence (P=0.008) in univariate analysis. During follow-up, there was no difference between the two groups in terms of xerostomia, dysgeusia, dysphagia or gastrostomy dependence in univariate analysis. CONCLUSION: Neck dissection prior to definitive chemoradiotherapy in N2-3 oropharyngeal squamous cell carcinoma was associated with high neck control without additional mid and long-term morbidity.

Comparison of machine learning methods for prediction of osteoradionecrosis incidence in patients with head and neck cancer.

OBJECTIVES: Mandible osteoradionecrosis (ORN) is one of the most severe toxicities in patients with head and neck cancer (HNC) undergoing radiotherapy (RT). The existing literature focuses on the correlation of mandible ORN and clinical and dosimetric factors. This study proposes the use of machine learning (ML) methods as prediction models for mandible ORN incidence. METHODS: A total of 96 patients (ORN incidence ratio of 1:1) treated between 2011 and 2015 were selected from the local HNC toxicity database. Demographic, clinical and dosimetric data (based on the mandible dose-volume histogram) were considered as model variables. Prediction accuracy (measured using a stratified fivefold nested cross-validation), sensitivity, specificity, precision and negative predictive value were used to evaluate the prediction performance of a multivariate logistic regression (LR) model, a support vector machine (SVM) model, a random forest (RF) model, an adaptive boosting (AdaBoost) model and an artificial neural network (ANN) model. The different models were compared based on their prediction accuracy and using the McNemar's hypothesis test. RESULTS: The ANN model (77% accuracy), closely followed by the SVM (76%), AdaBoost (75%) and LR (75%) models, showed the highest overall prediction accuracy. The RF model (71%) showed the lowest prediction accuracy. However, based on the McNemar's test applied to all model pair combinations, no statistically significant difference between the models was found. CONCLUSION: Based on our results, we encourage the use of ML-based prediction models for ORN incidence as has already been done for other HNC toxicity end points. ADVANCES IN KNOWLEDGE: This research opens a new path towards personalised RT for HNC using ML to predict mandible ORN incidence.

Intraoperative Stromal Vascular Fraction Therapy Improves Histomorphometric and Vascular Outcomes in Irradiated Mandibular Fracture Repair.

BACKGROUND: Cell-based treatments have demonstrated the capacity to enhance reconstructive outcomes in recent decades but are hindered in clinical utility by regulatory hurdles surrounding cell culture. This investigation examines the ability of a noncultured stromal vascular fraction derived from lipoaspirate to enhance bone healing during fracture repair to further the development of translatable cell therapies that may improve outcomes in irradiated reconstruction. METHODS: Isogenic male Lewis rats were divided into three groups: fracture, irradiated fracture, and irradiated fracture with stromal vascular fraction treatment. Irradiated groups received a fractioned dose of 35 Gy before mandibular osteotomy. Stromal vascular fraction was harvested from the inguinal fat of isogenic donors, centrifuged, and placed intraoperatively into the osteotomy site. All mandibles were evaluated for bony union and vascularity using micro-computed tomography before histologic analysis. RESULTS: Union rates were significantly improved in the irradiated fracture with stromal vascular fraction treatment group (82 percent) compared to the irradiated fracture group (25 percent) and were not statistically different from the fracture group (100 percent). Stromal vascular fraction therapy significantly improved all metrics of bone vascularization compared to the irradiated fracture group and was not statistically different from fracture. Osteocyte proliferation and mature bone formation were significantly reduced in the irradiated fracture group. Bone cellularity and maturity were restored to nonirradiated levels in the irradiated fracture with stromal vascular fraction treatment group despite preoperative irradiation. CONCLUSIONS: Vascular and cellular depletion represent principal obstacles in the reconstruction of irradiated bone. This study demonstrates the efficacy of stromal vascular fraction therapy in remediating these damaging effects and provides a promising foundation for future studies aimed at developing noncultured, cell-based therapies for clinical implementation.

Mandibular metastases in neuroblastoma: Outcomes and dental sequelae.

