First Phase Development of a Patient-reported Outcome Measure for Midface Oncology.

Background: Facial cancer surgery involving the midface (comprising the lower eyelids, nose, cheeks, and upper lip) can have debilitating life-changing functional, social, and psychological impacts on the patient. Midface symptoms are inadequately captured by existing patient-reported outcome measures (PROMs). PROMs are increasingly used for individual patient care, quality improvement, and standardized reporting of treatment outcomes. This study aimed to present our findings from the first phase of the development of a midface, specifically periocular and nasal, PROM. Methods: After international guidance for PROM development, the first phase comprised identification of salient issues and item generation. Fifteen patients who had midface surgery and 10 clinicians from various specialties with more than 5 years' experience treating these patients were recruited. Semi-structured interviews explored aesthetic, functional, social, and psychological outcomes, with specific attention to deficiencies in current PROMs. Thematic analysis was used to develop an item pool, and group interviews with clinicians were carried out to create and refine PROM scales. Results: Qualitative data from patient interviews were grouped into aesthetic, functional, and psychosocial domains for the eyelids and nose. Ninety-nine draft items were generated across these domains. Following focus group discussions, the final version of the midface-specific PROM contained 31 items (13 eye-specific, 10-nose-specific, eight general midface items). Conclusions: This midface-specific PROM is valuable in assessing and comparing patient-reported outcomes in those who have undergone complex resection and reconstruction of the midface. This PROM is currently undergoing field testing.

Predicting Recurrence-Free and Overall Survival for Patients With Stage II Melanoma: The MIA Calculator.

PURPOSE: Improvements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients. METHODS: Data were extracted from the Melanoma Institute Australia (MIA) database for patients diagnosed with stage II (clinical or pathological) melanoma (n = 3,220). Survival prediction models were developed using multivariable Cox regression analyses (MIA models) and externally validated twice using data sets from the United States and the Netherlands. Each model's performance was assessed using C-statistics and calibration plots and compared with Cox models on the basis of AJCC-8 staging (stage models). RESULTS: The 5-year and 10-year RFS C-statistics were 0.70 and 0.73 (MIA-model) versus 0.61 and 0.60 (stage-model), respectively. For OS, the 5-year and 10-year C-statistics were 0.71 and 0.75 (MIA-model) compared with 0.62 and 0.61 (stage-model), respectively. The MIA models were well calibrated and externally validated. CONCLUSION: The MIA models offer accurate and personalized estimates of both RFS and OS in patients with stage II melanoma even in the absence of pathological staging with SN biopsy. These models were robust on external validations and may be used in everyday practice both with (ideally) and without performing SN biopsy to identify high-risk patients for further management strategies. An online tool will be available at the MIA website (Risk Prediction Tools).

Associations between patient-level health literacy and diagnostic time intervals for head and neck cancer: A prospective cohort study.

BACKGROUND: Health literacy (HL) comprises skills and knowledge required to understand, access, and make decisions about healthcare. Our aim was to examine associations between patient HL and time intervals (defined in the Aarhus statement) along the pathway to treatment of head and neck cancer (HNC). METHODS: A prospective cohort study was conducted from October 2018 to March 2020. Participants completed the Health Literacy Questionnaire (HLQ®) and described key events and dates along the pathway to treatment using validated questionnaires. Correlations between six diagnostic time intervals and domains of HL were explored, and factors predicting exceeding maximum acceptable timeframes were assessed using logistic regression. RESULTS: One hundred patients with a diagnosis of HNC within the preceding 6 months were recruited. HLQ® Domain 2 (sufficient information to manage health) was significantly negatively associated with four intervals: the patient interval (first symptom to first presentation), primary care interval (first presentation to referral to secondary care), diagnostic interval (first presentation to diagnosis), and total interval (first symptom to treatment onset); correlation coefficients -0.25 to -0.27 (P < 0.05). Domain 8 (ability to find good information) was significantly negatively associated with three intervals (primary care interval, diagnostic interval, and total interval; correlation coefficients -0.23 to -0.34; P < 0.05). Higher education, age, and comorbidity levels were associated with shorter patient and diagnostic intervals. CONCLUSIONS: HL may be a potential target to improve timeliness of HNC diagnosis and reduce disparities in outcomes.

