The impact of multifocal perineural invasion in predicting survival in patients with oral squamous cell carcinoma: A multicenter investigation.

BACKGROUND: Perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) does not contribute to the current American Joint Committee on Cancer 8th edition (AJCC8) staging manual. This study seeks to validate the effect of multifocal PNI in a large cohort of patients. METHODS: Patients undergoing primary surgical treatment of OSCC with curative intent between 1995 and 2022 was retrieved from two Australian head and neck databases. PNI was categorized as a single focus or multiple foci. Study end points included disease-specific survival (DSS) and overall survival (OS). RESULTS: Complete data for survival analysis was available in 993 patients. Multifocal PNI was associated with a 61% increased risk of death due to OSCC (HR 1.61, 95% CI 1.11-2.33, p = 0.014) and a 32% increased risk of death from any cause (HR 1.32, 95% CI 1.01-1.73, p = 0.045). CONCLUSIONS: Multifocal PNI is a significant predictor of survival in OSCC.

Development of an implantable bionic for dynamic eye closure in facial nerve paralysis: Evolution of the design.

Facial nerve paralysis (FNP) presents with a constellation of clinical problems but its most concerning consequence is corneal exposure from lack of blinking. Bionic lid implant for natural closure (BLINC) is an implantable solution for dynamic eye closure in FNP. It uses an electromagnetic actuator to mobilise the dysfunctional eyelid by means of an eyelid sling. This study highlights issues relating to device biocompatibility and describes its evolution to overcome some of these issues. The essential components of the device are the actuator, the electronics including energy storage, and an induction link for wireless power transfer. Effective arrangement of these components within the anatomical confines and their integration is achieved through a series of prototypes. The response of each prototype is tested in a synthetic or cadaveric model for eye closure with the final prototype designed for acute and chronic animal trials.

Immunotherapy in advanced cutaneous squamous cell carcinoma: Sydney west cancer network experience.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in the Caucasian population. A minority of cases are inoperable at presentation, recur or develop metastatic disease with a historical 5-year overall survival of ~10%. Treatment options in this setting are generally palliative. Immunotherapy has emerged as a new paradigm in managing these patients. METHODS: Patients presenting to Sydney West Cancer Network with locally advanced or metastatic CSCC treated with the anti-PD1 agent cemiplimab were identified. Response to treatment was objectively assessed based on RECIST1.1 or PERCIST criteria. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), therapy toxicity, and predictors of treatment response. RESULTS: A total of 19 patients were identified with a median age of 76 (range 56-94) and 4 immunosuppressed. The longest follow up duration was 28 months. ORR, complete response (CR), and partial response (PR) were 68% (13/19), 53% (10/19), and 16% (3/19), respectively. Median PFS was 12 months (95% CI 9-14) whilst median OS was not reached by end of study. Responders (CR or PR) had significantly superior OS compared to those with no response (P < 0.01). A primary site of head and neck cancer was significantly associated with ORR (P = 0.04). A single patient experienced Grade 3 toxicity with the rest being Grades 0-1. CONCLUSION: This study confirms the clinical efficacy of cemiplimab in patients with advanced CSCC with many experiencing a durable response and an acceptable adverse effect profile.

Overcoming Facial Paralysis with an Implantable Actuator for Restoration of Blink.

The loss of the ability to blink the eyelid is considered the most severe effect of facial nerve paralysis. The delicate homeostasis of the eye is disrupted, and without frequent intervention, the cornea can become damaged, ultimately resulting in blindness. The psychosocial impact is also significant, with individuals withdrawing from society to hide what they perceive to be a disfigurement. Surgical and engineering interventions have been devised to reanimate blink, however, a solution has yet to be designed which addresses both functional and aesthetic concerns. Here we describe an implantable electromagnetic actuator to restore the capacity to blink. Triggered synchronously with the contralateral eye, and externally modifiable to tailor treatment post-operatively to the individual, this implant restores complete blinking and a natural appearance. Cadaver studies (N=12) have been used to validate the device design, including the form factor and force required to elicit a blink, while a passive in vivo study (N=1) has verified the surgical protocol and recovery.

Facial nerve palsy: Narrative review on the importance of the eye and its assessment.

