Pre-chemoradiotherapy high platelet counts predict jaw osteoradionecrosis in locally advanced nasopharyngeal carcinoma patients.

INTRODUCTION: This retrospective study aimed to investigate if pretreatment platelet (PLT) levels can predict the risk of osteoradionecrosis of the jaw (ORNJ) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC) who received concurrent chemoradiotherapy (CCRT). MATERIAL &METHODS: ORNJ instances were identified from LA-NPC patients' pre- and post-CCRT oral exam records. All pretreatment PLT values were acquired on the first day of CCRT. Receiver operating characteristic curve analysis was used to determine the optimal PLT cutoff that divides patients into two subgroups with distinctive ORNJ rates. The primary outcome measure was the association between pretreatment PLT values and ORNJ incidence rates. RESULTS: The incidence of ORNJ was 8.8 % among the 240 LA-NPC patients analyzed. The ideal pre-CCRT PLT cutoff which divided the patients into two significantly different ORNJ rate groups was 285,000 cells/µL (PLT ≤ 285,000 cells/µL (N = 175) vs. PLT > 285,000 cells/µL (N = 65)). A comparison of the two PLT groups revealed that the incidence of ORNJ was substantially higher in patients with PLT > 285,000 cells/L than in those with PLT≤285,000 cells/L (26.2% vs. 2.3 %; P < 0.001). The presence of pre-CCRT ≥3 tooth extractions, any post-CCRT tooth extractions, mean mandibular dose ≥ 34.1 Gy, mandibular V57.5 Gy ≥ 34.7 %, and post-CCRT tooth extractions > 9 months after CCRT completion were also associated with significantly increased ORNJ rates. A multivariate Cox regression analysis demonstrated that each characteristic had an independent significance on ORNJ rates after CCRT. CONCLUSION: An affordable and easily accessible novel biomarker, PLT> 285,000 cells/L, may predict substantially higher ORNJ rates after definitive CCRT in individuals with LA-NPC.

[Prevention, diagnosis and management of osteoradionecrosis: Where do we stand?] / Prévention, diagnostic et prise en charge de l'ostéoradionécrose : où en est-on ?

Osteoradionecrosis (ORN) is a late secondary iatrogenic complication of external radiotherapy for cancers of the upper aero-digestive tract. Despite the systematization of intensity-modulated radiotherapy and its potential for preserving salivary secretion and limiting the dose delivered to the supporting bone, ORN remains a feared and frequent complication. The objective of this literature review was to provide an overview of the management of ORN and to determine the key points that would make it possible to improve patient care. The diagnosis of ORN requires to eliminate tumor recurrence then is based on clinical arguments and imaging by CT or Cone Beam evolving in a chronic mode (more than 3-6 months). The harmonization of its classifications aims to offer comprehensive and multidisciplinary care as early as possible. Primary prevention is based on pre-therapeutic oral and dental preparation, then associated with fluoroprophylaxis if salivary recovery is insufficient and requires supervision of invasive dental care and prosthetic rehabilitation. Semi-automatic contouring tools make it possible to identify doses delivered to dental sectors and guide dental care with personalized dosimetric mapping. Conservative medical treatment is offered at an early stage where innovative medical treatments, highlighted by early studies, could be of interest in the future. In the event of advanced ORN, a non-conservative treatment is then proposed and frequently consists of interruptive mandibulectomy associated with reconstruction by bony free flap, the conditions of implantation remaining to be defined with the support of prospective clinical trials.

Extranodal natural killer/T cell lymphoma nasal type simulating osteoradionecrosis with metachronic B lymphoma in the pelvis: Case report.

Extranodal Natural Killer/T Cell Lymphoma Nasal Type (EN-NK/T-CL-NT) is a non-Hodgkin extranodal lymphoma of unfavorable prognosis due to its aggressive nature. This neoplasm mainly affects the paranasal sinuses, nasopharynx, oropharynx, oral cavity, palate, and rarely intestinal, gastric and skin regions. 50-year-old female with a history of lymphoma in nasal and pelvic region. At four years of tumors-free, has facial asymmetry, accompanied by sub-palpebral, nasal and lip edema. Intraoral examination revealed a large ulceration suggestive of osteoradionecrosis. Gum biopsy shows Extranodal NK/T Cell Lymphoma Nasal Type (EN-NK/T-CL-NT). In this case we highlight the characteristics of EN-NK/T-CL-NT with a presentation of osteoradionecrosis-like. Unfortunately, the nature of this tumor led to the patient's death. Clinical follow-up of patients with cancer is imperative to mend and/or decrease treatment complications, as well as to identify second primary tumors or the spread of the underlying disease.

