Patterns of recurrence in patients undergoing curative treatment for maxillary alveolus squamous cell carcinoma.

The aim of this paper was to examine patterns of recurrence in patients undergoing curative treatment for maxillary alveolus squamous cell carcinoma (MASCC). Clinicopathological data on 41 patients undergoing curative resection for MASCC between February 2006 and May 2020 were retrospectively gathered. Outcomes included local, regional, or distant failure as first site of treatment recurrence. Univariate analysis identified significant clinicopathological variables for type of recurrence. Multivariate regression analysis generated predictive models. Ten of 41 patients developed regional recurrence, and nine manifested contralateral recurrence following ipsilateral neck dissection. In three patients the ipsilateral neck was pN0. Nodal metastasis was predictive of regional recurrence, particularly with extranodal tumour extension (ENE). Multivariate analysis with regional recurrence confirmed that ENE was independently predictive. Nodal disease and ENE in patients with MASCC was found to be predictive of contralateral regional recurrence. Management of the neck in MASCC that extends to the palatal aspect should therefore be considered as midline disease.

Prognostic significance of dysplasia associated with oral squamous cell carcinoma in patients undergoing surgery with curative intent.

The aim of this study was to evaluate the prognostic significance of dysplasia in patients undergoing primary surgery with curative intent in the treatment of oral squamous cell carcinoma (OSCC). This study specifically aimed to demonstrate the effect of dysplasia on local recurrence, disease specific survival (DSS) and overall survival (OS). Data collection for 833 patients with OSCC undergoing treatment for curative intent was undertaken retrospectively for the period of February 2006 to May 2020. Analysis of any association between known clinicopathological prognostic categorical variables with respect to dysplasia was undertaken using the chi squared test. A Kaplan-Meier analysis was performed to demonstrate the impact of dysplasia on DSS and OS, and Cox's proportional-hazards model deployed to obtain hazard ratios associated with dysplasia and the outcomes of interest. Dysplasia was statistically significant in predicting disease specific and overall survival in patients undergoing primary surgery for OSCC (DSS p<0.001, HR 0.577; 95%CI 0.428 to 0.777), OS p<0.001 HR 0.691; 95%CI 0.562 to 0.850) with the absence of dysplasia predicting poorer outcomes. The absence of dysplasia correlated with pathological higher T and N stage, increased categorised depth of tumour invasion, non-cohesive invasive front, lymphovascular invasion, perineural invasion, extranodal extension and increased modified Glasgow Prognostic Score. No significant prognostic relationship was attributable to the presence of dysplasia at a surgical margin. The absence of dysplasia appeared to be a significant independent prognostic indicator for patients with OSCC. The presence or absence of dysplasia may provide a heuristic means of stratifying OSCC primary lesions in terms of disease hostility.

Machine learning methods applied to risk adjustment of cumulative sum chart methodology to audit free flap outcomes after head and neck surgery.

We describe a risk adjustment algorithm to benchmark and report free flap failure rates after immediate reconstruction of head and neck defects. A dataset of surgical care episodes for curative surgery for head and neck cancer and immediate reconstruction (n = 1593) was compiled from multiple NHS hospitals (n = 8). The outcome variable was complete flap failure. Classification models using preoperative patient demographic data, operation data, functional status data and tumour stage data, were built. Machine learning processes are described to model free flap failure. Overall complete flap failure was uncommon (4.7%) with a non-statistical difference seen between hospitals. The champion predictive model had acceptable discrimination (AUROC 0.66). This model was used to risk-adjust cumulative sum (CuSUM) charts. The use of CuSUM charts is a viable way to monitor in a 'Live Dashboard' this quality metric as part of the quality outcomes in oral and maxillofacial surgery audit.

The relative propensity for regional metastasis in floor of mouth squamous cell carcinoma versus other oral cavity subsites.