Prognostic and predictive biomarkers in head and neck cancer: something old, something new, something borrowed, something blue and a sixpence in your shoe.

A biomarker is a measurable indicator of biological or pathological processes or the response to an exposure or intervention and is used to guide management decisions. In head and neck pathology, biomarkers are assessed by histological criteria and immunohistochemical and molecular studies. Surgical resection remains the mainstay of management of many head and neck malignancies. Adjuvant radiotherapy and/or systemic therapy may be administered depending on the presence of adverse prognostic factors identified on histopathological or immunohistochemical examination. In this review, we outline the clinically relevant prognostic and predictive factors in head and neck malignancies including conventionally recognised factors such as tumour size, depth of invasion, lymphovascular and perineural invasion and margin status as well as novel evolving factors such as recurrent genetic rearrangements and assessment of immune checkpoints. Practical issues are discussed to assist with recognising and reporting of these factors. A summary of useful tools such as structured pathology report formats is also included to assist with comprehensive reporting of all clinically relevant parameters, minimise risk and improve workflow efficiencies.

Role of Concurrent Ultrasound Surveillance of Sentinel Node-Positive Node Fields in Melanoma Patients Having Routine Cross-Sectional Imaging.

PURPOSE: In sentinel node-positive (SN+ve) melanoma patients, active surveillance with regular ultrasound examination of the node field has become standard, rather than completion lymph node dissection (CLND). A proportion of these patients now receive adjuvant systemic therapy and have routine cross-sectional imaging (computed tomography [CT] or positron emission tomography [PET]/CT). The role of concurrent ultrasound (US) surveillance in these patients is unclear. The purpose of our study was to describe the modality of detection of nodal recurrence in SN+ve node fields. METHODS: SN+ve melanoma patients who did not undergo CLND treated at a single institution from January 1, 2016 to December 31, 2020 were included. RESULTS: A total of 225 SN+ve patients with a median follow-up of 23 months were included. Of these, 119 (53%) received adjuvant systemic therapy. Eighty (36%) developed a recurrence at any site; 24 (11%) recurred first in the SN+ve field, of which 12 (5%) were confirmed node field recurrence only at 2 months follow-up. The nodal recurrences were first detected by ultrasound in seven (3%), CT in seven (3%), and PET/CT in seven (3%) patients. All nodal recurrences evident on US were also evident on PET/CT and vice versa. CONCLUSIONS: The high rate of recurrences outside the node field and the identification of all US-detected nodal recurrences on concurrent cross-sectional imaging modalities suggest that routine concurrent ultrasound surveillance of the node-positive field may be unnecessary for SN+ve melanoma patients having routine cross-sectional imaging.

Use of Rare Anatomical Variant of the Free Fibula Flap to Reconstruct the Nasal Septum.

The osteocutaneous fibula free flap (FFF)'s skin paddle is commonly vascularized by the septocutaneous (SC) perforators of the peroneal artery that course through the posterior intercrural septum. However, a rare anatomical variant exists in which the skin paddle is vascularized via a separate arterial system to the fibula. We report the case of a 31-year-old man who was planned for osteocutaneous FFF reconstruction of his anterior maxilla and hard palate following resection of nasal septal chondrosarcoma. Intraoperatively, he was found to have a rare anatomical variant: the perforator to the skin paddle arose proximal to the peroneal artery, off the tibioperoneal trunk. This was a fortuitous, rare anatomical variant, as it enabled a double free flap reconstruction from a single donor site-an intraoral fasciocutaneous free flap oriented with its long axis perpendicular to that of an osseous FFF. This particular defect enabled reconstructive freedom beyond that of the standard osteocutaneous free flap, in which the skin paddle orientation is limited by the risk of kinking the septal perforator. This case report summarizes the flap raising technique and the learning points relevant to the osteocutaneous FFF with no SC perforators. The extant literature on this anatomical variant is then summarized. The average estimated rate of FFF with no SC perforators is between 3% and 25%, based on four published studies.

The Emerging Role of Artificial Intelligence Tools for Outcome Measurement in Facial Reanimation Surgery: A Review.