New solutions are emerging that address specific facial regions in facial nerve palsy (FNP). However the most dreaded consequence of FNP is paralytic lagophthalmos threatening the eye. A way to prioritize these regions is thus required. A review of the literature is conduced to capture the current concepts in evaluating FNP. Overall, patients are assessed from three perspectives: from the clinician's perspective using validated clinician-based grading instruments, from patient's perspective based on FNP-specific patient-reported outcome measures, and from the perspective of the layperson. The existing tools however provide limited information regarding the relative importance of different regions of the face. The eye appears to be an area of great concern for the patient where most surgical therapies are directed at. Addressing ocular problems in FNP carry a high priority but this is not clearly reflected by the standard systems.

Anatomy of the lateral orbital wall: A topographic investigation for identification of the lateral canthal attachment.

BACKGROUND: There is a growing effort to develop implantable bionics for restoring eye closure in paralytic lagophthalmos. Knowledge of the natural eyelid attachments is important for active implants that mobilise these attachments or replace them with a sling. Whitnall's tubercle (WT) is traditionally used to identify lateral canthal attachments; however, it is not always present. This study seeks an alternative means of identifying the insertion of the lateral canthus to aid the application of bionic implants. METHODS: Complete CT head scans of patients in the Sydney Head and Neck Cancer Institute database were retrieved for analysis. The CT scans were segmented using bone and soft-tissue thresholding and then reconstructed. The location of WT and the lateral canthal insertion were recorded and their relation to key anatomical landmarks assessed. RESULTS: Ninety orbits from 45 complete head scans were analysed. WT could be identified bilaterally in 18/45 (40%) samples. The average distance from WT to zygomaticofrontal suture and to lateral orbital margin was 10.8 ±â€¯0.4 mm and 4.4 ±â€¯0.2 mm, respectively. The average height of the lateral canthal insertion from the Jugale point was 13.9 ±â€¯1.8 mm. On regression analysis, the height of lateral canthal insertion was strongly predicted by the height of lateral orbital wall as the determined by the maximum distance of the ZFS from the Jugale point (p = <0.001). CONCLUSION: In the absence of WT, the height of the lateral orbital wall can be reliability used to localise the insertion site of the lateral canthus.

Facial nerve paralysis: A review on the evolution of implantable prosthesis in restoring dynamic eye closure.

Facial nerve paralysis (FNP) is a debilitating condition that leaves those affected with disfigurement and loss of function. The most important function of the facial nerve is protecting the eye through eye closure and blinking. A series of reanimation techniques have been reported to restore dynamic function in FNP, but the lack of a universally accepted method that is reliable and reproducible with immediate effect has led to the introduction of several implantable devices. Most of these devices have been applied to assist blinking; however, the delicate anatomy and unique mechanics of eye closure are difficult to replicate. Lid loading is the most frequently used implant today, which is a passive device that can aid in volitional eye closure but has a limited effect on blinking. Dynamic action can be achieved with active prostheses but achieving successful long-term function remains elusive. Device action must also be coupled with a real-time feedback mechanism in order to capture the natural variation in facial muscle movements. This review discusses all prostheses used for restoring eye closure and blinking to date and explores their relative merits.

Immunotherapy in advanced Merkel cell carcinoma: Sydney west cancer network experience.

INTRODUCTION: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with no survival benefit demonstrated using palliative cytotoxic chemotherapy in the setting of metastatic MCC. Recently, immune checkpoint inhibitors (anti-PD-L1/PD1) have been approved in this setting after durable clinical response was demonstrated in several clinical trials. In this series, we present a multicentre real-world experience in using anti-PD-L1/PD1 in advanced MCC. METHODS: A retrospective review was performed of all patients with metastatic MCC who were treated with at least one dose of anti-PD-L1/PD1 presenting to Sydney West Cancer Network (Westmead, Nepean and Blacktown hospitals) was performed between 2016 and 2020. Treatment response was assessed based on morphologic and/or metabolic changes of the disease on FDG-PET/CT scans. Primary end point investigated was objective response rate. Secondary outcomes included therapy toxicity, disease control and overall survival. RESULTS: Thirteen patients received anti-PD-L1/PD1 with a median age of 82 (range 62-89). Two patients had undergone prior palliative chemotherapy. The median follow-up time was 17 months (range 2-34). The overall, complete and partial response rates were 77% (10), 54% (7) and 23% (3), respectively. Treatment-related grade 1 or 2 toxicity was experienced by 69% with only 2 cases of greater severity. The median progression-free survival and overall survival were 18 months (95% CI 10-26 months) and 33 months (95% CI range 7.6-58.4 months), respectively. CONCLUSIONS: Consistent with clinical trial results, anti-PD-L1/PD1 therapy in this small series demonstrated efficacy and safety in patients with metastatic MCC.

Recreation of eyelid mechanics using the sling concept✰.

