International Expert-Based Consensus Definition, Staging Criteria, and Minimum Data Elements for Osteoradionecrosis of the Jaw: An Inter-Disciplinary Modified Delphi Study.

Purpose: Osteoradionecrosis of the jaw (ORNJ) is a severe iatrogenic disease characterized by bone death after radiation therapy (RT) to the head and neck. With over 9 published definitions and at least 16 diagnostic/staging systems, the true incidence and severity of ORNJ are obscured by lack of a standard for disease definition and severity assessment, leading to inaccurate estimation of incidence, reporting ambiguity, and likely under-diagnosis worldwide. This study aimed to achieve consensus on an explicit definition and phenotype of ORNJ and related precursor states through data standardization to facilitate effective diagnosis, monitoring, and multidisciplinary management of ORNJ. Methods: The ORAL Consortium comprised 69 international experts, including representatives from medical, surgical, radiation oncology, and oral/dental disciplines. Using a web-based modified Delphi technique, panelists classified descriptive cases using existing staging systems, reviewed systems for feature extraction and specification, and iteratively classified cases based on clinical/imaging feature combinations. Results: The Consortium ORNJ definition was developed in alignment with SNOMED-CT terminology and recent ISOO-MASCC-ASCO guideline recommendations. Case review using existing ORNJ staging systems showed high rates of inability to classify (up to 76%). Ten consensus statements and nine minimum data elements (MDEs) were outlined for prospective collection and classification of precursor/ORNJ stages. Conclusion: This study provides an international, consensus-based definition and MDE foundation for standardized ORNJ reporting in cancer survivors treated with RT. Head and neck surgeons, radiation, surgical, medical oncologists, and dental specialists should adopt MDEs to enable scalable health information exchange and analytics. Work is underway to develop both a human- and machine-readable knowledge representation for ORNJ (i.e., ontology) and multidisciplinary resources for dissemination to improve ORNJ reporting in academic and community practice settings.

Potential imaging targets in primary head and neck squamous cell carcinoma and lymph node metastases.

PURPOSE: To investigate glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) as potential fluorescent imaging markers by comparing their protein expression to epidermal growth factor receptor (EGFR). MATERIALS AND METHODS: Thirty-eight paired samples of untreated head and neck squamous cell carcinoma (HNSCC) primary tumours (PT) and corresponding synchronous lymph node metastases (LNM) were selected. After immunohistochemical staining, expression was assessed and compared by the percentage of positive tumour cells. Data were analysed using the Mann-Whitney test, effect sizes (ESr) and Spearman's correlation coefficient (r). RESULTS: GPNMB expression was observed in 100 % of PT, and median 80 % (range 5-100 %) of tumour cells, VEGF in 92 % and 60 % (0-100 %), EGFR in 87 % and 60 % (0-100 %) respectively. In corresponding LNM, GPNMB expression was observed in 100 % of LNM and median 90 % (20-100 %) of tumour cells, VEGF in 87 % and 65 % (0-100 %), and EGFR in 84 % and 35 % (0-100 %). A positive correlation was found between expression in PT and LNM for GPNMB (r = 0.548) and EGFR (r = 0.618) (p < 0.001), but not for VEGF (r = -0.020; p = 0.905). GPNMB expression was present in a higher percentage of tumour cells compared to EGFR in PT (p = 0.015, ESr = -0.320) and in LNM (p < 0.001, ESr = -0.478), while VEGF was not (p = 1.00, ESr = -0.109 and - 0.152, respectively). CONCLUSION: GPNMB expression is higher than EGFR in untreated HNSCC PT and corresponding LNM, while VEGF expression is comparable to EGFR. GPNMB is a promising target for fluorescent imaging in HNSCC.

Fluorescence-guided surgery using cetuximab-800CW in patients with penile carcinoma.