Valero's host index is useful in predicting radiation-induced trismus and osteoradionecrosis of the jaw risks in locally advanced nasopharyngeal carcinoma patients.

BACKGROUND: In the absence of previous research, we sought to assess the H-Index's predictive significance for radiation-induced trismus (RIT) and osteoradionecrosis of the jaw (ORNJ) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC) receiving concurrent chemoradiotherapy (C-CRT). PATIENTS AND METHODS: The research comprised 295 LA-NPC patients who had C-CRT and pre- and post-C-CRT oral exams between June 2010 and December 2021. The H-Index was calculated using neutrophils, monocytes, lymphocytes, hemoglobin, and albumin measurements obtained on the first day of C-CRT. Patients were divided into three and two H-index groups, respectively, based on previously established cutoff values (1.5 and 3.5) and the cutoff value determined by our receiver operating characteristic (ROC) curve analysis. The primary objective was the presence of any significant connections between pretreatment H-Index groups and post-C-CRT RIT and ORNJ rates. RESULTS: RIT and ORNJ was diagnosed in 46 (15.6%) and 13 (7.8%) patients, respectively. The original H-Index grouping could only categorize RIT and ORNJ risks at a cutoff value of 3.5, with no significant differences in RIT and ORNJ rates between groups with H-Index 1.5 and 1.5 to 3.5 (P < 0.05 for each). The ideal H-Index cutoff for both RIT and ORNJ rates was found to be 5.5 in ROC curve analysis, which divided the entire research population into two groups: H-Index ≤ 5.5 (N = 195) and H-Index > 5.5 (N = 110). Intergroup comparisons revealed that patients in the H-Index > 5.5 group had significantly higher rates of either RIT (31.8% vs. 5.9%; P < 0.001) or ORNJ (17.3% vs. 2.2%; P < 0.001) than their H-Index ≤ 5.5 counterparts. The results of the multivariate analysis showed that H-Index > 5.5 was independently linked to significantly higher RIT (P < 0.001) and ORNJ (P < 0.001) rates. CONCLUSION: Pre-C-CRT H-Index > 5.5 is associated with significantly increased RIT and ORNJ rates in LA-NPC patients receiving definitive C-CRT.

Review of the Pathogenesis, Diagnosis, and Management of Osteoradionecrosis of the Femoral Head.

Osteoradionecrosis (ORN) of the femoral head is an important issue for orthopedists and radiologists in clinical practice. With the rapid development of technological advances in radiation therapy and the improvement in cancer survival rates, the incidence of ORN is rising, and there is an unmet need for basic and clinical research. The pathogenesis of ORN is complex, and includes vascular injury, mesenchymal stem cell injury, bone loss, reactive oxygen species, radiation-induced fibrosis, and cell senescence. The diagnosis of ORN is challenging and requires multiple considerations, including exposure to ionizing radiation, clinical manifestations, and findings on physical examination and imaging. Differential diagnosis is essential, as clinical symptoms of ORN of the femoral head can resemble many other hip conditions. Hyperbaric oxygen therapy, total hip arthroplasty, and Girdlestone resection arthroplasty are effective treatments, each with their own advantages and disadvantages. The literature on ORN of the femoral head is incomplete and there is no criterion standard or clear consensus on management. Clinicians should gain a better and more comprehensive understanding on this disease to facilitate its early and better prevention, diagnosis, and treatment. This article aims to review the pathogenesis, diagnosis, and management of osteoradionecrosis of the femoral head.

Early detection of mandible osteoradionecrosis risk in a high comorbidity veteran population.