There are previous papers suggesting that floor of mouth (FOM) oral squamous cell carcinomas (OSCC) metastasise earlier than other oral cavity subsites. This report further evaluates that hypothesis. Between February 2006 and December 2019, 825 patients underwent curative resection of OSCC. Data on nodal metastases and depth of invasion (DOI) of the primary tumour were collated. The relationship between tumour DOI and likelihood of nodal metastases was examined. A total of 203 patients had a FOM OSCC, 75 of which had nodal metastases. No difference was found in the incidence of, or correlation with DOI, and occurrence of regional metastases when FOM was compared to other OSCC subsites. We conclude that FOM OSCC has a similar regional metastatic propensity as other subsites in the oral cavity.

Patterns of recurrence amongst patients undergoing resection of oral squamous cell carcinoma with curative intent.

This study was aimed to identify key clinicopathological variables that predict recurrence in those undergoing curative resection of oral squamous cell carcinoma (OSCC) with emphasis on initial treatment failure patterns. Between February 2006 to May 2020, clinicopathological data on 833 patients who underwent curative resection of OSCC were gathered. Outcomes of interest included local, regional, distant, and overall recurrence. Univariate analysis was performed to identify significant clinicopathological variables for each recurrence type, and a multivariate regression analysis was utilised to generate predictive models. A total of 187 patients (22.4%) developed recurrent disease; 79 local, 63 regional, and 46 distant. For local recurrence: tumour depth of invasion (DOI) >5--10 mm, tumour DOI >10 mm and modified Glasgow Prognostic Score (mGPS) 2 were independently predictive (c-index 0.708). For regional recurrence: primary OSCC of hard palate/maxilla, pN1, pN3b, and non-cohesive invasive front were independently predictive (c-index 0.738). For distant recurrence: pN1 pN2a, pN2b, pN2c, pN3b, and tumour DOI >10 mm were independently predictive (c-index 0.809). For recurrence at any site; pN1, pN2a, pN2b, pN2c, pN3b, tumour DOI >5-10 mm, tumour DOI >10 mm, mGPS 2, and involved surgical margins were independently predictive (c-index 0.750). Recurrence events after curative treatment for OSCC are relatively predictable on the basis of available clinicopathological characteristics. It seems likely that trials of adjuvant systemic therapy in high-risk OSCC will continue to be designed with emerging therapeutic agents. Trials should focus on those of highest risk of relapse and this study adds clarity to the selection of the correct target population.

Survival in node-positive early oral squamous cell carcinoma: sentinel node biopsy versus elective neck dissection.

Patients undergoing sentinel node biopsy (SLNB) for early oral squamous cell carcinoma (OSCC) who harbour occult metastases (pN+ve) may be at greater risk of mortality due to prolonged overall treatment times than those identified as pN+ve on elective neck dissection (ELND). A retrospective comparative survival analysis was therefore undertaken to test this hypothesis. Patients were identified from the South Glasgow multidisciplinary team (MDT) database. Group 1 comprised 38 patients identified as pN+ve, or who were false negative, on sentinel lymph node biopsy (SLNB). Group 2 comprised 146 patients staged pN+ve on ELND. The groups were compared with the Kaplan Meier method and Cox proportional hazards model. In addition, a matched-pair analysis was performed. A unique and specifically designed algorithm was deployed to optimise the pairings. No difference in disease-specific or overall survival was found between the groups. Patients undergoing SLNB as the initial neck staging modality in early OSCC and are identified as pN+ve do not appear to be at a survival disadvantage compared with those staged with ELND.

Sentinel lymph node biopsy for early oral cancer - accuracy and considerations in patient selection.