Importance: Surgeons treating facial paralysis with reanimation surgery measure the outcomes of surgery and adjust treatment to each patient's needs. Our objective is to review the current subjective facial paralysis assessment tools and the emerging computer-based objective analysis, which may involve artificial intelligence. Observations: In recent years, many new automated approaches to outcome measurement in facial reanimation surgery have been developed. Most of these tools utilize artificial intelligence to analyze emotional expression and symmetry of facial landmarks. Other tools have provided automated approaches to existing clinician-guided scales. Conclusions: Newly developed computer-based tools using artificial intelligence have been developed to both improve existing clinician-graded scales and provide new approaches to facial symmetry and emotional expressivity analysis.

Travel-associated cost savings to patients and the health system through provision of specialist head and neck surgery outreach clinics in rural New South Wales, Australia.

INTRODUCTION: Centralisation of head and neck surgical services means that patients in regional and remote Australia need to travel long distances for treatment and follow-up, imparting a significant financial burden on patients and the health system. OBJECTIVE: To estimate costs of travel to local outreach clinics and determine potential cost savings to patients and the health system by avoiding patient travel to major cities for head and neck surgical care. DESIGN: Retrospective audit of three head and neck surgery outreach clinics in New South Wales, Australia over 4 years (2017-2020). Direct costs of travel from a patient's residence to their local outreach clinic were estimated. Costs of travel and accommodation to Sydney for an appointment were calculated for different travel modes. Estimated reimbursements for travel through government support schemes were calculated based on published rates. FINDINGS: Some 657 patients attended the three clinics, accounting for 1981 appointments. Depending on mode of travel, the estimated median cost of return travel (including accommodation) to Sydney was $379 to $739 per patient per trip and the median government reimbursement ranged from $182 to $279 per trip. In comparison, the cost of return travel by car to local outreach clinics ranged from $28 to $163 per appointment. Outreach clinics were estimated to save patients a median of $285 per trip and avoided government reimbursements of $215 per trip. DISCUSSION: Despite uptake in telehealth, outreach medical services remain an important asset for people living in regional areas to address inequities in access. However, the cost benefits are likely to be underestimated as our approach did not account for indirect costs associated with travel. CONCLUSION: Outreach head and neck surgical services located in regional areas can reduce the financial burden on both patients and the healthcare system. Greater investment in outreach clinics could ensure sustainability of services to promote equitable access to specialised surgical services.

Epidemiology, staging and management of mucosal melanoma of the head and neck: a narrative review.

BACKGROUND AND OBJECTIVE: Mucosal melanoma of the head and neck (MMHN) are rare, aggressive neoplasms of melanocyte origin that remain incompletely understood and have a poor prognosis, with high rates of locoregional recurrence and distant metastasis. Several recent studies having expanded understanding of MMHN, we undertook a review of the latest evidence pertaining to its epidemiology, staging, and management. METHODS: A literature search was conducted for peer-reviewed articles reporting and discussing the epidemiology, staging, and management of MMHN. PubMed, Medline, Embase and the Cochrane Library were searched to identify relevant publications. KEY CONTENT AND FINDINGS: MMHN remains an uncommon disease. The current TNM staging system for MMHN provides inadequate risk stratification, and consideration of an alternative staging model such as one based on a nomogram may be justifiable. Tumour resection with clear histological margins remains the cornerstone of optimal treatment. Adjuvant radiotherapy may improve locoregional control but does not appear to affect survival. Immune checkpoint inhibitors and c-KIT inhibitors demonstrate promising efficacy in patients with advanced or unresectable mucosal melanomas, and warrant further research exploring the utility of combination therapies. Their roles as adjuvant therapies have not been determined. The efficacy of neoadjuvant systemic therapy is also not yet clear, although early results suggest that it may improve outcomes. CONCLUSIONS: New insights into the epidemiology, staging and management of MMHN have transformed the standard of care for this rare malignancy. Nonetheless, the results of ongoing clinical trials and future prospective studies are required to better understand this aggressive disease and optimise its management.

Does preoperative imaging for scalp non-melanocytic skin cancer accurately predict invasion of the cranial vault? A systematic review and meta-analysis.