OBJECTIVE: Osteoradionecrosis (ORN) of the mandible is a devastating complication of external beam radiation therapy (EBRT) for head and neck squamous cell carcinoma (HNSCC). We sought to ascertain ORN risk in a Veteran HNSCC population treatment with definitive or adjuvant EBRT and followed prospectively. STUDY DESIGN: Retrospective analysis of prospective cohort. SETTING: Tertiary care Veterans Health Administration (VHA) medical center. METHODS: Patients with HNSCC who initiated treatment at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) are prospectively tracked for quality of care purposes through the end of the cancer surveillance period (5 years post treatment completion). We retrospectively analyzed this patient cohort and extracted clinical and pathologic data for 164 patients with SCC of the oral cavity, oropharynx, larynx, and hypopharynx who received definitive or adjuvant EBRT (2016-2020). RESULTS: Most patients were dentate and 80 % underwent dental extractions prior to EBRT of which 16 (16 %) had complications. The rate of ORN was 3.7 % for oral cavity SCC patients and 8.1 % for oropharyngeal SCC patients. Median time to ORN development was 156 days and the earliest case was detected at 127 days post EBRT completion. All ORN patients were dentate and underwent extraction prior to EBRT start. CONCLUSION: ORN development can occur early following EBRT in a Veteran population with significant comorbid conditions but overall rates are in line with the general population. Prospective tracking of HNSCC patients throughout the post-treatment surveillance period is critical to early detection of this devastating EBRT complication.

Osteoradionecrosis of the jaws: A retrospective cohort study.

Introduction: Radiotherapy (RT) combined with chemotherapy and surgery is the indicated treatment for head and neck cancers. Even with the advent of modern technological advances in RT and improved oral hygiene awareness, osteoradionecrosis (ORN) still remains as one of the most debilitating side effects of RT. Methodology: This is a retrospective review assessing 72 patients aged over 18 years of age reporting in the Dental Department, for treatment of ORN from April 2010 to July 2019. Each patient was clinically examined and treated according to standard protocol. The stage of ORN was noted at the diagnosis and at follow-up. The demographic data, the tumor characteristics, and the treatment of patients were evaluated using descriptive statistics. Results: At the time of diagnosis, 84.7% of the study population was found to have Epstein Type II chronic persistent nonprogressive lesions and 11.1% of the cohort had Type III active progressive lesions. Statistically significant correlation (P = 0.00) was found for ORN grade at diagnosis and at follow-up. ORN being a chronic pathology, stabilization of the disease was observed in 72.3% of cases. The resolution of the necrotic lesion and down staging of the disease was seen only in 2.8% of patients. Conclusion: ORN is mainly a chronic long standing pathology which is difficult to treat completely. Stabilization of symptoms and preventing further spread of the necrotic lesion should be the ultimate aim of the treatment to improve the quality of life of the patients.

Are Bacteria Just Bystanders in the Pathogenesis of Inflammatory Jaw Conditions?

PURPOSE: It is unclear whether certain bacteria initiate the development of inflammatory jaw conditions, or whether these diseases create a milieu for dysbiosis and secondary colonization of indigenous flora. At present, there are no comparative studies on the types of bacteria that colonize different inflammatory jaw conditions. Accordingly, this study aims to identify and compare the types of bacteria isolated in osteomyelitis, osteoradionecrosis, and MRONJ. METHODS: This is a retrospective cohort study of patients diagnosed with inflammatory jaw conditions. The predictor variables were classification of bacteria as oral flora, categorized herein as resident bacteria, non-resident bacteria, or opportunistic organisms. The outcome variables were a diagnosis of osteomyelitis, osteoradionecrosis, and MRONJ. Covariates were age, sex, penicillin allergy, a diagnosis of diabetes and a history of smoking. Data analysis was performed using ANOVA and chi-squared tests. RESULTS: A total of 105 patients with inflammatory jaw conditions were enrolled. The final sample size was 69 subjects of which 16 were diagnosed with osteomyelitis, 20 with osteoradionecrosis, and 33 with MRONJ. There was no difference in the frequency that resident bacteria were isolated. Non-resident bacteria, which included Staphylococcus and Enterococcus among others, were isolated more frequently at 75% in osteomyelitis compared to 60% in osteoradionecrosis and 48% in MRONJ cases. There is weak evidence of significant difference when comparing osteomyelitis and MRONJ cases (P = .08). Opportunistic organisms, which included Mycobacterium and Candida, were isolated more frequently in osteoradionecrosis at 30% compared to 12.5% in osteomyelitis and 12.12% in MRONJ cases. There is weak evidence of significant difference when comparing osteoradionecrosis and MRONJ cases (P = .1). CONCLUSION: Non-resident bacteria including Staphylococcus and Enterococcus may be more frequently isolated in patients with osteomyelitis, while opportunistic organisms like Mycobacterium and Candida may be more frequently found in patients diagnosed with osteoradionecrosis.

