Andrew Lyons

Osteoradionecrosis of the jaws : current understanding of its pathophysiology and treatment

During the past 80 years a number of theories about the pathogenesis of osteoradionecrosis (ORN) have been proposed, with consequent implications for its treatment. Until recently tissue hypoxia and its consequences were accepted as the primary cause, and this led to the use of hyperbaric oxygen (HBO) for both treatment and prevention of complications of radiotherapy in the head and neck. The benefit of HBO has not been validated. A new theory for the pathogenesis of ORN has proposed that damage to bone is caused by radiation-induced fibrosis. Cells in bone are damaged as a result of acute inflammation, free radicals, and the chronic activation of fibroblasts by a series of growth factors. New treatments have therefore been devised that include pentoxifylline, a vasodilator that also inhibits fibrosis, and tocopherol (vitamin E) to reduce damage caused by free radicals. Impressive results in terms of reversing the process of ONR have been reported using these agents. It has been suggested that this theory and these agents could be the basis of future treatment and prevention of ORN.

Osteoradionecrosis—A review of current concepts in defining the extent of the disease and a new classification proposal

Osteoradionecrosis (ORN) is potentially a debilitating and serious consequence of radiotherapy to the head and neck. Although it is often defined as an area of exposed bone that does not heal, it can also exist without breaching the mucosa or the skin. Currently, 3 classifications of ORN are in use, but they depend on the use of hyperbaric oxygen or are too complicated to be used as a simple aide-mémoire, and include features that do not necessarily influence its clinical management. We propose a new classification to cover these shortcomings and to take into account the increasingly widespread use of antifibrotic medical treatment. We classified a series of 85 patients with varying severities of ORN into 4 groups. An analysis of the outcomes of the series showed that the classification staged the severity of the condition simply and that the stage was relevant to both treatment and outcome. The new classification was therefore verified by the series presented.

Sentinel Lymph Node Biopsy for T1/T2 Oral Cavity Squamous Cell Carcinoma—A Prospective Case Series

BackgroundSentinel lymph node biopsy (SLNB) is an established technique in breast and melanoma surgery and is gaining acceptance in the management of oral cavity squamous cell carcinoma. We report a single institution’s experience of SLNB between 2006 and 2010.MethodsProspective consecutive cohort study of 59 patients recruited between 2006 and 2010. All patients underwent SLNB with preoperative lymphoscintigraphy, intraoperative blue dye, and handheld gamma probe. Sentinel nodes were evaluated with step-serial sectioning and immunohistochemistry. Endpoints included: overall survival (OS), disease-specific survival (DSS), local recurrence-free survival (LRFS), and regional recurrence-free survival (RRFS).ResultsA total of 59 patients (36 male and 23 female) were operated on. Of these, 42 patients (71%) were pT1 and 17 patients (29%) were pT2. In two patients the sentinel node was not identified and proceeded to elective neck dissection. A total of 150 nodes were harvested from the remaining 57 patients of which 21 nodes were positive in 17 patients; three patients had positive contralateral nodes. The 2-year OS, DSS, LRFS, and RRFS for the SLNB negative patients were 97.5, 100, 95.8, and 95.8% and for the SLNB positive patients 68.2, 81.8, 83.9, and 100% respectively. Only OS and DSS approached statistical significance with P values of 0.07 and 0.06.ConclusionsSLNB is a safe and accurate diagnostic technique for staging the neck with a negative predictive value in our series of 97.5%. Furthermore, in our series three patients (5%) had positive contralateral neck drainage that would have been missed by conventional ipsilateral neck dissection.Sentinel lymph node biopsy (SLNB) is an established technique in breast and melanoma surgery and is gaining acceptance in the management of oral cavity squamous cell carcinoma. We report a single institution’s experience of SLNB between 2006 and 2010. Prospective consecutive cohort study of 59 patients recruited between 2006 and 2010. All patients underwent SLNB with preoperative lymphoscintigraphy, intraoperative blue dye, and handheld gamma probe. Sentinel nodes were evaluated with step-serial sectioning and immunohistochemistry. Endpoints included: overall survival (OS), disease-specific survival (DSS), local recurrence-free survival (LRFS), and regional recurrence-free survival (RRFS). A total of 59 patients (36 male and 23 female) were operated on. Of these, 42 patients (71%) were pT1 and 17 patients (29%) were pT2. In two patients the sentinel node was not identified and proceeded to elective neck dissection. A total of 150 nodes were harvested from the remaining 57 patients of which 21 nodes were positive in 17 patients; three patients had positive contralateral nodes. The 2-year OS, DSS, LRFS, and RRFS for the SLNB negative patients were 97.5, 100, 95.8, and 95.8% and for the SLNB positive patients 68.2, 81.8, 83.9, and 100% respectively. Only OS and DSS approached statistical significance with P values of 0.07 and 0.06. SLNB is a safe and accurate diagnostic technique for staging the neck with a negative predictive value in our series of 97.5%. Furthermore, in our series three patients (5%) had positive contralateral neck drainage that would have been missed by conventional ipsilateral neck dissection.