BACKGROUND: Although metastatic involvement of bony sites including cranial bones is common in neuroblastoma (NB), mandibular metastases (MM) are uncommon, and specific outcomes have not been reported upon in the modern therapeutic era. METHODS: In this retrospective study, medical records on patients with MM from NB were reviewed. Statistical analysis was performed using the Kaplan-Meier method. RESULTS: Of 29 patients, nine (31%) had MM at diagnosis, whereas in 20 (69%) MM were first detected at NB relapse at a median time of 26 (6-89) months from diagnosis. Median maximal diameter of lesions was 3 (range 0.8-4.9) cm. MM were unilateral in 83% of patients, with ascending ramus (55%) and mandibular body (38%) being the two most common sites. All patients received systemic chemotherapy, and 26 (93%) patients received radiotherapy to MM. At a median follow-up of 37.3 (24.2-219.5) months, eight of nine patients with MM at diagnosis did not experience mandibular progressive disease. Eighteen of 20 patients with MM at relapse received therapeutic radiotherapy; objective responses were noted in 78%. Seventy-two percent (5/18) had not experienced relapse within the radiation field at a median of 12 (2-276) months postradiotherapy. Dental findings at follow-up after completion of NB therapy included hypodontia, hypocalcification of enamel, and trismus. Median 3-year overall survival in patients with relapsed MM was 51 ± 12% months from relapse. CONCLUSION: MM when detected at diagnosis is associated with a prognosis similar to that for other skeletal metastases of NB. Radiotherapy is effective for control of MM detected both at diagnosis and relapse. Significant dental abnormalities posttherapy warrant regular dental evaluations and appropriate intervention.

Osteoradionecrosis: Exposing the Evidence Not the Bone.

Osteoradionecrosis is a relatively rare but potentially morbid and costly complication of radiation therapy for head and neck cancer. Multidisciplinary diagnosis and treatment are essential. Despite evidence guiding individual aspects of care for osteoradionecrosis, there is a lack of broad consensus on the overall diagnosis and management of this condition. This study comprehensively reviews the literature, with a focus on the past 10 years, to guide evaluation and treatment.

Comparing two radiotherapy techniques of whole central nervous system tumors, considering tumor and critical organs' dose provided by treatment planning system and direct measurement.

AIMS: In central nervous system (CNS) tumors, surgery combined with radiotherapy may cure many tumors. The basic technique in conventional radiotherapy is craniospinal radiotherapy; in this technique, spinal cord can be treated with electron or photon beams. This study was aimed to compare two radiotherapy techniques in craniospinal radiotherapy, (a) treatment of spine with a single photon beam and (b) with a combination of photon and electron beams. MATERIALS AND METHODS: The two techniques were planned. In the first technique, both brain and spine were irradiated with 6 MV photon beams. In the second technique, brain was irradiated with 6 MV photon and spine with 18 MeV electron beams. To compensate the dose deficiency in lumbar area, an anterior field of 15 MV photon beam was also applied in the second technique. The dose to target volume and organ at risks (OARs) were measured by thermoluminescent dosimeter and compared with the corresponding values calculated by Isogray treatment planning system. RESULTS: OARs including heart, mandible, thyroid, and lungs received lower dose from technique 2 compared with technique 1; kidneys were exceptions which received higher dose in the technique 2. CONCLUSIONS: The dose to thyroid, mandible, heart, and lungs were lower in technique 2, while kidneys received higher dose in technique 2. This was caused by using the anterior 15 MV photon beam. Based on these results, for children, instead of photon beam for treatment of spinal cord, it is wiser to use electron beam.