BACKGROUND: Paralytic lagophthalmos causes major functional, aesthetic and psychological problems in patients with facial paralysis. The Bionic Lid Implant for Natural Closure (BLINC) project aims to restore eyelid function using an implanted electromagnetic actuator combined with an eyelid sling. The authors performed a preliminary study using cadaveric heads to investigate the optimal application of an eyelid sling in various configurations around the orbit. METHODS: The sling was tested in a cadaveric sheep head using 2 medial anchor points and 4 lateral ostectomy points. An impulse was generated using gravitational force to test each combination of medial and lateral sling insertion sites using weights between 10 and 50 g. Each generated blink was recorded and analysed. The final result was validated in a human cadaveric model. RESULTS: The maximum amount of eye closure and closure speed displayed in sheep were 83.7 ±â€¯9.4% of total closure and 70.6 ±â€¯6.9 mm/s at a maximum force of 490 mN, respectively. The 2 inferior lateral attachments performed better at displacing the eyelid than the superior attachments. The position with the highest degree of eye-closure (improvement of 21.6%, p < 0.001) and speed (improvement of 30.4 mm/s, p < 0.001) was the combination of a posterior medial attachment and an inferior-posterior lateral attachment, which resulted in a near physiological closure in human cadaver. CONCLUSION: Closure improved with an inferior lateral position due to increased force acting in the direction of closure. Posterior positioning increases force acting radially, towards the centre of eyelid movement. The latter directs the closure force to effectively move the eyelid around the curved globe.

Regional Metastasis in Head and Neck Cutaneous Squamous Cell Carcinoma: An Update on the Significance of Extra-Nodal Extension and Soft Tissue Metastasis.

BACKGROUND: Soft tissue metastases (STMs) are reported to predict worse prognosis than extra-nodal extension (ENE) in metastatic head and neck cutaneous squamous cell carcinoma. This study aimed to update the authors' previous analysis of STM in a larger series. METHODS: The study analyzed 535 cases of consecutive cSCC metastatic to the parotid and/or neck treated by primary surgical resection between 1987 and 2007. A Cox proportional hazard model was used to determine the effect of STM, with adjustment for other relevant prognostic factors. Overall survival (OS) and disease-specific survival (DSS) were the primary end points. RESULTS: Of the 535 patients, 275 (51.4%) had STM. After adjustment for the effects of age, tumor location, number of metastatic deposits, and adjuvant radiotherapy, both STM (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.08-2.22; p = 0.018) and ENE (HR, 1.56; 95% CI 1.10-2.22; p = 0.013) were shown to be independent predictors of reduced OS, with similar size of effect. CONCLUSION: In metastatic cSCC of the head and neck, STM is an independent predictor of reduced survival and has an impact on survival similar to that of ENE.

Chimeric Vastus Lateralis and Anterolateral Thigh Flap for Restoring Facial Defects and Dynamic Function following Radical Parotidectomy.

BACKGROUND: Extirpation of malignant tumors of the parotid results in creation of a complex facial defect often in combination with facial nerve palsy. This study presents the authors' experience using vastus lateralis muscle as a chimeric flap with anterolateral thigh flap to allow both soft-tissue reconstruction and dynamic reanimation in radical parotidectomy. METHODS: A retrospective review of the medical records of cancer patients who had undergone radical parotidectomy and reconstruction using a chimeric vastus lateralis and anterolateral thigh flap between March of 2013 and May of 2017 was performed using the Sydney Head and Neck Cancer Institute database. The return of dynamic midface movement was the primary outcome investigated. Electronic, clinician-graded facial function scale grades were used to formally assess postoperative outcomes. RESULTS: A total of 27 patients were included in the study with an average age of 72 years (range, 31 to 88 years). Thirteen patients (48 percent) had developed dynamic function by the end of the study period. Young age predicted a more rapid return to dynamic function (p = 0.018). Both being a woman and having an intact facial nerve before surgery improved dynamic midface movement (p = 0.005 and p = 0.036, respectively). On multivariable analysis, superior midface dynamic function was associated with neurotization using midface facial nerve branches as opposed to using nerve-to-masseter alone (p = 0.05). CONCLUSION: The chimeric vastus lateralis and anterolateral thigh flap is a suitable option for restoring defects and dynamic function following radical parotidectomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Multifocal perineural invasion is a better prognosticator than depth of invasion in oral squamous cell carcinoma.