p53 Mutations in Deep Tissues Are More Strongly Associated with Recurrence than Mutation-Positive Mucosal Margins

Purpose: Application of ultrasensitive diagnostics has shown that small numbers of p53 mutation-positive cells may signify the presence of residual tumor in histologically normal tissues after resection of squamous cell carcinomas arising in the head and neck area. To date, most studies in this area have focused on analysis of tissues at the mucosal aspect of the resection and highlighted the importance of molecular changes in the field with respect to the risk of recurrence. Experimental Design: In the present investigation, we analyzed normal tissues from mucosal and deep surgical margins, referred to as “molecular margins,” for the presence of the signature p53 mutation identified for each tumor. Results: The p53 mutation status of these carcinomas did not correlate with clinical or histopathologic variables, but these mutations provided an excellent target for ultrasensitive analysis of margin status. We found that 11 of 16 (68%) of cases with histologically tumor-free (including 9 without dysplasia), but with p53 mutation-positive molecular margins, developed recurrence. The probability of developing local recurrence was significantly higher for the group with p53 mutation-positive margins when compared with the group with clear margins (P = 0.048) and more strongly associated with p53 mutation-positive deep molecular margins than mutation-positive mucosal molecular margins or positivity at both sites (P = 0.009). Conclusions: This shows that although persistent mucosal fields may contribute to recurrence, clonal p53 mutations in deep tissues are an important cause of treatment failure, and molecular margins from both sites should be analyzed in future prospective series.

Factors Affecting Survival and Usefulness of Implants Placed in Vascularized Free Composite Grafts Used in Post–Head and Neck Cancer Reconstruction

Background: Bone-containing vascularized grafts have been used successfully to reconstruct post-cancer surgical defects. Dental implants can be placed in these bone-containing grafts to allow implant-supported prosthodontic reconstruction of these patients. Purpose: The aim of this study was to evaluate the survival of dental implants used in the rehabilitation of subjects treated with bone-containing vascularized grafts to compare usability of implants placed at the time of reconstruction and after healing. Materials and Methods: A cross-sectional study was undertaken to examine survival rates of implants placed in vascularized bone-containing grafts either immediately at the time of surgical reconstruction or after 3 months healing. Other factors such as graft type, whether radiation therapy was given, and implant type were recorded. Results: A total of 41 patients had 145 implants placed in 47 vascularized bone-containing flaps. Increased failure rate of implants was seen in immediately placed implants. There was also a significant increase in the number of osseointegrated implants that were prosthodontically unusable or sub-optimally placed in the immediate placement group. Radiation therapy was associated with a significant increase in failure rate. Modern implant surfaces appeared to perform better than machined/turned surfaces. Graft donor site did not influence implant survival. Conclusion: This study demonstrated the difficulties encountered with immediate placement of dental implants at the time of post-cancer reconstructive surgery.BACKGROUND Bone-containing vascularized grafts have been used successfully to reconstruct post-cancer surgical defects. Dental implants can be placed in these bone-containing grafts to allow implant-supported prosthodontic reconstruction of these patients. PURPOSE The aim of this study was to evaluate the survival of dental implants used in the rehabilitation of subjects treated with bone-containing vascularized grafts to compare usability of implants placed at the time of reconstruction and after healing. MATERIALS AND METHODS A cross-sectional study was undertaken to examine survival rates of implants placed in vascularized bone-containing grafts either immediately at the time of surgical reconstruction or after 3 months healing. Other factors such as graft type, whether radiation therapy was given, and implant type were recorded. RESULTS A total of 41 patients had 145 implants placed in 47 vascularized bone-containing flaps. Increased failure rate of implants was seen in immediately placed implants. There was also a significant increase in the number of osseointegrated implants that were prosthodontically unusable or sub-optimally placed in the immediate placement group. Radiation therapy was associated with a significant increase in failure rate. Modern implant surfaces appeared to perform better than machined/turned surfaces. Graft donor site did not influence implant survival. CONCLUSION This study demonstrated the difficulties encountered with immediate placement of dental implants at the time of post-cancer reconstructive surgery.

