A new classification of mandibular fractures.

There is no accepted method of reporting mandibular fracture that reflects incidence, treatment and outcome for individual cases. As most series include anatomical site only for all fractures, the aim was to establish a new method to report fractures based on a systematic review of the literature and an internal audit. The classification proposed is: Class I; condyle, II; angle, IIc; II+condyle, III; body/symphysis, IIIc; III+condyle, IV; multiple fractures not including condyle, IVc; IV+condyle, V; bilateral condyle±other fracture(s). A total of 10,971 adult and 914 paediatric cases were analyzed through systematic review, and 833 from the regional audit. Only 32% (14/44) of reported series could be reclassified which, when added to the audit data, showed Class IV was most common (29%), with similar proportions of Class III, Class IIIc and Class II (18-23%). External validation (literature review) in terms of treatment and outcome was non-informative, but the internal validation (audit) demonstrated an increasing requirement for adding maxillomandibular fixation (MMF) to open reduction and internal fixation (ORIF) as class increased. The heterogeneity of data reporting found in the systematic review confirms the need for a classification such as this, likely to enhance comparison of varying management protocols.

NICO Phase II clinical trial - focus on an emerging immunotherapy strategy for the adjuvant treatment of locally-advanced oral cancers.

Outcomes remain poor for patients presenting with locally-advanced oral cancers and it remains imperative to re-evaluate adjuvant therapies to provide improved outcomes, ideally without compromising on long-term quality of life. We present current available evidence that supports the use of immune checkpoint inhibitors (ICI) in squamous cell carcinoma (SCC) of the head and neck and discuss trials examining the integration of ICI into the locoregional management of such lesions that are resectable. We focus particularly on the Neoadjuvant and adjuvant nivolumab as Immune Checkpoint inhibition in Oral cavity cancer (NICO) trial which is investigating the integration of neoadjuvant and adjuvant ICI into the treatment of resectable locally-advanced oral cavity cancers.

Adjuvant management of locally advanced oral squamous cell carcinoma - real-world challenges and opportunities.

Patients with locally advanced oral squamous cell cancer (LAOSCC) are treated with adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) following surgical ablation. This depends on the pathological risk factors and aims to reduce the risk of local recurrence and improve survival. Delivery of these aggressive treatments is, however, challenging particularly following major surgery. To inform the adaptations necessary to deliver gold-standard therapy, we aimed to describe real-world delivery of multimodality treatment in LAOSCC, in a UK population with high levels of disease incidence and low socioeconomic status. Patients with LAOSCC (T1-4 N1-3/T3-4 N0) who were treated between October 2014 and October 2016 and had a minimum follow up of 24 months were included. They were identified using the Somerset Cancer Register and data were collected through retrospective case note review. Approval was obtained from the audit departments at the relevant NHS institutions, and data were analysed using IBM SPSS Statistics for Windows version 24 (IBM Corp). The analysis included 129 patients with 82% having an initial performance status (PS) of 0-1. The most frequent change in PS was a one point drop (46%). Twenty of the 93 eligible patients (22%) underwent adjuvant CRT. A total of 37 (40%) began adjuvant CRT/RT within 42 days, and 79 (85%) within 56 days. A delay in initiating adjuvant therapy was associated with higher rates of complications and a longer postoperative hospital stay. Concordance between imaging and pathological nodal staging was poor (cK 0.223). PS frequently declines after complex surgical procedures and long postoperative recovery periods, leading to difficulties providing adjuvant treatments within the national guidance of 42 days. Frequent deviation from planned adjuvant therapies highlights the need for improved treatment strategies.

Hip abductor muscle volumes are smaller in individuals affected by patellofemoral joint osteoarthritis.