OBJECTIVES: Prognostic significance of perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) characterized as unifocal and multifocal was compared to depth of invasion (DOI) and extranodal extension (ENE). MATERIALS AND METHODS: Univariable and multivariable analyses of 861 consecutive patients with OSCC undergoing treatment between 1995 and 2018 were performed, with local failure (LF) and disease-specific mortality (DSS) as the primary endpoints. RESULTS: After adjusting for other adverse histopathological factors and adjuvant therapy, multifocal PNI was associated with a greater risk of LF (P = .01) and DSS (P = 0.02) compared to DOI. The effect of multifocal PNI was comparable to the effect of nodal metastases without ENE (P = 0.02). LF and DSS were not improved by the administration of adjuvant radiotherapy within unifocal or multifocal PNI groups. CONCLUSION: Multifocal PNI is associated with a greater risk of death in OSCC than DOI. Its effect is comparable to that of nodal metastases (without ENE).

Positive survival trend in metastatic head and neck cutaneous squamous cell carcinoma over four-decades: Multicenter study.

BACKGROUND: This study assessed changes over time of survival of head and neck cutaneous squamous cell carcinoma (HNcSCC) with lymph node metastases. METHODS: A multicenter analysis of 1301 patients with metastatic HNcSCC treated between 1980 and 2017. Differences in disease-specific survival (DSS) and overall survival (OS) by decade were assessed using multivariate Cox regression. RESULTS: Over the study period, we noted an increase in the proportion of patients aged over 80 years (3.9%-31.7%; P < .001) and immunosuppression (1.9%-9.9%; P = .03). After adjusting for number and size of metastatic nodes, extranodal extension, perineural invasion, immunosuppression, treatment, and institution, there was a reduction in risk of cancer-related mortality from 0.47 in 1990-1999 (P = .04) to 0.30 in 2000-2009 (P < .001) when compared to 1980-1989. This remained stable at 0.30 in 2010-2017 (P = .001). OS remained stable after 1990. CONCLUSION: Despite an aging and more frequently immunosuppressed population, fewer patients are dying from metastatic HNcSCC.

Temperature Selection in Antegrade Cerebral Perfusion for Aortic Arch Surgery: A Meta-Analysis.

BACKGROUND: The increasing use of antegrade cerebral perfusion (ACP) during aortic arch surgery has corresponded with a trend toward warmer target temperatures for hypothermic circulatory arrest. This meta-analysis examined the clinical outcomes using colder or warmer circulatory arrest targets with ACP. METHODS: Electronic searches were performed using four databases from their inception to February 2017. Comparative studies of adult patients who underwent aortic arch operations using ACP at different circulatory arrest temperatures were included. Data were extracted by 2 independent researchers and analyzed according to predefined end points using a random-effects model. RESULTS: The literature search identified 18 comparative studies, with 1,215 patients in the "cold" cohort and 1,417 in the "warm" cohort. Mean hypothermic circulatory arrest temperatures were 20.3°C and 26.5°C in the cold and warm groups, respectively. A trend existed for increased permanent neurologic deficit overall when colder targets were used (odds ratio, 1.45; 95% confidence interval, 0.98 to 2.13; p = 0.06); this became significant when adjusted estimates were aggregated (odds ratio, 1.65; 95% confidence interval, 1.06 to 2.55; p = 0.03). No difference in the mortality rate was seen when adjusted effects were aggregated. Temporary neurologic deficit, postoperative dialysis, ventilator time, and intensive care unit stay were significantly reduced in the warm cohort overall. No significant differences in reexploration for bleeding were found. CONCLUSIONS: ACP with warmer circulatory arrest temperatures may reduce the incidence of permanent neurologic deficit as well as potentially other clinical outcomes. Further studies are required to determine the safe circulatory arrest durations for visceral organs at warmer temperatures.

Adjunct retrograde cerebral perfusion provides superior outcomes compared with hypothermic circulatory arrest alone: A meta-analysis.