OBJECTIVE: To investigate the feasibility of fluorescence molecular imaging (FMI), using cetuximab-800CW, as an intraoperative tool to determine surgical margins in penile squamous cell carcinoma (PSCC). PATIENTS AND METHODS: A total of 11 patients with PSCC received 75 mg cetuximab followed by 15 mg cetuximab-800CW 2 days before surgery. FMI of the whole excision specimen and tissue slices was performed. Fluorescence visualisation was correlated to histopathology. Based on tumour and healthy tissue regions of interest, mean fluorescence intensity was calculated for each individual patient. RESULTS: Significant differences between tumour and healthy mean fluorescence intensity were found with tumour-to-background ratios of a median (IQR) of 1.51 (0.99) and a mean (SD) of 1.51 (0.32) in the excision specimen and tissue slices, respectively. One patient showed a high relative fluorescence intensity with a signal-to-background ratio of 1.79, corresponding to a tumour-positive margin on fresh frozen sectioning. CONCLUSION: In this Phase I study we showed that cetuximab-800CW seems suitable to discriminate PSCC from background tissue. The tracer was well tolerated, and no false positive spots were seen.

Identification of new head and neck squamous cell carcinoma molecular imaging targets.

OBJECTIVES: Intraoperative fluorescence imaging (FI) of head and neck squamous cell carcinoma (HNSCC) is performed to identify tumour-positive surgical margins, currently using epidermal growth factor receptor (EGFR) as imaging target. EGFR, not exclusively present in HNSCC, may result in non-specific tracer accumulation in normal tissues. We aimed to identify new potential HNSCC FI targets. MATERIALS AND METHODS: Publicly available transcriptomic data were collected, and a biostatistical method (Transcriptional Adaptation to Copy Number Alterations (TACNA)-profiling) was applied. TACNA-profiling captures downstream effects of CNAs on mRNA levels, which may translate to protein-level overexpression. Overexpressed genes were identified by comparing HNSCC versus healthy oral mucosa. Potential targets, selected based on overexpression and plasma membrane expression, were immunohistochemically stained. Expression was compared to EGFR on paired biopsies of HNSCC, adjacent macroscopically suspicious mucosa, and healthy mucosa. RESULTS: TACNA-profiling was applied on 111 healthy oral mucosa and 410 HNSCC samples, comparing expression levels of 19,635 genes. The newly identified targets were glucose transporter-1 (GLUT-1), placental cadherin (P-cadherin), monocarboxylate transporter-1 (MCT-1), and neural/glial antigen-2 (NG2), and were evaluated by IHC on samples of 31 patients. GLUT-1 was expressed in 100 % (median; range: 60-100 %) of tumour cells, P-cadherin in 100 % (50-100 %), EGFR in 70 % (0-100 %), MCT-1 in 30 % (0-100 %), and NG2 in 10 % (0-70 %). GLUT-1 and P-cadherin showed higher expression than EGFR (p < 0.001 and p = 0.015). CONCLUSIONS: The immunohistochemical confirmation of TACNA-profiling results showed significantly higher GLUT-1 and P-cadherin expression than EGFR, warranting further investigation as HNSCC FI targets.

Improved intraoperative identification of close margins in oral squamous cell carcinoma resections using a dual aperture fluorescence ratio approach: first in-human results.

Significance: Surgical excision is the main treatment for solid tumors in oral squamous cell carcinomas, where wide local excision (achieving a healthy tissue margin of >5 mm around the excised tumor) is the goal as it results in reduced local recurrence rates and improved overall survival. Aim: No clinical methods are available to assess the complete surgical margin intraoperatively while the patient is still on the operating table; and while recent intraoperative back-bench fluorescence-guided surgery approaches have shown promise for detecting "positive" inadequate margins (<1 mm), they have had limited success in the detection of "close" inadequate margins (1 to 5 mm). Here, a dual aperture fluorescence ratio (dAFR) approach was evaluated as a means of improving detection of close margins. Approach: The approach was evaluated on surgical specimens from patients who were administered a tumor-specific fluorescent imaging agent (cetuximab-800CW) prior to surgery. The dAFR approach was compared directly against standard wide-field fluorescence imaging and pathology measurements of margin thickness in specimens from three patients and a total of 12 margin locations (1 positive, 5 close, and 6 clear margins). Results: The area under the receiver operating characteristic curve, representing the ability to detect close compared to clear margins (>5 mm) was found to be 1.0 and 0.57 for dAFR and sAF, respectively. Improvements in dAFR were found to be statistically significant (p<0.02). Conclusions: These results provide evidence that the dAFR approach potentially improves detection of close surgical margins.