Sentinel lymph node biopsy (SLNB) for staging oral squamous cell carcinoma (OSCC) patients presenting with early (T1 and T2 N0) disease in preference to elective neck dissection (END) remains controversial worldwide. A retrospective analysis of 145 patients who underwent sentinel lymph node biopsy for a previously untreated early oral cancer between 2010 and 2020 was performed. The primary outcome measures were predictors of occult metastases, accuracy of SLNB and disease specific plus overall survival. The negative predictive value, the false negative rate, and sensitivity for SLNB were 97%, 7.8%, and 92%, respectively. Depth of invasion (DOI) was a significant predictor of N status, overall survival, and disease specific survival. There was a significant difference in the incidence of the neck node metastasis in patients with DOI <5mm compared to those with DOI >5mm. For tumours >5mm there was a moderate to good correlation between radiological depth on contrast enhanced computed tomography (CECT) and histopathological DOI. Preoperative estimation of DOI may be a useful tool in the counselling of patients in the selection of either SLNB or END for N staging purposes in early OSCC.

Systemic inflammatory response in predicting outcomes of patients undergoing curative resection for oral squamous cell carcinoma.

This study aimed to evaluate the prognostic significance of the modified Glasgow prognostic score (mGPS), neutrophil:lymphocyte ratio (NLR), and platelet:lymphocyte ratio (PLR) in patients undergoing resection of oral squamous cell carcinoma (OSCC) with curative intent. We also aimed to explore the relation between activated systemic inflammation and adverse tumour characteristics. Between February 2006 and December 2019, data on 825 patients undergoing curative resection of OSCC were retrospectively gathered. Preoperative C-reactive protein and serum albumin levels were obtained to calculate a mGPS. Full blood count parameters were collected to calculate NLR and PLR values. Categorical factors were analysed using the chi squared test. Multivariate regression was performed to identify independent prognostic variables and the predictive value of each model generated. For disease-specific survival (DSS) and overall survival (OS), mGPS (DSS and OS both p<0.001), NLR (DSS and OS both p<0.001) and PLR (DSS and OS both p<0.001) were significant on univariate analysis. Independent predictive variables for DSS included mGPS, clinical node stage, categorised depth of tumour invasion, non-cohesive invasive front, and lymphovascular invasion. The concordance index was acceptable (0.756) for this model. Replacing mGPS with NLR or PLR as a marker of systemic inflammation demonstrated the same preoperative variables as independently predictive for DSS. The concordance index for these models were acceptable (NLR 0.76 and PLR 0.756). The systemic inflammatory response is prognostically significant in patients undergoing curative resection of OSCC. The potential link between an inflammatory tumour microenvironment and activated systemic inflammation merits further investigation.

The relevance of surgical margins in clinically early oral squamous cell carcinoma.

OBJECTIVES: There is controversy regarding surgical margins in the management of early oral squamous cell carcinoma (OSCC). The main objectives of this study were to assess the: relevance of the margin independent of tumour variables; threshold for a safe margin; relevance of dysplasia at the margin. MATERIALS & METHODS: UK based retrospective multicenter cohort study of patients with previously untreated and clinically early OSCC between 1998 and 2016. All patients had surgery as the primary modality and had surgical staging of the neck. Minimum follow-up was 2 years. Margins were classified as: clear ≥5.0 mm; close 1.0-4.9 mm; involved not cut-through (INC-T) 0.1-0.9 mm; cut-through (C-T) 0 mm. RESULTS: 669 patients were included. After adjusting for tumour variables Cox multivariate regression analysis demonstrated that close margins had similar survival outcomes to clear margins (Hazard Ratio(HR) 0.99 (95%CI 0.50-1.95) for Local Recurrence Free Survival (LRFS); HR 1.08 (95%CI 0.7-1.66) for Disease Free Survival (DFS); HR 0.74 (95%CI 0.44-1.25) for Disease Specific Survival (DSS); HR 0.80 (95%CI 0.58-1.11) for Overall Survival (OS)). C-T margins had significantly worse LRFS (HR 5.01 (95%CI 2.02-12.39)) and DFS (HR 2.58 (95%CI 1.28-5.20)). INC-T margins had significantly worse DFS (HR 1.98 (95% CI 1.01-3.87)). Time dependent receiver operating characteristic curve analysis did not demonstrate a clear margin threshold for LRFS within 24 months (AUC = 0.53 (95%CI 0.41-0.64)). Dysplasia at the margin did not influence LRFS or DFS. CONCLUSION: Only resection margins <1 mm independently affected survival outcomes. This should be considered when making decisions regarding adjuvant treatment.