PURPOSE: This study aimed to determine the diagnostic accuracy of CT and MRI in the preoperative detection of bone involvement for non-melanoma skin cancers (NMSCs) located on the scalp. This study further aimed to evaluate the predictive value of these imaging modalities in determining the need for craniectomy and to identify gaps in the existing literature. METHODS: Electronic searches of the MEDLINE, Embase, Cochrane and Google Scholar databases were performed for English language studies of any type. Studies reporting detection or exclusion of histopathologically confirmed bone involvement through preoperative imaging were identified according to PRISMA guidelines. Studies reporting dural involvement, non-scalp tumours, and lacking tumour type(s) or outcome data were excluded. Outcomes were preoperative imaging result and histopathologically confirmed bone invasion. Meta-analysis was performed and sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated (excluding case report and MRI data due to insufficient quality and quantity respectively). RESULTS: Four studies with a total of 69 patients were included in the final review, of which two studies totalling 66 patients were included in the meta-analysis. Preoperative CT had a sensitivity of 38%, specificity of 98%, PPV of 90% and NPV of 73%. CONCLUSIONS: The available data suggests that a preoperative CT finding of calvarial involvement by a scalp NMSC is likely to be real, but the absence of such a finding is unreliable. Current evidence suggests that preoperative imaging cannot exclude the necessity for craniectomy and future research is needed, particularly on the role of MRI.

External validation in an Australian population of the EORTC-DeCOG nomogram predicting recurrence, distant metastasis and overall mortality in melanoma patients with positive sentinel lymph nodes.

BACKGROUND: Calculating an accurate prognosis for melanoma patients who have a positive sentinel node (SN) biopsy is important both for them and for their treating doctors to guide decision-making, particularly when adjuvant systemic therapy is being considered. The recently published EORTC-DeCOG nomograms aim to provide this via an online portal that predicts 5-year rates for recurrence, distant metastasis and overall mortality. The present study provides external validation of these nomograms. METHODS/MATERIALS: De-identified data from patients with a positive SN biopsy between 2003 and 2015 were extracted from the prospectively maintained Melanoma Institute Australia (MIA) research database. ROC-curves with C-statistics, regression co-efficients and Decision Curve Net Benefit analyses were performed using the integrated private validation portal on the nomograms' hosting platform (Evidencio). RESULTS: Complete data were available for 352 patients. The respective C-statistics for recurrence, distant metastasis and overall mortality nomogram validations were 0.68, 0.69 and 0.66. CONCLUSION: The performance of the nomograms in predicting recurrence and distant metastasis was similar in the MIA and the development populations, suggesting that they are robust. However, the overall mortality nomogram performance was significantly poorer in the MIA population (C-statistic 0.66) than in the original EORTC-DeCOG derivation cohort (C-statistic 0.70) and may therefore be less reliable for clinical use.

Improving Selection for Sentinel Lymph Node Biopsy Among Patients With Melanoma.

Importance: Refining eligibility guidelines may identify more appropriate patients to undergo useful medical procedures. Objective: To improve cost-effectiveness in selecting patients with melanoma for sentinel lymph node biopsy (SLNB). Design, Setting, and Participants: This hybrid prognostic study/decision analytical model was conducted among patients with melanoma who were eligible for SLNB at 2 melanoma centers from Australia and the US from 2000 to 2014. Participants consisted of 2 cohorts of patients with melanoma undergoing SLNB and a cohort of eligible patients without SLNB. Individualized probabilities of SLNB positivity generated by a patient-centered methodology (PCM) were compared with those generated by conventional multiple logistic regression analysis investigating 12 prognostic factors. Prognostic accuracy was assessed by the area under the receiver operating characteristic curve (AUROC) for each methodology and by matched-pair analyses. Interventions: Triaging appropriate patients to undergo SLNB. Main Outcomes and Measures: Total number of SLNBs performed (giving total cost) vs number of SLNB-positive outcomes (a measure of effectiveness) was evaluated. Improved cost-effectiveness through judicious patient selection was interpreted as increased numbers of SLNB-positive outcomes achieved, decreased numbers of SLNBs performed, or both outcomes simultaneously. Results: Among 7331 patients with melanoma, SLNB outcomes were assessed in 3640 Australian patients (2212 males [60.8%]; 2447 aged >50 years [67.2%]) and 1342 US patients (774 males [57.7%]; 885 aged >50 years [66.0%]); 2349 patients eligible for SLNB who did not undergo the procedure were included in the simulation. PCM-generated probabilities achieved an AUROC of 0.803 in predicting SLNB positivity in the Australian cohort and 0.826 in the US cohort, higher than corresponding AUROCs generated by conventional logistic regression analysis. In simulation, adopting many SLNB-positive probabilities as minimally acceptable patient-selection criteria resulted in fewer procedures performed or increased the expected numbers of positive SLNBs. A minimally acceptable PCM-generated probability of 8.7% elicited the same number of SLNBs as historically performed (3640 SLNBs), with 1066 positive SLNBs (29.3%), constituting an improvement of 287 additional positive SLNBs compared with 779 actual positive SLNBs (36.8% improvement). In contrast, adopting a 23.7% PCM-generated minimum cutoff probability resulted in performing 1825 SLNBs, or 1815 fewer SLNBs than the actual experience (49.9%). It resulted in the same expected number of positive results (779 SLNBs), for a 42.7% positivity rate. Conclusions and Relevance: This prognostic study/decision analytical model found that the PCM approach outperformed conventional multiple logistic regression analysis in predicting which patients would have positive results on SLNB. These findings suggest that systematically producing and exploiting more accurate SLNB-positivity probabilities could improve the selection of patients with melanoma for SLNB compared with using established guidelines, thus improving the cost-effectiveness of the selection process. Eligibility guidelines to undergo SLNB should include a context-tailored minimum cutoff probability.