Quantifying Articulatory Working Space in Individuals Surgically Treated for Oral Cancer With Electromagnetic Articulography.

PURPOSE: The purpose of this study was to quantify sentence-level articulatory kinematics in individuals treated for oral squamous cell carcinoma (ITOC) compared to control speakers while also assessing the effect of treatment site (jaw vs. tongue). Furthermore, this study aimed to assess the relation between articulatory-kinematic measures and self-reported speech problems. METHOD: Articulatory-kinematic data from the tongue tip, tongue back, and jaw were collected using electromagnetic articulography in nine Dutch ITOC and eight control speakers. To quantify articulatory kinematics, the two-dimensional articulatory working space (AWS; in mm2), one-dimensional anteroposterior range of motion (AP-ROM; in mm), and superior-inferior range of motion (SI-ROM in mm) were calculated and examined. Self-reported speech problems were assessed with the Speech Handicap Index (SHI). RESULTS: Compared to a sex-matched control group, ITOC showed significantly smaller AWS, AP-ROM, and SI-ROM for both the tongue tip and tongue back sensor, but no significant differences were observed for the jaw sensor. This pattern was found for both individuals treated for tongue and jaw tumors. Moderate nonsignificant correlations were found between the SHI and the AWS of the tongue back and jaw sensors. CONCLUSIONS: Despite large individual variation, ITOC showed reduced one- and two-dimensional tongue, but not jaw, movements compared to control speakers and treatment for tongue and jaw tumors resulted in smaller tongue movements. A larger sample size is needed to establish a more generalizable connection between the AWS and the SHI. Further research should explore how these kinematic changes in ITOC are related to acoustic and perceptual measures of speech.

3D surgical planning including patient-specific drilling guides for tibial plateau fractures.

Aims: Proper preoperative planning benefits fracture reduction, fixation, and stability in tibial plateau fracture surgery. We developed and clinically implemented a novel workflow for 3D surgical planning including patient-specific drilling guides in tibial plateau fracture surgery. Methods: A prospective feasibility study was performed in which consecutive tibial plateau fracture patients were treated with 3D surgical planning, including patient-specific drilling guides applied to standard off-the-shelf plates. A postoperative CT scan was obtained to assess whether the screw directions, screw lengths, and plate position were performed according the preoperative planning. Quality of the fracture reduction was assessed by measuring residual intra-articular incongruence (maximum gap and step-off) and compared to a historical matched control group. Results: A total of 15 patients were treated with 3D surgical planning in which 83 screws were placed by using drilling guides. The median deviation of the achieved screw trajectory from the planned trajectory was 3.4° (interquartile range (IQR) 2.5 to 5.4) and the difference in entry points (i.e. plate position) was 3.0 mm (IQR 2.0 to 5.5) compared to the 3D preoperative planning. The length of 72 screws (86.7%) were according to the planning. Compared to the historical cohort, 3D-guided surgery showed an improved surgical reduction in terms of median gap (3.1 vs 4.7 mm; p = 0.126) and step-off (2.9 vs 4.0 mm; p = 0.026). Conclusion: The use of 3D surgical planning including drilling guides was feasible, and facilitated accurate screw directions, screw lengths, and plate positioning. Moreover, the personalized approach improved fracture reduction as compared to a historical cohort.

Site-specific radiation dosage and implant survival in oral cancer patients: A cohort study.