OBJECTIVE: The aims of this study were twofold: firstly, to compare hip abductor muscle volumes in individuals with patellofemoral joint (PFJ) osteoarthritis (PFJ OA) against those of healthy controls; and secondly, to determine whether hip muscle volumes and hip kinematics during walking are related in individuals with PFJ OA and healthy controls. METHODS: Fifty-one individuals with PFJ OA and thirteen asymptomatic, age-matched healthy controls ≥40 years were recruited. Volumes of the gluteus medius, gluteus minimus and tensor fasciae latae were obtained from magnetic resonance (MR) images. Video motion capture was used to measure three-dimensional hip joint kinematics during overground walking. RESULTS: Significantly smaller gluteus medius (P = 0.017), gluteus minimus (P = 0.001) and tensor fasciae latae (P = 0.027) muscle volumes were observed in PFJ OA participants compared to controls. Weak correlations were observed between smaller gluteus minimus volume and larger hip flexion angle at contralateral heel strike (CHS) (r = -0.279, P = 0.038) as well as between smaller gluteus minimus volume and increased hip adduction angle at CHS (r = -0.286, P = 0.046). CONCLUSION: Reduced hip abductor muscle volume is a feature of PFJ OA and is associated with increased hip flexion and adduction angles during the late stance phase of walking for PFJ OA participants and healthy controls.

Molecular pathogenesis of proliferative verrucous leukoplakia: a systematic review.

Proliferative verrucous leukoplakia (PVL) is a potentially premalignant lesion that undergoes malignant transformation in over 40% of cases. Its clinical homogeneity suggests that a single or a small number of molecular pathogenic pathways may exist. Using the Cochrane protocol for systematic reviews, we have looked at the reported evidence of the molecular aetiology and pathogenesis of PVL and compared it with that of conventional oral epithelial dysplasia (OED). Of the 43 papers studied, 19 met the inclusion criteria including 13 proteins assayed in 344 tissues, and genes investigated were TP53, p14ARF, and p16INK4A. In all studies the research objectives were defined and outcomes were clearly stated. This review has shown that the transformation of PVL does not follow the same pathway as that of OED. There was weak evidence to suggest possible correlations between DNA aneuploidy, loss of heterozygosity at locus 9p21, and specific expression of Mcm (mini chromosome maintenance) protein, to transformation of PVL. To show important or distinct pathways of this condition, further studies are needed to access the somatic genomic alterations that are found in malignancies.

Differences in in vivo muscle fascicle and tendinous tissue behavior between the ankle plantarflexors during running.

The primary human ankle plantarflexors, soleus (SO), medial gastrocnemius (MG), and lateral gastrocnemius (LG) are typically regarded as synergists and play a critical role in running. However, due to differences in muscle-tendon architecture and joint articulation, the muscle fascicles and tendinous tissue of the plantarflexors may exhibit differences in their behavior and interactions during running. We combined in vivo dynamic ultrasound measurements with inverse dynamics analyses to identify and explain differences in muscle fascicle, muscle-tendon unit, and tendinous tissue behavior of the primary ankle plantarflexors across a range of steady-state running speeds. Consistent with their role as a force generator, the muscle fascicles of the uniarticular SO shortened less rapidly than the fascicles of the MG during early stance. Furthermore, the MG and LG exhibited delays in tendon recoil during the stance phase, reflecting their ability to transfer power and work between the knee and ankle via tendon stretch and storage of elastic strain energy. Our findings add to the growing body of evidence surrounding the distinct mechanistic functions of uni- and biarticular muscles during dynamic movements.

Modulating the DNA Damage Response to Improve Treatment Response in Cervical Cancer.

Cervical cancer is the fourth most common cause of cancer-related death in women worldwide and new therapeutic approaches are needed to improve clinical outcomes for this group of patients. Current treatment protocols for locally advanced and metastatic disease consist of ionising radiation and chemotherapy. Chemoradiation induces cytotoxic levels of DNA double-strand breaks, which activates programmed cell death via the DNA damage response (DDR). Cervical cancers are unique given an almost exclusive association with human papillomavirus (HPV) infection; a potent manipulator of the DDR, with the potential to alter tumour sensitivity to DNA-damaging agents and influence treatment response. This review highlights the wide range of therapeutic strategies in development that have the potential to modulate DDR and sensitise cervical tumours to DNA-damaging agents in the context of HPV oncogenesis.