Has the advent of modern adjuvant systemic therapy for melanoma rendered sentinel node biopsy unnecessary?

The prognostic value of sentinel node biopsy (SNB) is well established and SNB was therefore adopted as a requirement for pathological staging of melanomas>1 mm thick in the American Joint Committee on Cancer (AJCC) 8th edition. Consequently, a negative SNB status became an eligibility criterion for clinical trials of adjuvant systemic therapy in resected stage IIB/C melanoma. However, since the Keynote 716 trial demonstrated an improvement in relapse-free survival (RFS) in patients with Stage IIB/C melanoma, all of whom had SNB staging, some have argued that SNB is no longer required for patients with T3 and T4 primary melanomas. The rationale for omitting SNB is that these patients will be able to access adjuvant immunotherapy regardless of SNB status, avoiding the costs and potential complications of SNB. However, this argument overlooks the prognostic value of knowing a patient's nodal status and the therapeutic benefit of SNB in regional disease control. Based on extrapolation of data from multiple sources, we demonstrate that the risk of regional node-field relapse with SNB and immunotherapy for T3b and T4 melanomas is around 7-9% but is 20-27% without SNB. Similarly, the node-field recurrence rate with SNB alone is around 14% compared to around 40% with no SNB or immunotherapy. Consequently, in the absence of prospective data, we propose that the optimal management of the regional node-field for high-risk T3b and T4 primary melanomas is likely to be achieved by combining SNB and adjuvant immunotherapy for those patients who are suitable, rather than either treatment alone.

Comparing Genomic Landscapes of Oral and Cutaneous Squamous Cell Carcinoma of the Head and Neck: Quest for Novel Diagnostic Markers.

Squamous cell carcinoma is the most common head and neck malignancy arising from the oral mucosa and the skin. The histologic and immunohistochemical features of oral squamous cell carcinoma (OSCC) and head and neck cutaneous squamous cell carcinoma (HNcSCC) are similar, making it difficult to identify the primary site in cases of metastases. With the advent of immunotherapy, reliable distinction of OSCC and HNcSCC at metastatic sites has important treatment and prognostic implications. Here, we investigate and compare the genomic landscape of OSCC and HNcSCC to identify diagnostically useful biomarkers. Whole-genome sequencing data from 57 OSCC and 41 HNcSCC patients were obtained for tumor and matched normal samples. Tumor mutation burden (TMB), Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, frequent chromosomal alterations, somatic single nucleotide, and copy number variations were analyzed. The median TMB of 3.75 in primary OSCC was significantly lower (P < .001) than that of 147.51 mutations/Mb in primary HNcSCC. The COSMIC mutation signatures were significantly different (P < .001) between OSCC and HNcSCC. OSCC showed COSMIC single-base substitution (SBS) mutation signature 1 and AID/APOBEC activity-associated signature 2 and/or 13. All except 1 HNcSCC from hair-bearing scalp showed UV damage-associated COSMIC SBS mutation signature 7. Both OSCC and HNcSCC demonstrated a predominance of tumor suppressor gene mutations, predominantly TP53. The most frequently mutated oncogenes were PIK3CA and MUC4 in OSCC and HNcSCC, respectively. The metastases of OSCC and HNcSCC demonstrated TMB and COSMIC SBS mutation signatures similar to their primary counterparts. The combination of high TMB and UV signature in a metastatic keratinizing squamous cell carcinoma suggests HNcSCC as the primary site and may also facilitate decisions regarding immunotherapy. HNcSCC and OSCC show distinct genomic profiles despite histologic and immunohistochemical similarities. Their genomic characteristics may underlie differences in behavior and guide treatment decisions in recurrent and metastatic settings.