OBJECTIVES: We assessed the radiation dosages (Dmean ) on implant regions to identify the threshold for implant loss in patients with an intraoral malignancy treated with dental implants to support a mandibular denture during ablative surgery before volumetric-modulated arc therapy (VMAT). MATERIALS AND METHODS: Data was collected prospectively from 28 patients treated surgically for an intraoral malignancy, followed by postoperative radiotherapy (VMAT) and analyzed retrospectively. Patients received 2 implants in the native mandible during ablative surgery. Implant-specific Dmean values were retrieved from the patients' files. Radiographic bone loss was measured 1 year after implant placement and during the last follow-up appointment. Implant survival was analyzed with the Kaplan-Meier method. Univariate logistic regression and Cox-regression analyses were performed to investigate the effect of increasing implant-specific radiation dosages on implant loss. RESULTS: Five out of 56 placed implants were lost during follow-up (median 36.0 months, IQR 39.0). Radiographically, peri-implant bone loss occurred in implants with a Dmean > 40 Gy. Implant loss occurred only in implants with a Dmean > 50 Gy. CONCLUSION: An implant-specific Dmean higher than 50 Gy is related to more peri-implant bone loss and, eventually, implant loss.

Prefabricated fibula free flaps in reconstruction of maxillofacial defects: Two cases of transplanting a fractured fibula.

BACKGROUND: The two-staged prefabricated vascularized fibula free flap is used in maxillofacial reconstruction. We describe the possible cause and management of two cases of fibula fracture after implant placement. METHODS: The patients were treated with two-stage reconstruction with a prefabricated vascularized fibula free flap. Six dental implants were placed in both fibulas. Fibula fractures occurred during the osseointegration period before the second procedure. The reconstruction was continued as planned. RESULTS: Both fibulas fractured in the distal segment, possibly due to a thinner cortex more distally. Harvesting of a fractured fibula flap is more difficult than normally due to callus formation and fibrosis. Both transplants became fully functional with extended healing and additional surgery. CONCLUSION: The fracture apparently did not compromise the vascularisation of the fibula and proved still sufficient for successful harvest and transfer of the flap. The patient should be made aware that additional corrective surgery may be indicated.

Initial and Residual 3D Fracture Displacement Is Predictive for Patient-Reported Functional Outcome at Mid-Term Follow-Up in Surgically Treated Tibial Plateau Fractures.

BACKGROUND: Conventional measures of fracture displacement have low interobserver reliability. This study introduced a novel 3D method to measure tibial plateau fracture displacement and its impact on functional outcome. METHODS: A multicentre study was conducted on patients who had tibial plateau fracture surgery between 2003 and 2018. Eligible patients had a preoperative CT scan (slice thickness ≤ 1 mm) and received a Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. A total of 362 patients responded (57%), and assessment of initial and residual fracture displacement was performed via measurement using the 3D gap area (mm2). Patients were divided into four groups based on the 3D gap area size. Differences in functional outcome between these groups were assessed using analysis of variance (ANOVA). Multiple linear regression was used to determine the association between fracture displacement and patient-reported outcome. RESULTS: Functional outcome appeared significantly worse when initial or residual fracture displacement increased. Multivariate linear regression showed that initial 3D gap area (per 100 mm2) was significantly negatively associated with all KOOS subscales: symptoms (-0.9, p < 0.001), pain (-0.0, p < 0.001), ADL (-0.8, p = 0.002), sport (-1.4, p < 0.001), and QoL (-1.1, p < 0.001). In addition, residual gap area was significantly negatively associated with the subscales symptoms (-2.2, p = 0.011), ADL (-2.2, p = 0.014), sport (-2.6, p = 0.033), and QoL (-2.4, p = 0.023). CONCLUSION: A novel 3D measurement method was applied to quantify initial and residual displacement. This is the first study which can reliably classify the degree of displacement and indicates that increasing displacement results in poorer patient-reported functional outcomes.

EGFR-targeted fluorescence molecular imaging for intraoperative margin assessment in oral cancer patients: a phase II trial.

Inadequate surgical margins occur frequently in oral squamous cell carcinoma surgery. Fluorescence molecular imaging (FMI) has been explored for intraoperative margin assessment, but data are limited to phase-I studies. In this single-arm phase-II study (NCT03134846), our primary endpoints were to determine the sensitivity, specificity and positive predictive value of cetuximab-800CW for tumor-positive margins detection. Secondary endpoints were safety, close margin detection rate and intrinsic cetuximab-800CW fluorescence. In 65 patients with 66 tumors, cetuximab-800CW was well-tolerated. Fluorescent spots identified in the surgical margin with signal-to-background ratios (SBR) of ≥2 identify tumor-positive margins with 100% sensitivity, 85.9% specificity, 58.3% positive predictive value, and 100% negative predictive value. An SBR of ≥1.5 identifies close margins with 70.3% sensitivity, 76.1% specificity, 60.5% positive predictive value, and 83.1% negative predictive value. Performing frozen section analysis aimed at the fluorescent spots with an SBR of ≥1.5 enables safe, intraoperative adjustment of surgical margins.