Fibrin sealants in soft tissue surgery of the head and neck: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Fibrin sealants (FS) are commercially available products used in surgical wounds as adjuncts to haemostasis and closure of dead space. The role of FS in soft tissue head and neck surgery has not been established. OBJECTIVES: To assess whether FS improves wound-related outcomes in patients undergoing soft tissue surgery of the head and neck anatomical region that would commonly require a drain. TYPE OF REVIEW: Systematic review and meta-analysis of randomised controlled trials (RCTs). SEARCH STRATEGY: MEDLINE (1946-2016), EMBASE (1974-2016), PubMed (2016), CENTRAL (2016), ClinicalTrials.gov (2016), WHO International Clinical Trials Registry and Platform (2016), Research Gate (2016). EVALUATION METHOD: Two independent reviewers screened and selected studies. Included studies were assessed for risk of bias and data extracted using a predetermined data collection form. RESULTS: Of the 421 studies that were screened, 11 RCTs met the inclusion criteria. There were two RCTs on thyroidectomy, three on "surgery involving neck dissection" (central or lateral), five on rhytidectomy and one on parotidectomy. There was a tendency for FS to reduce "mean total drainage volume" (mean difference -26.86 mL, 95% CI -43.41 to -10.31, I2 =97%, P=.001). Subgroup analysis of thyroidectomy (mean difference -36.36 mL, 95% CI -72.82 to 0.10, I2 =79%, P=.05), "surgery involving neck dissection" (mean difference -33.21 mL, 95% CI -70.01 to 3.59, I2 =94%, P=.08) and rhytidectomy (mean difference -13.79 mL, 95% CI -17.57 to -10.01, I2 =0%, P < .00001) concurred with the overall analysis. There was a suggestion that FS may reduce "mean retention time of drains" by 1.24 days (95% CI -3.32 to 0.85, I2 =99%, P=.25) and "hospital length of stay" by 2.09 days (95% CI -5.18 to 0.99, I2 =97%, P=.18), but this was not statistically significant. There was also a suggestion that FS may protect against adverse events (RR 0.69, 95% CI 0.35 to 1.38, I2 =0%, P=.29) and haematoma/seroma formation (RR 0.49, 95% CI 0.22 to 1.07, I2 =0%, P=0.07). CONCLUSIONS: There was considerable heterogeneity within the RCTs included in this study, thus restricting definitive conclusions. FS has however shown a definite benefit in rhytidectomy and potential benefit in other soft tissue head and neck surgical procedures. Further pragmatic trials are required particularly in the field of lateral neck dissection.

Exercise, education, manual-therapy and taping compared to education for patellofemoral osteoarthritis: a blinded, randomised clinical trial.

OBJECTIVE: Patellofemoral joint osteoarthritis (PFJ OA) contributes considerably to knee OA symptoms. This study aimed to determine the efficacy of a PFJ-targeted exercise, education manual-therapy and taping program compared to OA education alone, in participants with PFJ OA. METHODS: A randomised, participant-blinded and assessor-blinded clinical trial was conducted in primary-care physiotherapy. 92 people aged ≥40 years with symptomatic and radiographic PFJ OA participated. Physiotherapists delivered the PFJ-targeted exercise, education, manual-therapy and taping program, or the OA-education (control condition) in eight sessions over 12 weeks. Primary outcomes at 3-month (primary) and 9-month follow-up: (1) patient-perceived global rating of change (2) pain visual analogue scale (VAS) (100 mm); and (3) activities of daily living (ADL) subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS). RESULTS: 81 people (88%) completed the 3-month follow-up and data analysed on an intention-to-treat basis. Between-group baseline similarity for participant characteristics was observed. The exercise, education, manual-therapy and taping program resulted in more people reporting much improvement (20/44) than the OA-education group (5/48) (number needed to treat 3 (95% confidence interval (CI) 2 to 5)) and greater pain reduction (mean difference: -15.2 mm, 95% CI -27.0 to -3.4). No significant effects on ADL were observed (5.8; 95% CI -0.6 to 12.1). At 9 months there were no significant effects for self-report of improvement, pain (-10.5 mm, 95% CI -22.7 to 1.8) or ADL (3.0, 95% CI -3.7 to 9.7). CONCLUSION: Exercise, education, manual-therapy and taping can be recommended to improve short-term patient rating of change and pain severity. However over 9-months, both options were equivalent. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12608000288325): https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=82878.