Trismus following radiotherapy to the head and neck is likely to have distinct genotype dependent cause.

OBJECTIVES Trismus frequently occurs as a consequence of radiotherapy or chemo-radiotherapy to the head and neck, with a loss of function that can reduce the overall quality of life. Radiation can trigger an intense fibrosis within the masticatory muscles and transforming growth factor beta 1 (TGF β1) is involved in this process. As in other tissues the degree of fibrosis may be related to a single nucleotide polymorphism; C-T at position -509 in the TGF β1 gene. MATERIALS AND METHODS Trismus was measured in 62 patients before and after radiotherapy or chemoradiotherapy, blood was taken for DNA extraction, and genotype analysis of the TGF β1 gene. Trismus was analysed against, patient age, sex, tumour site and stage, radiotherapy, and chemotherapy. RESULTS AND CONCLUSIONS After radiotherapy or chemo-radiotherapy the reduction in mouth opening was shown to be significantly related to the presence of the T allele (p<0.001), with patients homozygous the most likely to be severely affected. No other patient, tumour or treatment factors were significant. Hence the TGF β1 genotype is likely to be an important predictor of the degree of post radiotherapy or chemo-radiotherapy trismus.

Head and neck sarcomas: clinical and histopathological presentation, treatment modalities, and outcomes

BACKGROUND Sarcoma of the head and neck is a rare condition that poses significant challenges in management and often requires radical multimodality treatment. OBJECTIVES This study aimed to analyse current clinical presentation, evaluation, management dilemmas and oncological outcomes. METHODS Computer records and case notes were analysed, and 39 patients were identified. Variables were compared using Pearsons chi-square test and the log-rank test, while survival outcomes were calculated using the Kaplan-Meier method. RESULTS The histopathological diagnosis was Kaposi sarcoma in 20.5 per cent of cases, chondrosarcoma in 15.3 per cent and osteosarcoma in 10.2 per cent. A range of other sarcomas were diagnosed in the remaining patients. The site of disease was most commonly sinonasal, followed by the oral cavity and larynx. CONCLUSION Wide local excision with clear resection margins is essential to achieve local control and long-term survival. There is a need for cross-specialty collaboration in order to accrue the evidence which will be necessary to improve long-term outcomes.

The utility of molecular diagnostics to predict recurrence of head and neck carcinoma

Background:Locoregional recurrence is the major cause of treatment failure after surgery for oral squamous cell carcinoma. Molecular diagnostics have the potential to improve on clinicopathological parameters to predict this recurrence and plan adjuvant treatment. The test most frequently applied is based on detecting TP53 mutations, but alternative methodology is required for cases that harbour the wild-type gene.Methods:One hundred and two cases with tumour-adjacent margins, considered to be clear margins by microscopy, were examined using carefully optimised molecular diagnostics based on detection of the TP53 and Ly-6D markers. The markers were also combined to provide a dual approach.Results:The dual molecular diagnostic identified cases with a significant increase in the probablility of developing locoregional recurrence when tumour-adjacent positive and clear margins were compared (P=0.0001). These tests were most useful when the clearance at the resection margins was 5 mm or less. The TP53-based diagnostic was a better predictor of locoregional recurrence than established clinicopathological parameters.Conclusion:The optimised TP53-based diagnostic rapidly identifies an important subgroup of cases with close margins that will benefit from new treatment modalities to reduce the risk of recurrence.

Outcomes of intensity‐modulated radiotherapy as primary treatment for oropharyngeal squamous cell carcinoma – a European single institution analysis

To analyse survival and toxicity outcomes in patients treated with primary intensity‐modulated radiotherapy (IMRT) for oropharyngeal squamous cell carcinoma (OPSCC) in the era of routine human papilloma virus (HPV) testing.

Pentoxifylline – a review of its use in osteoradionecrosis

Pentoxifylline has been used to treat complications related to fibrosis for over 20 years. Formerly used to treat those after radiotherapy such as osteoradionecrosis (ORN), it is now being tried for medication-related osteonecrosis of the jaw (MRONJ), which can occur after prolonged use of bisphosphonates. We review theories on the formation of fibrosis in patients with ORN, discuss the pharmacology of pentoxifylline and vitamin E, and report published outcomes. To our knowledge no prospective randomised controlled trial has investigated the benefits of these agents in cases of ORN, but reported outcomes in many published case series are encouraging.