Predictors of osteoradionecrosis following irradiated tooth extraction.

BACKGROUND: Tooth extraction post radiotherapy is one of the most important risk factors of osteoradionecrosis of the jawbones. The objective of this study was to determine the predictors of osteoradionecrosis (ORN) which were associated with a dental extraction post radiotherapy. METHODS: A retrospective analysis of medical records and dental panoramic tomogram (DPT) of patients with a history of head and neck radiotherapy who underwent dental extraction between August 2005 to October 2019 was conducted. RESULTS: Seventy-three patients fulfilled the inclusion criteria. 16 (21.9%) had ORN post dental extraction and 389 teeth were extracted. 33 sockets (8.5%) developed ORN. Univariate analyses showed significant associations with ORN for the following factors: tooth type, tooth pathology, surgical procedure, primary closure, target volume, total dose, timing of extraction post radiotherapy, bony changes at extraction site and visibility of lower and upper cortical line of mandibular canal. Using multivariate analysis, the odds of developing an ORN from a surgical procedure was 6.50 (CI 1.37-30.91, p = 0.02). Dental extraction of more than 5 years after radiotherapy and invisible upper cortical line of mandibular canal on the DPT have the odds of 0.06 (CI 0.01-0.25, p < 0.001) and 9.47 (CI 1.61-55.88, p = 0.01), respectively. CONCLUSION: Extraction more than 5 years after radiotherapy, surgical removal procedure and invisible upper cortical line of mandibular canal on the DPT were the predictors of ORN.

Temporal Bone Osteoradionecrosis: An 18-year, Single-Institution Experience.

OBJECTIVES/HYPOTHESIS: To report the largest single-institution review of temporal bone osteoradionecrosis (TBORN), and characterize the disease's natural history, prognostic factors, management, and outcomes. STUDY DESIGN: Retrospective chart review. METHODS: Retrospective review was conducted to identify patients with TBORN. Pertinent data were extracted. Descriptive statistics were used to summarize patient, tumor, and treatment characteristics. Multivariable analyses were conducted to explore associations between these characteristics and time to TBORN diagnosis and risk of developing diffuse disease. RESULTS: TBORN was identified in 145 temporal bones from 128 patients. Mean age at diagnosis was 62 years, and mean time to diagnosis after radiotherapy was 10 years. Age greater than 50 years was associated with earlier diagnosis. According to the Ramsden criteria, 76% of TBs had localized and 24% had diffuse disease at initial diagnosis; 37% had diffuse disease at last follow-up. On multivariable analysis, diabetes, three-dimensional conformal radiotherapy (3D-CRT), and periauricular skin malignancy were significant risk factors for developing diffuse disease. Localized disease was successfully managed with conservative measures, whereas surgery was often necessary for diffuse disease. When TBORN spread outside the mastoid or infratemporal fossa, conservative measures were always unsuccessful. CONCLUSIONS: TBORN occurs earlier in older patients. While diffuse disease is less common than localized disease, it occurs more frequently in patients with diabetes, history of 3D-CRT, and periauricular skin malignancies. Conservative management is appropriate for localized disease, while surgery is often necessary for diffuse disease. The prognostic factors identified helped propose a TBORN staging system and treatment guidelines which may improve patient risk stratification and disease management. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2578-2585, 2021.

[Predictive factors for mandibular osteoradionecrosis after irradiation of head and neck cancers]. / Facteurs prédictifs de l'ostéoradionécrose mandibulaire après irradiation des cancers des voies aérodigestives supérieures.

The identification of the different risk factors for mandibular osteoradionecrosis (ORN) must be done before and after the management of patients with head and neck cancer. Various clinical criteria for this severe radiation-induced complication are related to the patient (intrinsic radiosensitivity, malnutrition associated with thin weight loss, active smoking intoxication, microcapillary involvement, precarious oral status, hyposalivation) and/or related to the disease (oral cavity, large tumor size, tumor mandibular invasion). Therapeutic risk factors are also associated with a higher risk of ORN (primary tumor surgery, concomitant radio-chemotherapy, post-irradiation dental avulsion, preventive non-observance with the absence of stomatological follow-up and daily installation of gutters fluoride and, non-observance curative healing treatments). Finally, various dosimetric studies have specified the parameters in order to target the dose values distributed in the mandible, which increases the risk of ORN. An mean mandibular dose greater than 48-54Gy and high percentages of mandibular volume receiving 40 to 60Gy appear to be discriminating in the risk of developing an ORN.