Aumento da hiperdensidade da cortical óssea línguo-basal após radioterapia em região de cabeça e pescoço: relato de caso / Hyperdensity of the lingual-basal bone cortex incresead after radiotherapy in the head and neck region: case report

Objetivo: relatar um caso de aumento da hiperdensidade da cortical óssea línguo-basal pós-radioterapia em região de cabeça e pescoço por meio de avaliação imaginológica. Relato de caso: paciente do sexo feminino, 80 anos, procurou tratamento odontológico com a finalidade de reabilitação oral com implantes dentários. Na anamnese, relatou histórico de carcinoma espinocelular em regiões distintas da cavidade oral. No exame clínico, notou-se que a paciente era edêntula total e foi solicitado um exame de tomografia computadorizada de feixe cônico. Foi observado, na região anterior inferior, aumento da hiperdensidade da cortical óssea línguo-basal, com osso compacto mais espesso, achado incomum na literatura após radioterapia. Considerações finais: os efeitos da radioterapia em mandíbula estão relatados na literatura. No caso clínico em questão, detectou-se uma alteração pouco notada em pacientes submetidos à radioterapia, fazendo surgir novos questionamentos, sendo eles sobre o diagnóstico dessa modificação na estrutura óssea e suas repercussões. (AU)

Objective: to report a case of increased hyperdensity of the lingual-basal bone cortex after radiotherapy in the head and neck region by means of imaging evaluation. Case report: female patient, 80 years old, sought dental treatment for the purpose of oral rehabilitation with dental implants. In the anamnesis, she reported a history of squamous cell carcinoma in different regions of the oral cavity. Upon clinical examination, it was noted that the patient was total edentulous and a cone beam computed tomography examination was requested. An increase in the hyperdensity of the lingual-basal bone cortex was observed in the lower anterior region, with thicker compact bone, an unusual finding in the literature after radiotherapy. Final considerations: the effects of radiotherapy on the mandible are reported in the literature. In the clinical case in question, a little-noticed change was detected in patients undergoing radiotherapy, leading to new questions, concerning the diagnosis of this change in bone structure and its repercussions.(AU)

Dosimetric impact of switching from AAA to Acuros dose-to-water and dose-to-medium for RapidArc plans of nasopharyngeal carcinomas.

PURPOSE: This work aims to evaluate the dosimetric consequences of replacing the Anisotropic Analytical Algorithm (AAA) by Acuros XB (AXB), dose-to-water (Dw) or dose-to-medium (Dm), for RapidArc plans of nasopharyngeal carcinomas (NPC). MATERIALS AND METHODS: Seventeen NPC plans created with AAA (v15.6) were recalculated with AXB (v15.6) Dw and Dm. The dose-volume parameters to the planning target volumes (PTV) and relevant organs at risk (OAR) were compared. The high dose PTV was divided into bone, air and tissue components and the comparison was performed for each of them. RESULTS: AXB Dw revealed no significant differences in the PTVs compared to AAA. Lower values were observed to spinal cord, brainstem, oral cavity and parotids (0.5% to 2.3%), and higher values to cochleas (up to 5.4%) and mandible (up to 6.7%). AXB Dm predicted lower values than AAA for all PTVs and OARs (2.0% to 6.1%). For the bone PTV subvolume, AXB Dw and Dm predicted respectively higher (2.4%) and lower (2.2% to 3.4%) values. No significant differences were noted in air. AXB predicted lower values than AAA in soft tissues (0.4% to 1.6%). The largest difference was found to the mandible V60Gy parameter, with median differences of 6.7% for AXB Dw and -6.0% for AXB Dm. CONCLUSION: Significant dose differences are expected when switching from AAA to AXB in NPC cases. The dose prescriptions and the tolerance limits for some OARs, especially those of high density, may need to be adjusted depending on the selected dose calculation algorithm and reporting mode.

Assessment of irradiated socket healing in the rabbit's mandible: Experimental study.

As bone healing is altered after external radiation therapy, its evaluation is mandatory and lacks in clinical practice. The aim of the pilot study was to validate micro computed tomography (microCT) as a simple and reliable technique for assessing irradiated bone healing in the rabbit's mandible and compare with histologic findings. Nineteen rabbits (female New Zealand white) were used. The radiation protocol consisted of 5 sessions delivering 8.5 Gy each. MicroCT was performed at D0, D7, D14, D28 and D42 for the control group and D0, D28 and D42 for the irradiated group. A modified Perry's score was determined on histologic samples, and comparison between microCT and histological findings was performed. The main differences between irradiated and non-irradiated rabbits were observed at Day 28 and 42. There was a strong correlation between imaging and histologic findings. Radiation decreases bone quality and bone mineral density. As the correlation was strong between microCT and histologic findings, micro imaging could be considered as a simple and reliable technique to assess bone healing after radiation therapy and allows an easy comparison between samples, without invasive procedures. Great attention should be kept on the parameters and on the region of interest. The development of in-vivo microCT enlarges the perspectives of microCT use in experimental studies, avoiding invasive procedures, and preserving animal lives and well-being, and furthermore lead to clinical applications.