Surgical consensus guidelines on sentinel node biopsy (SNB) in patients with oral cancer.

BACKGROUND: The eighth international symposium for sentinel node biopsy (SNB) in head and neck cancer was held in 2018. This consensus conference aimed to deliver current multidisciplinary guidelines. This document focuses on the surgical aspects of SNB for oral cancer. METHOD: Invited expert faculty selected topics requiring guidelines. Topics were reviewed and evidence evaluated where available. Data were presented at the consensus meeting, with live debate from panels comprising expert, nonexpert, and patient representatives followed by voting to assess the level of support for proposed recommendations. Evidence review, debate, and voting results were all considered in constructing these guidelines. RESULTS/CONCLUSION: A range of topics were considered, from patient selection to surgical technique and follow-up schedule. Consensus was not achieved in all areas, highlighting potential issues that would benefit from prospective studies. Nevertheless these guidelines represent an up-to-date pragmatic recommendation based on current evidence and expert opinion.

DNA damage marker phosphorylated histone H2AX is a potential predictive marker for progression of epithelial dysplasia of the oral cavity.

AIMS: To evaluate the relationships between immunohistochemical markers related to cellular senescence, cell proliferation and histological grade of epithelial dysplasia (OD) of the oral cavity. In addition, the predictive value of these markers for progression of OD was assessed. METHODS AND RESULTS: Retrospective immunohistochemical analyses were performed on 86 formalin-fixed paraffin-embedded specimens of OD and oral squamous cell carcinoma (OSCC) for Ki67, phosphorylated histone H2AX (γH2AX), p53, p16, trimethyl-histone H3 (Lys9) (H3K9me3) and cyclin D1 (CycD1). Three separate areas representing the highest severity of OD on each slide were annotated digitally by two independent pathologists. Mean automated histoscores of the selected markers were generated and compared to that of age-matched healthy controls (n = 24). Follow-up data of OD were retrieved and anonymized by a clinical team member and linked using unique participant identifiers. The median follow-up was 10.9 years (interquartile range: 10.1-11.5). Ki67 (P < 0.0001), γH2AX (P = 0.03) and p53 (P = 0.04) were increased significantly with higher histological grade of OD. γH2AX (P = 0.03), but not histological grade of OD (P = 0.73), was associated prospectively with disease progression. Using the median histoscore for γH2AX (median histoscore = 17) as a cut-off, histoscore ≥17 was associated with an increased risk of disease progression [hazard ratio (HR) = 3.15, 95% confidence interval (CI): 1.41-7.39, P = 0.0064]. CONCLUSIONS: Although proliferation marker Ki67, DNA damage/checkpoint markers γH2AX and p53 were increased in higher grade of OD, only γH2AX was predictive of disease progression. These observations may reflect the role of DNA replicative stress in the transformation from OD to OSCC. Larger studies should evaluate whether γH2AX can be used as a predictive marker of OD.

Anterolateral corridor approach to the infratemporal fossa and central skull base in maxillectomy: rationale and technical aspects.

We describe the technical aspects and report our clinical experience of a surgical approach to the infratemporal fossa that aims to reduce local recurrence after operations for cancer of the posterior maxilla. We tested the technique by operating on 3 cadavers and then used the approach in 16 patients who had posterolateral maxillectomy for disease that arose on the maxillary alveolus or junction of the hard and soft palate (maxillary group), and in 19 who had resection of the masticatory compartment and central skull base for advanced sinonasal cancer (sinonasal group). Early proximal ligation of the maxillary artery was achieved in all but one of the 35 patients. Access to the infratemporal fossa enabled division of the pterygoid muscles and pterygoid processes under direct vision in all cases. No patient in the maxillary group had local recurrence at median follow up of 36 months. Four patients (21%) in the sinonasal group had local recurrence at median follow up of 27 months. Secondary haemorrhage from the cavernous segment of the internal carotid artery resulted in the only perioperative death. The anterolateral corridor approach enables controlled resection of tumours that extend into the masticatory compartment.