Is hip range of motion and strength impaired in people with hip chondrolabral pathology?

OBJECTIVE: The aims of this study were to: i) to compare physical impairments in people with chondrolabral pathology identified at hip arthroscopy 12-24 months previously to age-matched healthy people; and ii) to understand whether sex has any influence on impairments. METHODS: 84 patients (42 female; age=36±10) 12-24 months post hip arthroscopy and 60 controls (41 female; age=36±10) were included. Measurements of active hip ROM and strength were assessed. Two-way analyses of co-variance examined the effect of sex and chondrolabral pathology on hip ROM and strength. RESULTS: Patients exhibited less hip internal rotation (IR) ROM (p=0.001) and more extension (p=0.014) ROM; and less hip adduction (p<0.001), extension (p=0.001), flexion (p<0.001), ER (p=0.044) and IR (p<0.001) strength when compared to controls. For abduction strength, a significant interaction was found between the presence of chondrolabral pathology and sex (p=0.035). CONCLUSIONS: People with hip chondrolabral pathology have differences in hip ROM and strength when compared to controls. Rehabilitation programs should focus on addressing these specific physical impairments in order to enhance outcomes. This information may be of great value to both researchers and clinicians alike in determining interventions to improve outcomes in people with early hip OA.

Reduced biceps femoris myoelectrical activity influences eccentric knee flexor weakness after repeat sprint running.

The aim of this study was to determine whether declines in knee flexor strength following overground repeat sprints were related to changes in hamstrings myoelectrical activity. Seventeen recreationally active men completed maximal isokinetic concentric and eccentric knee flexor strength assessments at 180°/s before and after repeat sprint running. Myoelectrical activity of the biceps femoris (BF) and medial hamstrings (MHs) was measured during all isokinetic contractions. Repeated measures mixed model [fixed factors = time (pre- and post-repeat sprint) and leg (dominant and nondominant), random factor = participants] design was fitted with the restricted maximal likelihood method. Repeat sprint running resulted in significant declines in eccentric, and concentric, knee flexor strength (eccentric = 26 ± 4 Nm, 15% P < 0.001; concentric 11 ± 2 Nm, 10% P < 0.001). Eccentric BF myoelectrical activity was significantly reduced (10%; P = 0.035). Concentric BF and all MH myoelectrical activity were not altered. The declines in maximal eccentric torque were associated with the change in eccentric BF myoelectrical activity (P = 0.013). Following repeat sprint running, there were preferential declines in the myoelectrical activity of the BF, which explained declines in eccentric knee flexor strength.

The effects of a varus unloader brace for lateral tibiofemoral osteoarthritis and valgus malalignment after anterior cruciate ligament reconstruction: a single case study.

We investigated the immediate effects of a varus knee brace on knee symptoms and knee-joint biomechanics in an individual with predominant lateral tibiofemoral joint osteoarthritis (TFJOA) and valgus malalignment after anterior cruciate ligament (ACL) reconstruction. A varus unloader brace was prescribed to a 48-year-old male with predominant lateral radiographic and symptomatic TFJOA and valgus malalignment eight-years following ACL reconstruction. During a step-down task, the participant rated knee pain, task-difficulty, knee-stability and knee-confidence on four separate visual analogue scales. Quantitative gait analysis was conducted during self-selected walking trials under three test conditions in a randomized order: (i) no brace; (ii) brace without frontal plane adjustment (no varus re-alignment); and (ii) brace with frontal plane adjustment (varus re-alignment). Post-processing of gait data involved calculation of knee kinematics and net joint moments for the reconstructed limb. The participant reported improved pain (3%), task difficulty (41%), stability (46%) and confidence (49%) when performing the step-down task with the brace. The varus brace resulted in immediate reductions in knee abduction angle (24%) and internal rotation angle (56%), and increased knee adduction moment (18%). These findings provide preliminary evidence for potentially beneficial effects of bracing on knee-symptoms and biomechanics in individuals with lateral TFJOA after reconstruction.