Development of patient-specific osteosynthesis including 3D-printed drilling guides for medial tibial plateau fracture surgery.

PURPOSE: A substantial proportion of conventional tibial plateau plates have a poor fit, which may result in suboptimal fracture reduction due to applied -uncontrolled- compression on the bone. This study aimed to assess whether patient-specific osteosyntheses could facilitate proper fracture reduction in medial tibial plateau fractures. METHODS: In three Thiel embalmed human cadavers, a total of six tibial plateau fractures (three Schatzker 4, and three Schatzker 6) were created and CT scans were made. A 3D surgical plan was created and a patient-specific implant was designed and fabricated for each fracture. Drilling guides that fitted on top of the customized plates were designed and 3D printed in order to assist the surgeon in positioning the plate and steering the screws in the preplanned direction. After surgery, a postoperative CT scan was obtained and outcome was compared with the preoperative planning in terms of articular reduction, plate positioning, and screw direction. RESULTS: A total of six patient-specific implants including 41 screws were used to operate six tibial plateau fractures. Three fractures were treated with single plating, and three fractures with dual plating. The median intra-articular gap was reduced from 6.0 (IQR 4.5-9.5) to 0.9 mm (IQR 0.2-1.4), whereas the median step-off was reduced from 4.8 (IQR 4.1-5.3) to 1.3 mm (IQR 0.9-1.5). The median Euclidean distance between the centre of gravity of the planned and actual implant was 3.0 mm (IQR: 2.8-3.7). The lengths of the screws were according to the predetermined plan. None of the screws led to screw penetration. The median difference between the planned and actual screw direction was 3.3° (IQR: 2.5-5.1). CONCLUSION: This feasibility study described the development and implementation of a patient-specific workflow for medial tibial plateau fracture surgery that facilitates proper fracture reduction, tibial alignment and accurately placed screws by using custom-made osteosynthesis plates with drilling guides.

Radiographic Predictors of Conversion to Total Knee Arthroplasty After Tibial Plateau Fracture Surgery: Results in a Large Multicenter Cohort.

BACKGROUND: Radiographic measurements of initial displacement of tibial plateau fractures and of postoperative reduction are used to determine treatment strategy and prognosis. We assessed the association between radiographic measurements and the risk of conversion to total knee arthroplasty (TKA) at the time of follow-up. METHODS: A total of 862 patients surgically treated for tibial plateau fractures between 2003 and 2018 were eligible for this multicenter cross-sectional study. Patients were approached for follow-up, and 477 (55%) responded. The initial gap and step-off were measured on the preoperative computed tomography (CT) scans of the responders. Condylar widening, residual incongruity, and coronal and sagittal alignment were measured on postoperative radiographs. Critical cutoff values for gap and step-off were determined using receiver operating characteristic curves. Postoperative reduction measurements were categorized as adequate or inadequate on the basis of cutoff values in international guidelines. Multivariable analysis was performed to assess the association between each radiographic measurement and conversion to TKA. RESULTS: Sixty-seven (14%) of the patients had conversion to TKA after a mean follow-up of 6.5 ± 4.1 years. Assessment of the preoperative CT scans revealed that a gap of >8.5 mm (hazard ratio [HR] = 2.6, p < 0.001) and step-off of >6.0 mm (HR = 3.0, p < 0.001) were independently associated with conversion to TKA. Assessment of the postoperative radiographs demonstrated that residual incongruity of 2 to 4 mm was not associated with increased risk of TKA compared with adequate fracture reduction of <2 mm (HR = 0.6, p = 0.176). Articular incongruity of >4 mm resulted in increased risk of TKA. Coronal (HR = 1.6, p = 0.05) and sagittal malalignment (HR = 3.7 p < 0.001) of the tibia were strongly associated with conversion to TKA. CONCLUSIONS: Substantial preoperative fracture displacement was a strong predictor of conversion to TKA. Postoperative gaps or step-offs of >4 mm as well as inadequate alignment of the tibia were strongly associated with an increased risk of TKA. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

3D assessment of initial fracture displacement of tibial plateau fractures is predictive for risk on conversion to total knee arthroplasty at long-term follow-up.