Modeling Methods in Craniofacial Virtual Surgical Planning.

Despite the widespread use of virtual surgical planning (VSP), few papers describe the modeling methods used to generate the digital simulations that underpin VSP. This paper aims to review the modeling methods that are currently available for use in VSP and the implications of their use in clinical practice. A literature review was undertaken of the two broad categories of modeling techniques; contour-based planning-namely mirroring from the contralateral side, templating from a normative database, and extrapolation from surrounding landmarks-and occlusal-based planning (OBP). The indications for each modeling method were discussed, including mandibular/maxillary reconstruction, pediatric craniofacial surgery, and orthognathic, as well as the limitations to the accuracy of modeling types. Unilateral defects of the upper/midface, wherein contour accuracy is paramount, are best reconstructed using mirroring methods, whereas bilateral defects-or cases with asymmetry due to craniofacial dysmorphology-are most suited to normative-data-based methods. Cases involving resection of the alveolar margin, in which functional occlusion is the primary outcome are best managed with OBP. Similarly, orthognathic surgery typically uses OBP, although complex cases involving asymmetry, such as clefts, may benefit from a combination of OBP and normative data methods. The choice of modeling methods is, therefore, largely driven by the defect type and the goals of reconstruction.

Fascio-cutaneous and fascio-periosteal free flaps for treatment of intermediate stage osteoradionecrosis of the jaws.

OBJECTIVES: Osteoradionecrosis (ORN) of the jaw is a potentially devastating consequence of head and neck irradiation. Despite recent advances, there are patients who fail to respond to conventional therapies. Historically, free flaps were reserved for advanced cases requiring segmental resection and composite reconstruction, with early and intermediate disease treated more conservatively. We have adopted a more active surgical approach in selected intermediate cases. STUDY DESIGN: A retrospective review of patients with intermediate stage ORN who received debridement and either fascio-cutaneous or fascio-periosteal free flap reconstruction was performed. Demographic data, ORN severity, treatment, and outcomes are described. RESULTS: From 2019, 9 cases in 7 patients were identified. All cases were Notani grade II. There were 6 Epstein stage IIa and 3 Epstein stage IIIa. The mandible was the most common site (n = 8). Of the 7 patients, 2 had oropharyngeal primaries treated with chemoradiation, and 5 had oral cavity primaries treated with surgery and adjuvant radiation therapy. Three patients had prior hyperbaric oxygen therapy, and 2 had pentoxifylline/tocopherol therapy. After debridement, the radial forearm, ulnar artery perforator, and antero-lateral thigh fascio-cutaneous free flaps were each used in 1 case and the temporoparietal fascio-periosteal free flap was used in 6 cases. There was no recurrence or progression of ORN at the site of surgery, but 2 patients developed additional sites of ORN. CONCLUSIONS: For patients with unresponsive intermediate ORN, debridement and soft tissue free flap reconstruction is an alternative to ongoing conservative management or composite resection and reconstruction.

Genomic Profiling of Metastatic Basal cell Carcinoma Reveals Candidate Drivers of Disease and Therapeutic Targets.