[The past, present and future of diagnosis and treatment of osteoradionecrosis of the jaws].

Osteoradionecrosis of the jaw (ORNJ) is one of the most devastating complications caused by radiation therapy in head and neck region, which is among the greatest challenges within stomatology. Treatment methods have been enriched because of expanded understanding of the pathogenic mechanism of ORNJ. Meanwhile, the diagnosis and treatment of ORNJ have been uniformed and improved gradually in China, making progress on several aspects from the establishment of classification and hierarchy system and publication of the consensus on ORNJ treatment. In the present comment, the author reviewed the history and current situation of diagnosis and treatment of ORNJ and prospected the hot topics of basic, translational and clinical research.

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.

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.

Assessment of jaw osteonecrosis diagnostic criteria in cancer patients with a history of radiation therapy and exposure to bone-modifying agents.

BACKGROUND: Osteoradionecrosis (ORN) of the jaw is currently defined by the development of osteonecrosis in head/neck irradiated patients, regardless of lesion exposure. To diagnose medication-related osteonecrosis of the jaw (MRONJ), a history of any radiation therapy to the jaw region must be ruled out. The aim of this study was to assess the accuracy of current osteonecrosis criteria, while introducing new modifications for improved diagnosis and treatment. METHODS: One hundred and forty-one necrotic lesions were analyzed from patients exposed to bone-modifying agents (BMAs) and/or received head and neck regional radiation therapy, where the maximal dose of radiation exposure to the jaw osteonecrosis site was calculated. Modified diagnostic criteria were used to reassess all cases and a comparison of outcomes was performed using Pearson's Chi-Square/Fisher's exact test. RESULTS: Only in patients with primary head and neck carcinomas did the maximal mean radiation dose in the necrotic jaw site reach ranges associated with ORN formation (>40 Gy), with individual cases showing exposures as low as 0-2 Gy. Based on the modified diagnostic criteria almost 2/3 of the necrotic cases diagnosed as ORN should be diagnosed as MRONJ. CONCLUSIONS: ORN diagnosis should only be considered in cases of radiation exposure >40 Gy to prevent misdiagnosis and suboptimal treatment. A modified criterion for MRONJ diagnosis is recommended where radiation exposure <40 Gy in the necrotic site is included. In cases with exposure >40 Gy and BMA administration, an additional modification to diagnostic criteria of 'medication- and radiation-related osteonecrosis of the jaw', should be used.

Labiomental sensation after segmental mandibulectomy and inferior alveolar nerve preservation for osteoradionecrosis.

Advanced mandibular osteoradionecrosis requires a segmental mandibulectomy with reconstruction using a free fibular flap. The conservation of labiomental sensation by lateralization of the inferior alveolar nerve is unusual during a segmental mandibulectomy. A protocol for the evaluation of labiomental sensation has been created for the clinical follow-up of operated patients. The patients included were patients with mandibular osteoradionecrosis who underwent a segmental mandibulectomy with reconstruction by free fibular flap and whose pre-operative labiomental sensation was preserved. All patients were followed-up by the same examiner and operated on by the same surgeon. The neuro-sensitive examination analyses the different forms of sensation at 1 week and at 12 months postoperatively. Between May 2017 and May 2018, 3 consecutive patients were assessed. The results of the labiomental sensitive evaluation using our evaluation protocol attest to the preservation of labiomental sensation. The operating time was increased by an average of 35 min per surgical procedure. The conservation and re-routing of the inferior alveolar nerve in segmental mandibulectomy with fibula free flap reconstruction in patients with osteoradionecrosis allows for the preservation of labiomental sensation, which improves the quality of life of patients. Our protocol can be used in all surgical procedure that affect sensibility.

Long-term recurrences of jaw osteoradionecrosis after apparent healing with the PENTOCLO protocol.

Osteoradionecrosis of the jaws (ORNJ) is a late complication of head and neck irradiation estimated at around 3% of irradiated patients. The PENTO protocol (Pentoxyfilline and Tocopherol), with the eventual adjunction of Clodronate (PENTOCLO), showed interesting results even in advanced ORNJ. The current literature does not describe the long-term outcomes and particularly after the completion of the protocol. The PENTO or PENTOCLO protocol should be prescribed as a life-long treatment or the outcome should be monitored at least as long as the duration of the protocol after its end.