Validation of a novel diagnostic standard in HPV-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV) testing in oropharyngeal squamous cell carcinoma (OPSCC) is now advocated. Demonstration of transcriptionally active high-risk HPV (HR-HPV) in fresh tumour tissue is considered to be the analytical 'gold standard'. Clinical testing has focused on formalin-fixed paraffin-embedded (FFPE) tissue at the expense of sensitivity and specificity. Recently, a novel RNA in situ hybridisation test (RNAscope) has been developed for the detection of HR-HPV in FFPE tissue; however, validation against the 'gold standard' has not been reported. METHODS: A tissue microarray comprising FFPE cores from 79 OPSCC was tested using HR-HPV RNAscope. Analytical accuracy and prognostic capacity were established by comparison with the reference test; qRT-PCR for HR-HPV on matched fresh-frozen samples. RESULTS: High-risk HPV RNAscope had a sensitivity and specificity of 97 and 93%, respectively, against the reference test. Kaplan-Meier estimates of disease-specific survival (DSS, P=0.001) and overall survival (OS, P<0.001) by RNAscope were similar to the reference test (DSS, P=0.003, OS, P<0.001) and at least, not inferior to p16 immunohistochemistry +/- HR-HPV DNA-based tests. CONCLUSION: HR-HPV RNAscope demonstrates excellent analytical and prognostic performance against the 'gold standard'. These data suggest that the test could be developed to provide the 'clinical standard' for assigning a diagnosis of HPV-related OPSCC.

The epigenetic landscape of oral squamous cell carcinoma.

BACKGROUND: There is relatively little methylation array data available specifically for oral squamous cell carcinoma (OSCC). This study aims to compare the DNA methylome across a large cohort of tumour/normal pairs. METHODS: DNA was extracted from 44 OSCCs and paired normal mucosa. DNA methylation analysis employed the Illumina GoldenGate high-throughput array comprising 1505 CpG loci selected from 807 epigenetically regulated genes. This data was correlated with extracapsular spread (ECS), human papilloma virus (HPV) status, recurrence and 5-year survival. RESULTS: Differential methylation levels of a number of genes distinguished the tumour tissue sample from the matched normal. Putative methylation signatures for ECS and recurrence were identified. The concept of concordant methylation or CpG island methylator phenotype (CIMP) in OSCC is supported by our data, with an association between 'CIMP-high' and worse prognosis. Epigenetic deregulation of NOTCH4 signalling in OSCC was also observed, as part of a possible methylation signature for recurrence, with parallels to recently discovered NOTCH mutations in HNSCC. Differences in methylation in HPV-driven cases were seen, but are less significant than that has been recently proposed in other series. CONCLUSION: Although OSCC seems as much an 'epigenetic' as a genetic disease, the translational potential of cancer epigenetics has yet to be fully exploited. This data points to the application of epigenetic biomarkers and targets available to further the development of therapy in OSCC.

Altered hip muscle forces during gait in people with patellofemoral osteoarthritis.