PURPOSE: Currently used classification systems and measurement methods are insufficient to assess fracture displacement. In this study, a novel 3D measure for fracture displacement is introduced and associated with risk on conversion to total knee arthroplasty (TKA). METHODS: A multicenter cross-sectional study was performed including 997 patients treated for a tibial plateau fracture between 2003 and 2018. All patients were contacted for follow-up and 534 (54%) responded. For all patients, the 3D gap area was determined in order to quantify the degree of initial fracture displacement. A cut-off value was determined using ROC curves. Multivariate analysis was performed to assess the association of 3D gap area with conversion to TKA. Subgroups with increasing levels of 3D gap area were identified, and Kaplan-Meier survival curves were plotted to assess survivorship of the knee free from conversion to TKA. RESULTS: A total of 58 (11%) patients underwent conversation to TKA. An initial 3D gap area ≥ 550 mm2 was independently associated with conversion to TKA (HR 8.4; p = 0.001). Four prognostic groups with different ranges of the 3D gap area were identified: excellent (0-150 mm2), good (151-550 mm2), moderate (551-1000 mm2), and poor (> 1000 mm2). Native knee survival at 10-years follow-up was 96%, 95%, 76%, and 59%, respectively, in the excellent, good, moderate, and poor group. CONCLUSION: A novel 3D measurement method was developed to quantify initial fracture displacement of tibial plateau fractures. 3D fracture assessment adds to current classification methods, identifies patients at risk for conversion to TKA at follow-up, and could be used for patient counselling about prognosis. LEVEL OF EVIDENCE: Prognostic Level III.

Four-Dimensional Determination of the Patient-Specific Centre of Rotation for Total Temporomandibular Joint Replacements: Following the Groningen Principle.

For patients who suffer from severe dysfunction of the temporomandibular joint (TMJ), a total joint replacement (TJR) in the form of a prosthesis may be indicated. The position of the centre of rotation in TJRs is crucial for good postoperative oral function; however, it is not determined patient-specifically (PS) in any current TMJ-TJR. The aim of this current study was to develop a 4D-workflow to ascertain the PS mean axis of rotation, or fixed hinge, that mimics the patient's specific physiological mouth opening. Twenty healthy adult patients were asked to volunteer for a 4D-scanning procedure. From these 4D-scanning recordings of mouth opening exercises, patient-specific centres of rotation and axes of rotation were determined using our JawAnalyser tool. The mean CR location was positioned 28 [mm] inferiorly and 5.5 [mm] posteriorly to the centre of condyle (CoC). The 95% confidence interval ranged from 22.9 to 33.7 [mm] inferior and 3.1 to 7.8 [mm] posterior to the CoC. This study succeeded in developing an accurate 4D-workflow to determine a PS mean axis of rotation that mimics the patient's specific physiological mouth opening. Furthermore, a change in concept is necessary for all commercially available TMJ-TJR prostheses in order to comply with the PS CRs calculated by our study. In the meantime, it seems wise to stick to placing the CR 15 [mm] inferiorly to the CoC, or even beyond, towards 28 [mm] if the patient's anatomy allows this.

Quantitative Three-Dimensional Measurements of Acetabular Fracture Displacement Could Be Predictive for Native Hip Survivorship.