Evaluating holistic needs assessment in outpatient cancer care--a randomised controlled trial: the study protocol.

INTRODUCTION: People living with and beyond cancer are vulnerable to a number of physical, functional and psychological issues. Undertaking a holistic needs assessment (HNA) is one way to support a structured discussion of patients' needs within a clinical consultation. However, there is little evidence on how HNA impacts on the dynamics of the clinical consultation. This study aims to establish (1) how HNA affects the type of conversation that goes on during a clinical consultation and (2) how these putative changes impact on shared decision-making and self-efficacy. METHODS AND ANALYSIS: The study is hosted by 10 outpatient oncology clinics in the West of Scotland and South West England. Participants are patients with a diagnosis of head and neck, breast, urological, gynaecological and colorectal cancer who have received treatment for their cancer. Patients are randomised to an intervention or control group. The control group entails standard care--routine consultation between the patient and clinician. In the intervention group, the patient completes a holistic needs assessment prior to consultation. The completed assessment is then given to the clinician where it informs a discussion based on the patient's needs and concerns as identified by them. The primary outcome measure is patient participation, as determined by dialogue ratio (DR) and preponderance of initiative (PI) within the consultation. The secondary outcome measures are shared decision-making and self-efficacy. It is hypothesised that HNA will be associated with greater patient participation within the consultation, and that shared decision-making and feelings of self-efficacy will increase as a function of the intervention. ETHICS AND DISSEMINATION: This study has been given a favourable opinion by the West of Scotland Research Ethics Committee and NHS Research & Development. Study findings will be disseminated through peer-reviewed publications and conference attendance. TRAIL REGISTRATION NUMBER: Clinical Trials.gov NCT02274701.

Osteocutaneous radial forearm free flap in subtotal nasal reconstruction.

A 66-year-old man presented with a large squamous cell carcinoma of the right nasal vestibule. He underwent partial rhinectomy and medial maxillectomy followed by staged reconstruction. Reconstruction of a full-thickness nasal defect requires repair of three distinct layers: the skin-soft tissue envelope, subsurface framework and intranasal lining. We report the first use in the UK of an osteocutaneous radial forearm free flap in the reconstruction of a subtotal nasal deficit. The skin of the radial forearm free flap was tubed to recreate the nasal lining and the radial bone reconstructed the dorsal contour of the nose. A full-thickness paramedian forehead flap supplied external coverage. The osteocutaneous radial forearm free flap and forehead flap is a viable option for large nasal defects requiring reconstruction of framework, nasal lining and external covering.

Radiological assessment of bioengineered bone in a muscle flap for the reconstruction of critical-size mandibular defect.