OBJECTIVES: The study aimed to (1) assess whether higher vasti (VASTI), gluteus medius (GMED), gluteus maximus (GMAX) and gluteus minimus (GMIN) forces are associated with participant characteristics (lower age, male gender) and clinical characteristics (lower radiographic disease severity, lower symptom severity and higher walking speed); and (2) determine whether hip and knee muscle forces are lower in people with patellofemoral joint (PFJ) osteoarthritis (OA) compared to those without PFJ OA. DESIGN: Sixty participants with PFJ OA and 18 (asymptomatic, no radiographic OA) controls ≥40 years were recruited from the community or via referrals. A three-dimensional musculoskeletal model was used in conjunction with optimisation theory to calculate lower-limb muscle forces during walking. Associations of peak muscle forces with participant and clinical characteristics were conducted using Pearson's r or independent t-tests and between-group comparisons of mean peak muscle forces performed with walking speed as a covariate. RESULTS: Peak muscle forces were not significantly associated with participant, symptomatic or radiographic-specific characteristics. Faster walking speed was associated with higher VASTI muscle force in the PFJ OA (r = 0.495; P < 0.001) and control groups (r = 0.727; P = 0.001) and higher GMAX muscle force (r = 0.593; P = 0.009) in the control group only. Individuals with PFJ OA (N = 60) walked with lower GMED and GMIN muscle forces than controls (N = 18): GMED, mean difference 0.15 [95% confidence interval (CI): 0.01 to 0.29] body weight (BW); GMIN, 0.03 [0.01 to 0.06] BW. No between-group differences were observed in VASTI or GMAX muscle force: VASTI, 0.10 [-0.11 to 0.31] BW; GMAX, 0.01 [-0.11 to 0.09] BW. CONCLUSION: Individuals with PFJ OA ambulate with lower peak hip abductor muscle forces than their healthy counterparts.

Quantitative promoter methylation differentiates carcinoma ex pleomorphic adenoma from pleomorphic salivary adenoma.

BACKGROUND: potential epigenetic biomarkers for malignant transformation to carcinoma ex pleomorphic adenoma (Ca ex PSA) have been sought previously with and without specific comparison with the benign variant, pleomorphic salivary adenoma (PSA). Previous analysis has been limited by a non-quantitative approach. We sought to demonstrate quantitative promoter methylation across a panel of tumour suppressor genes (TSGs) in both Ca ex PSA and PSA. METHODS: quantitative methylation-specific real-time polymerase chain reaction (qMSP) analysis of p16(INK4A), CYGB, RASSF1, RARß, human telomerase reverse transcriptase (hTERT), Wilms' tumour 1 (WT1) and TMEFF2 gene promoters was undertaken on bisulphite-converted DNA, previously extracted from archival fixed tissue specimens of 31 Ca ex PSA and an unrelated cohort of 28 PSA. All target regions examined had formerly been shown to be hypermethylated in salivary and/or mucosal head and neck malignancies. RESULTS: the qMSP demonstrated abnormal methylation of at least one target in 20 out of 31 (64.5%) Ca ex PSA and 2 out of 28 (7.1%) PSA samples (P<0.001). RASSF1 was the single gene promoter for which methylation is shown to be a statistically significant predictor of malignant disease (P<0.001) with a sensitivity of 51.6% and a specificity of 92.9%. RARß, TMEFF2 and CYGB displayed no apparent methylation, while a combinatory epigenotype based on p16, hTERT, RASSF1 and WT1 was associated with a significantly higher chance of detecting malignancy in any positive sample (odds ratio: 24, 95% CI: 4.7-125, P<0.001). CONCLUSIONS: we demonstrate the successful application of qMSP to a large series of historical Ca ex PSA samples and report on a panel of TSGs with significant differences in their methylation profiles between benign and malignant variants of pleomorphic salivary adenoma. qMSP analysis could be developed as a useful clinical tool to differentiate between Ca ex PSA and its benign precursor.

Predictors of swallowing outcome in patients treated with surgery and radiotherapy for advanced oral and oropharyngeal cancer.

Retaining effective swallowing is a key element when optimising outcomes in the management of head and neck cancer. We report the functional swallowing outcomes for a cohort of 31 individuals with advanced oral and oropharyngeal cancer who underwent free or pedicled flap reconstruction of surgical defects. Swallowing was assessed pre and immediately post surgery and at four months post treatment. Swallowing assessments were related to site, size and volume of defect and composition of flap reconstruction. The effect of radiotherapy on swallowing was assessed among 17 of the 31 individuals who were submitted to radiotherapy after surgery. The proportion of patients on a total oral diet four months post treatment varied significantly by site of defect (Fishers exact test p=0.006), from 100% (7/7) of patients with a lateral defect to only 22% (2/9) of patients with a central defect. The proportion of patients on a total oral diet at the final assessment did not vary by flap reconstruction or radiotherapy.