Radiation Therapy and Mandibular Osteoradionecrosis: State of the Art.

PURPOSE OF REVIEW: This article aims to provide an update on literature data related to mandibular osteoradionecrosis (MORN) secondary to the irradiation of the head and neck region. RECENT FINDINGS: Radiotherapy (RT) plays a crucial role in the contemporary management of head and neck cancer (HNC) patients and, despite intensity-modulated technique (IMRT), mandibular osteoradionecrosis (MORN) remains a significant RT-related complication. Based on its clinical manifestation, MORN can negatively affect patients' quality of life. Preventive interventions should be prioritized. This manuscript is expected to represent an opportunity to guide a clear proposal for clinical measures in the individual MORN situations.

Development of a Rat Model of Mandibular Irradiation Sequelae for Preclinical Studies of Bone Repair.

Repairing mandibular bone defects after radiotherapy of the upper aerodigestive tract is clinically challenging. Although bone tissue engineering has recently generated a number of innovative treatment approaches for osteoradionecrosis (ORN), these modalities must be evaluated preclinically in a relevant, reproducible, animal model. The objective of this study was to evaluate a novel rat model of mandibular irradiation sequelae, with a focus on the adverse effects of radiotherapy on bone structure, intraosseous vascularization, and bone regeneration. Rats were irradiated with a single 80 Gy dose to the jaws. Three weeks after irradiation, mandibular bone defects of different sizes (0, 1, 3, or 5 mm) were produced in each hemimandible. Five weeks after the surgical procedure, the animals were euthanized. Explanted mandibular samples were qualitatively and quantitatively assessed for bone formation, bone structure, and intraosseous vascular volume by using micro-computed tomography, scanning electron microscopy, and histology. Twenty irradiated hemimandibles and 20 nonirradiated hemimandibles were included in the study. The bone and vessel volumes were significantly lower in the irradiated group. The extent of bone remodeling was inversely related to the defect size. In the irradiated group, scanning electron microscopy revealed a large number of polycyclic gaps consistent with periosteocytic lysis (described as being pathognomonic for ORN). This feature was correlated with elevated osteoclastic activity in a histological assessment. In the irradiated areas, the critical-sized defect was 3 mm. Hence, our rat model of mandibular irradiation sequelae showed hypovascularization and osteopenia. Impact statement Repairing mandibular bone defects after radiotherapy of the upper aerodigestive tract is clinically challenging. Novel tissue engineering approaches for healing irradiated bone must first be assessed in animal models. The current rat model of mandibular irradiation sequelae is based on tooth extraction after radiotherapy. However, the mucosal sequelae of radiotherapy often prevent the retention of tissue-engineered biomaterials within the bone defect. We used a submandibular approach to create a new rat model of mandibular irradiation sequelae, which enables the stable retention of biomaterials within the bone defect and should thus facilitate the assessment of bone regeneration.

Effect of α2­macroglobulin in the early stage of jaw osteoradionecrosis.