This study presents a comprehensive radiographic evaluation of bone regeneration within a pedicled muscle flap for the reconstruction of critical size mandibular defect. The surgical defect (20 mm × 15 mm) was created in the mandible of ten experimental rabbits. The masseter muscle was adapted to fill the surgical defect, a combination of calcium sulphate/hydroxyapatite cement (CERAMENT™ |SPINE SUPPORT), BMP-7 and rabbit mesenchymal stromal cells (rMSCs) was injected inside the muscle tissue. Radiographic assessment was carried out on the day of surgery and at 4, 8, and 12 weeks postoperatively. At 12 weeks, the animals were sacrificed and cone beam computerized tomography (CBCT) scanning and micro-computed tomography (µ-CT) were carried out. Clinically, a clear layer of bone tissue was identified closely adherent to the border of the surgical defect. Sporadic radio-opaque areas within the surgical defect were detected radiographically. In comparison with the opposite non operated control side, the estimated quantitative scoring of the radio-opacity was 46.6% ± 15, the mean volume of the radio-opaque areas was 63.4% ± 20. Areas of a bone density higher than that of the mandibular bone (+35% ± 25%) were detected at the borders of the surgical defect. The micro-CT analysis revealed thinner trabeculae of the regenerated bone with a more condensed trabecular pattern than the surrounding native bone. These findings suggest a rapid deposition rate of the mineralised tissue and an active remodelling process of the newly regenerated bone within the muscle flap. The novel surgical model of this study has potential clinical application; the assessment of bone regeneration using the presented radiolographic protocol is descriptive and comprehensive. The findings of this research confirm the remarkable potential of local muscle flaps as local bioreactors to induce bone formation for reconstruction of maxillofacial bony defects.

The use of TriCalcium Phosphate (TCP) and stem cells for the regeneration of osteoperiosteal critical-size mandibular bony defects, an in vitro and preclinical study.

The investigation aims to assess the reconstruction of critical-size mandibular bone defects in rabbits using beta-Tricalcium Phosphate (ß-TCP) scaffolding loaded with stem cells. A 20 mm-long mandibular osteoperiosteal continuity defect was created in 8 New Zealand rabbits and filled with ß-TCP scaffolding. In 6 cases bone marrow stem cells (BMSCs) harvested, and enriched, from the posterior iliac crest of the same rabbit were seeded into the scaffolding, while a scaffold was used alone in two cases chosen at random. Radiographic analysis was carried out immediately following surgery and 4, 8 and 12 weeks postoperatively. Cone Beam CT (CBCT) scanning, biomechanical testing and histology assessments were carried out on the explanted mandibles three months postoperatively. The radiography showed minimal new bone formation in all the cases, with significant amounts of undegraded scaffold material visible. Sporadic areas of bone formation were seen, these did not bridge the gap of the created surgical defect. The mechanical properties of the regenerated bone were of an inferior quality when compared with that of the contralateral non-operated side. The addition of BMSCs to the biodegradable ß-TCP scaffold did not improve reconstruction of the created mandibular defect. Despite successful aspiration and culture of BMSCs, the survival of these cells in vivo was questionable.

LIHNCS - Lugol's iodine in head and neck cancer surgery: a multicentre, randomised controlled trial assessing the effectiveness of Lugol's iodine to assist excision of moderate dysplasia, severe dysplasia and carcinoma in situ at mucosal resection margins of oral and oropharyngeal squamous cell carcinoma: study protocol for a randomised controlled trial.

BACKGROUND: Oral cavity and oropharynx cancer are increasing in incidence worldwide but survival outcomes have not significantly improved over the last three decades. The presence of dysplasia or carcinoma in situ at surgical margins following resection of squamous carcinoma of the mucosal surfaces of the head and neck has been shown to be associated with a higher incidence of local recurrence and reduced survival. While invasive carcinoma in mucosal surfaces can usually be distinguished from adjacent normal mucous membrane, pre-malignant disease is much less readily distinguished at operation. We describe a protocol for a randomised, controlled trial in which we will assess the effectiveness of Lugol's iodine staining in allowing visualisation and excision of cancer margin dysplasia at time of primary surgery. METHODS/DESIGN: We will recruit 300 patients diagnosed with oral cavity or oropharynx squamous cell carcinoma. All participants will be planned for primary surgery with curative intent. After completion of baseline assessment participants will be randomised into either a standard surgical treatment arm or surgical treatment including Lugol's iodine staining. DISCUSSION: This paper describes the rationale and design of a unique trial in head and neck surgical oncology. If margin dysplasia visualisation with Lugol's iodine allows complete excision of high-risk, pre-cancer mucosa at time of primary surgery, this may lead to a reduction in local recurrence and improved survival. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03712770.