Basal cell carcinomas (BCCs) are human beings' most common malignant tumors. Most are easily managed by surgery or topical therapies, and metastasis is rare. Although BCCs can become locally advanced, metastatic BCCs are very uncommon and may be biologically distinct. We assessed the clinicopathologic characteristics of 17 patients with metastatic BCC and pursued whole-exome sequencing of tumor and germline DNA from 8 patients. Genomic profiling revealed aberrant activation of Hedgehog signaling and alterations in GLI transcriptional regulators and Notch and Hippo signaling. Matched local recurrences of primary BCCs and metastases from 3 patients provided evidence of a clonal origin in all cases. Mutations associated with YAP inhibition were found exclusively in 2 hematogenously-spread lung metastases, and metastatic BCCs were enriched for mutations in the YAP/TAZ-binding domain of TEAD genes. Accordingly, YAP/TAZ nuclear localization was associated with metastatic types and Hippo mutations, suggesting an enhanced oncogenic role in hematogenously-spread metastases. Mutations in RET, HGF, and phosphatidylinositol 3­kinase (PI3K)/protein kinase B (AKT) signaling were enriched compared with a cohort of low clinical-risk BCCs. Our results implicate Hippo and PI3K/AKT dysregulation in metastatic progression of BCCs, making these potential therapeutic targets in metastatic disease. The common clonal origin of matched recurrent and metastatic BCCs suggests that molecular profiling can assist in determining the nature/origin of poorly differentiated metastatic tumors of uncertain type. Genes and pathways enriched for mutations in this cohort are candidate drivers of metastasis and can be used to identify patients at high risk of metastasis who may benefit from aggressive local treatment and careful clinical follow-up.

Anterolateral thigh, radial forearm and superficial circumflex iliac perforator flaps in oral reconstruction: a comparative analysis.

BACKGROUND: Anterolateral thigh (ALT) and Radial forearm free flaps (RFFF) are historically the most common methods of oral reconstruction. The Superficial circumflex iliac artery perforator flap (SCIP) is an alternative providing a donor site that can be readily closed primarily with improved cosmesis in younger patients, due to its concealability. METHODS: We reviewed 135 patients who received ALT, RFFF or SCIP flaps for oral reconstruction in our institution. Our aim was to compare operative and perioperative outcomes between each cohort. ANOVA and χ2 test were used for statistical analysis. RESULTS: There were 37 ALT, 64 RFFF and 35 SCIP reconstructions. Patients reconstructed with SCIP flaps had smaller resection volumes (P < 0.001) and earlier T and N classifications (P = 0.001, P = 0.008), and consequently reduced tracheostomy rates (P < 0.001), reduced need for enteral feeding at discharge (P < 0.001) and shorter length of stay and perioperative times (P < 0.001). SCIP flaps were more common in younger patients (P < 0.01). ALT flaps were used for more advanced disease (P = 0.001) and had larger resection volumes (P < 0.001) and increased need for assisted enteral feeding (P < 0.001). There were no significant differences in flap or donor site outcomes. There were two flap failures, both RFFF. CONCLUSION: Each flap plays an important role in the reconstruction of oral defects, with larger defects preferentially reconstructed with ALT flaps. SCIP appears to be a reliable alternative in small defects with excellent perioperative and postoperative outcomes.

Voluntary and Spontaneous Smile Quantification in Facial Palsy Patients: Validation of a Novel Mobile Application.

Introduction: Restoration of spontaneous smiling is a key goal in facial reanimation. A major obstacle to quantifying recovery of spontaneous smiling is the current lack of a uniform and objective means of smile quantification. Objective: To compare the facial movements during smiling in patients with facial paralysis as measured by an automated application and human observers. Methods: Video recordings of 25 patients with unilateral facial palsy (FP) watching humorous videos were utilized. Application-derived smile timestamping was compared with manual observer interpretation. Internal reliability of measurements was evaluated through a test-retest approach. Results: Application-derived smile identification demonstrated almost perfect agreement with manual interpretation (kappa 0.861, p < 0.001). There was no statistically significant difference in mean number of smiles between detection method (p = 0.354). Automated smile identification demonstrated a high degree of specificity (95.4%), accuracy (93.1%), positive-predictive value (94.7%), and negative-predictive value (91.8%). This method demonstrated a high degree of reliability (kappa 0.864, p < 0.01). Conclusion: The novel "SmileCheck" mobile phone application performed accurate and reliable smile quantification in FP patients in comparison with manual observation.