This study aims to develop a three-dimensional (3D) measurement for acetabular fracture displacement, determine the inter- and intra-observer variability, and correlate the measurement with clinical outcome. Three-dimensional models were created for 100 patients surgically treated for acetabular fractures. The '3D gap area', the 3D surface between all the fracture fragments, was developed. The association between the 3D gap area and the risk of conversion to a total hip arthroplasty (THA) was determined by an ROC curve and a Cox regression analysis. The 3D gap area had an excellent inter-observer and intra-observer reliability. The preoperative median 3D gap area for patients without and with a THA was 1731 mm2 versus 2237 mm2. The median postoperative 3D gap area was 640 mm2 versus 845 mm2. The area under the curve was 0.63. The Cox regression analysis showed that a preoperative 3D gap area > 2103 mm2 and a postoperative 3D gap area > 1058 mm2 were independently associated with a 3.0 versus 2.4 times higher risk of conversion to a THA. A 3D assessment of acetabular fractures is feasible, reproducible, and correlates with clinical outcome. Three-dimensional measurements could be added to the current classification systems to quantify the level of fracture displacement and to assess operative results.

RANKL inhibition for giant cell lesions of the jaw: A retrospective cohort analysis.

BACKGROUND: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ). METHODS: A retrospective cohort study was conducted compromising patients treated with a 1-year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety. RESULTS: Twenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0-62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8-43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0-50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity. CONCLUSION: High-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ.

Comparison of narrow band and fluorescence molecular imaging to improve intraoperative tumour margin assessment in oral cancer surgery.

OBJECTIVE: New techniques have emerged to aid in preventing inadequate margins in oral squamous cell carcinoma (OSCC) surgery, but studies comparing different techniques are lacking. Here, we compared narrow band imaging (NBI) with fluorescence molecular imaging (FMI), to study which intraoperative technique best assesses the mucosal tumour margins. MATERIALS AND METHODS: NBI was performed in vivo and borders were marked with three sutures. For FMI, patients received 75 mg of unlabelled cetuximab followed by 15 mg cetuximab-800CW intravenously-two days prior to surgery. The FMI borders were defined on the excised specimen. The NBI borders were correlated with the FMI outline and histopathology. RESULTS: Sixteen patients were included, resulting in 31 NBI and 30 FMI measurements. The mucosal border was delineated within 1 mm of the tumour border in 4/31 (13 %) of NBI and in 16/30 (53 %) FMI cases (p = 0.0008), and within 5 mm in 23/31 (74 %) of NBI and in 29/30 (97 %) of FMI cases (p = 0.0048). The median distance between the tumour border and the imaging border was significantly greater for NBI (3.2 mm, range -6.1 to 12.8 mm) than for FMI (0.9 mm, range -3.0 to 7.4 mm; p = 0.028). Submucosal extension and previous irradiation reduced NBI accuracy. CONCLUSION: Ex vivo FMI performed more accurately than in vivo NBI in mucosal margin assessment, mainly because NBI cannot detect submucosal extension. NBI adequately identified the mucosal margin especially in early-stage and not previously irradiated tumours, and may therefore be preferable in these tumours for practical and cost-related reasons.

Quantitative Three-Dimensional Computed Tomography Measurements Provide a Precise Diagnosis of Fractures of the Mandibular Condylar Process.

As 2D quantitative measurements are often insufficient, a standardized 3D quantitative measurement method was developed to analyze mandibular condylar fractures, and correlate the results with the mandibular condylar fracture classifications of Loukota and Spiessl and Schroll and clinical parameters. Thirty-two patients with a unilateral mandibular condylar fracture were evaluated using OPT, 2D (CB)CT images, and 3D imaging to measure the extent of the fractures. The maximum mouth opening (MMO) was measured. Ramus height loss could be measured only in OPT, but not in 2D CT images. The Intraclass Correlation Coefficient was excellent in the 3D measurements. In the Loukota classification, condylar neck fractures had the largest median 3D displacement and the highest rotations of the fracture fragments. The largest fracture volume was observed in base fractures. According to the Spiessl and Schroll classification, type V fractures had the largest median 3D displacement and the highest rotation in the X-axis and Z-axis. Type I fractures had the largest fracture volume. We found a moderate negative correlation between MMO and 3D displacement and rotation on Z-axis. The 2D quantitative analysis of condylar fractures is limited, imprecise, and not reproducible, while quantitative 3D measurements provide extensive, precise, objective, and reproducible information.