Advanced osteoradionecrosis (ORN) is one of the most serious complications in patients with head and neck cancer, resulting in poor prognosis. Numerous studies have therefore focused on the pathogenesis and interventions of ORN early stage. The present study aimed to investigate whether α2­macroglobulin (α2M) could prevent early­stage jaw osteoradionecrosis caused by radiotherapy (RT). Following local injection of α2M, a single dose of 30 Gy was delivered to rats for pathological exploration. For 28 days, the irradiated mandible and soft tissues were examined for potential changes. Furthermore, primary human bone marrow mesenchymal stem cells pretreated with α2M followed by 8 Gy irradiation (IR) were also used. Tartrate­resistant acid phosphatase assay, terminal uridine deoxynucleotidyl nick end labeling assay and immunohistochemical staining were performed on irradiated mandibular bone, tongue or buccal mucosa tissues from rats. Cell proliferation was assessed by evaluating the cell morphology by microscopy and by using the cell counting kit­8. Fluorescence staining, flow cytometry and western blotting were conducted to detect the reactive oxygen species level, cell apoptosis and protein expression of superoxide dismutase 2 (SOD2), heme oxygenase­1 (HO­1) and phosphorylated Akt following irradiation. The results demonstrated that α2M attenuated physical inflammation, osteoclasts number and fat vacuole accumulation in mandibular bone marrow and bone marrow cell apoptosis following IR in vivo. Furthermore, α2M pretreatment suppressed the expression of 8­hydroxy­2'­deoxyguanosine in mandibular bone and tongue paraffin embedded sections, which is a marker of oxidative damage, and increased SOD2 expression in mucosa and tongue paraffin embedded sections. The present study demonstrated the efficient regulation of antioxidative enzymes, including SOD2 and heme oxygenase­1, and reduction in oxidative damage by α2M. In addition, in vitro results confirmed that α2M may protect cells from apoptosis and suppress reactive oxygen species accumulation. Overall, the present study demonstrated that α2M treatment may exert some radioprotective effects in early­stage ORN via antioxidant mechanisms, and may therefore be considered as a potential alternative molecule in clinical prophylactic treatments.

Reduced radiation-induced toxicity by using proton therapy for the treatment of oropharyngeal cancer.

Patients with squamous cell carcinoma of the oropharynx are generally treated with (chemo) radiation. Patients with oropharyngeal cancer have better survival than patients with squamous cell carcinoma of other head and neck subsites, especially when related to human papillomavirus. However, radiotherapy results in a substantial percentage of survivors suffering from significant treatment-related side-effects. Late radiation-induced side-effects are mostly irreversible and may even be progressive, and particularly xerostomia and dysphagia affect health-related quality of life. As the risk of radiation-induced side-effects highly depends on dose to healthy normal tissues, prevention of radiation-induced xerostomia and dysphagia and subsequent improvement of health-relatedquality of life can be obtained by applying proton therapy, which offers the opportunity to reduce the dose to both the salivary glands and anatomic structures involved in swallowing.This review describes the results of the first cohort studies demonstrating that proton therapy results in lower dose levels in multiple organs at risk, which translates into reduced acute toxicity (i.e. up to 3 months after radiotherapy), while preserving tumour control. Next to reducing mucositis, tube feeding, xerostomia and distortion of the sense of taste, protons can improve general well-being by decreasing fatigue and nausea. Proton therapy results in decreased rates of tube feeding dependency and severe weight loss up to 1 year after radiotherapy, and may decrease the risk of radionecrosis of the mandible. Also, the model-based approach for selecting patients for proton therapy in the Netherlands is described in this review and future perspectives are discussed.

A randomized clinical trial comparing the efficacy of low-level laser therapy (LLLT) and laser acupuncture therapy (LAT) in patients with temporomandibular disorders.

This study compared the efficacy of low-level laser therapy (LLLT) versus laser acupuncture therapy (LAT) in patients with temporomandibular disorders (TMDs). In this randomized, double-blind clinical trial, 45 TMD patients were randomly divided into three groups. In group 1 (LLLT), a GaAlAs laser was applied on painful masticatory muscles and TMJs (810 nm, 200 mW, 30 s per point, Gaussian beam, spot size 0.28 cm2, 21 J/cm2) two times a week for 5 weeks. In group 2 (LAT), the laser was emitted bilaterally on acupuncture points (ST6, ST7, LI4) with the same settings as the LLLT group. Group 3 (placebo) underwent treatment with sham laser. The patients were evaluated before treatment (T1), after 5 (T2) and 10 (T3) laser applications, and 1 month later (T4). The mandibular range of motion as well as pain intensity in masticatory system was recorded at each interval. There was no significant difference in mouth opening between the groups (p > 0.05), but the amount of lateral excursive and protrusive movements was significantly greater in LLLT and LAT groups than the placebo group at some intervals (p < 0.05). The overall pain intensity and pain degree at masticatory muscles (except temporal muscle) and TMJs were significantly lower in both experimental groups than the placebo group at most intervals after therapy (p < 0.05). Both LLLT and LAT were effective in reducing pain and increasing excursive and protrusive mandibular motion in TMD patients. LAT could be suggested as a suitable alternative to LLLT, as it provided effective results while taking less chair time.