OBJECTIVE: Retrograde cerebral perfusion is becoming less frequently used as a method of neuroprotection during aortic surgery. The present meta-analysis aims to compare outcomes after arch surgery with hypothermic circulatory arrest versus hypothermic circulatory arrest + retrograde cerebral perfusion. METHODS: Electronic searches were performed using 7 databases from their inception to September 2016. Relevant comparative studies that included patient groups who underwent aortic arch surgery using hypothermic circulatory arrest with continuous retrograde cerebral perfusion or hypothermic circulatory arrest alone were identified, and data were extracted by 2 independent researchers. Data were aggregated using a random-effects model per predefined clinical end points. RESULTS: Twenty-eight comparative studies were identified, with 2705 hypothermic circulatory arrest cases and 2817 hypothermic circulatory arrest + retrograde cerebral perfusion cases. No significant differences were seen between both groups in terms of age, gender, proportion of dissections and aneurysms, and hemiarch/total arch repair. The hypothermic circulatory arrest + retrograde cerebral perfusion group had slightly longer cardiopulmonary bypass time and lower body arrest time. Mortality was significantly increased for the hypothermic circulatory arrest cohort compared with the hypothermic circulatory arrest + retrograde cerebral perfusion cohort (odds ratio, 1.75; 95% confidence interval, 1.16-2.63; P = .007; I2 = 54%), but not on pooling of adjusted estimates. Stroke was also increased for the hypothermic circulatory arrest cohort (odds ratio, 1.50; 95% confidence interval, 1.07-2.10; P = .02; I2 = 29%). No difference in temporary neurologic deficit was identified (P = .66). Meta-regression found the treatment effect for mortality and stroke to be less pronounced in more contemporary series. CONCLUSIONS: These results suggest that the addition of retrograde cerebral perfusion during aortic arch surgery may provide better outcomes than using hypothermic circulatory arrest alone, although significant confounders exist. Further robust studies are required to confirm the utility of retrograde cerebral perfusion in arch surgery.

Validation of the Clinician-Graded Electronic Facial Paralysis Assessment.

BACKGROUND: Facial paralysis remains a debilitating condition despite advances in medical, surgical, and adjunctive interventions. Established grading systems used to assess facial paralysis and interventional outcomes have well-described limitations. The Electronic Facial Paralysis Assessment, a clinician-graded zone-based facial function scale, has recently emerged as a grading tool that may provide greater sensitivity when assessing incomplete paralysis and postsurgical improvement. The authors perform the first comprehensive validation of this tool. METHODS: Video recordings of 83 facial paralysis patients were assessed. Grading was performed in two sittings by three individuals with varying degrees of experience in assessing facial paralysis. Interobserver reliability; intraobserver reliability; administration time; and agreement with the Facial Disability Index, House-Brackmann, Sunnybrook, and Sydney facial grading systems were assessed. RESULTS: The Electronic Facial Paralysis Assessment demonstrated high intra observer and interobserver reliability (intraclass correlation coefficient, 0.84 to 0.91 and 0.81 to 0.83, respectively). It correlated well with the House-Brackmann, Sunnybrook, and Sydney facial grading systems (Spearman rho, 0.73, 0.77 and 0.77, respectively). In subdomain analysis, it correlated well with the Sunnybrook and Sydney systems in dynamic movement (Spearman rho, 0.90 and 0.89, respectively) and synkinesis (Spearman rho, range 0.74 and 0.72, respectively). It had poor agreement with the Facial Disability Index (Spearman rho, 0.25). The mean time to complete the tool was 116 ± 61 seconds. CONCLUSIONS: The Electronic Facial Paralysis Assessment is a valid facial assessment tool with high reliability and correlation with the established facial paralysis grading systems. It also provides an efficient and detailed analysis of paralysis according to each facial zone. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II.

Restoration of eye closure in facial paralysis using implantable electromagnetic actuator.

The most devastating outcome of facial nerve paralysis is the inability to completely close the eye as it can lead to corneal ulceration and loss of vision. Gravity-assisted eye closure with upper lid loading is commonly used; however it is limited in replicating physiological eye closure to adequately lubricate the cornea. Superior results can be obtained using more advanced reconstructive approaches, however they depend on nerve regrowth which may be unpredictable and prolonged. This report describes a novel technique for creating an active eye closure using an implantable actuator. A generated magnetic field creates lateral movement in an electromagnet that is translated to the eyelid through a sling design. The device is powered wirelessly through a transcutaneous induction link and can be hermetically encapsulated for patient safety. The initial phase of device development is presented including data of a fully functioning prototype and the results of its application in animal and human cadavers.

Creating eye closure in patients with facial nerve paralysis using an implantable solenoid actuator.

This paper proposes the use of an implantable solenoid actuator to create a more natural eyelid closure over current lid loading therapies in patients with facial nerve paralysis (FNP). The actuator works by moving a magnet when a solenoid is activated. This is used to tension a sling applied to the upper eyelid which closes the eye. The sling design has been described elsewhere and creating eye closure using it requires a force of 627 (± 128) mN over a movement of approximately 6 mm. The actuator described here was able to successfully achieve these parameters and repeatedly perform eyelid closure in a cadaveric rabbit model. Device limitations and future improvements have also been identified and discussed.