Intraoral photobiomodulation diminishes pain and improves functioning in women with temporomandibular disorder: a randomized, sham-controlled, double-blind clinical trial : Intraoral photobiomodulation diminishes pain in women with temporomandibular disorder.

The aim of the present study was to evaluate the effect of intraoral photobiomodulation involving super-pulsed laser (905 nm) combined with red (640 nm) and infrared (875 nm) light-emitting diodes on pain, mandibular range of motion, and functioning in women with myogenous temporomandibular disorder. A randomized, sham-controlled, double-blind clinical trial was conducted involving 30 women with myogenous temporomandibular disorder diagnosed using the Research Diagnostic Criteria for Temporomandibular Disorders. The participants were randomly allocated to two groups (active and sham photobiomodulation). The evaluations involved this use of the visual analog scale, digital calipers, and a functional scale. Photobiomodulation was administered intraorally in the region of the pterygoid muscles, bilaterally, in all participants for a total of six sessions. Evaluations were performed on five occasions: prior to the intervention, immediately after the first session, 24 h and 48 h after the first session, and after the six sessions. Significant differences between groups were found regarding pain (p ≤ 0.01) and functioning (p ≤ 0.04). However, no statistically significant difference was found regarding range of mandibular motion. The findings demonstrate that intraoral photobiomodulation involving super-pulsed laser (905 nm) combined with red (640 nm) and infrared (875 nm) light-emitting diodes diminishes pain and improves functioning but does not exert an influence on mandibular range of motion in women with temporomandibular disorder.Trial registration: NCT02839967.

Challenges threaten, opportunity awaits hyperbaric medicine and the head and neck cancer patient.

Over the past four decades, hyperbaric oxygen (HBO2) therapy has played a prominent role in both the prevention and treatment of mandibular osteoradionecrosis (ORN). It has done so on the strength of laboratory observations and clinical reports, yet only limited efficacy data. This dual role has come under increasing scrutiny in the modern radiotherapy (RT) and surgical eras. The ability to spare healthy "non-target" tissue has markedly improved since the two-dimensional planning and delivery techniques in use when HBO2's prophylactic value was first demonstrated. A recent study failed to identify this same benefit in patients who received high-precision imaging and conformal RT. HBO2 therapy is under challenge as preferred treatment for early stage ORN. A recently introduced "fibroatrophic" mechanism contrasts with the hypovascular-hypocellular-hypoxic injury pattern that formed the basis for HBO2's therapeutic use. This alternative pathophysiologic state appears to benefit from an oral antioxidant medication regimen. The continuing necessity of HBO2 in support of mandibular reconstruction for advanced ORN is in question. Microsurgery-based vascularized bone flaps increasingly represent standard care, invariably in the absence of perioperative HBO2. Renewed interest in hyperbaric oxygen as a radiation sensitizer offers some promise. Hypoxia remains a critical radio-resistant factor in many solid tumors. Malignant gliomas have been a primary focus of several small studies, with resulting improvements in local control and median survival. Hyperbaric radiation sensitization has recently addressed oropharyngeal cancer. Preliminary data indicates that addition of HBO2 to chemo-radiation standard of care is technically feasible, well tolerated and safe. A Phase II efficacy trial will investigate the potential for of HBO2 to improve progression-free and relapse-free survival in newly diagnosed locally advanced head and neck cancers. What follows is a review and summary of relevant peer-reviewed literature.