Virtual planning and 3D-printed guides for mandibular reconstruction: Factors impacting accuracy.

Objectives: Examine accuracy and factors impacting accuracy for mandibular reconstruction with virtual surgical planning, 3D printed osteotomy guides and preoperatively bent mandibular reconstruction plate (VSP/3Dprinted-guide/plate). Method: Retrospective review of osseous-free-flap mandibular reconstructions with VSP/3Dprinted-guide/plate between January 2015 and July 2020 at a single academic medical center.Patient demographics, disease, and treatment variables were extracted. Accuracy was assessed by 3D-model-overlay with cephalometric and donor-bone segment length measurements. Multivariate analyses were performed to determine factors impacting cephalometric accuracy. Results: 60 cases met criteria: 41 (68%) cancer, 14 (23%) osteoradionecrosis (ORN), 5 (8%) secondary mandibular reconstruction. Thirteen cases (22%) were Brown class III or IV. Thirty-nine cases (65%) had ≥2 flap bone segments. Average donor-bone length was 82 mm (SD: 28). 3D-model-overlay accuracy demonstrated minimal deviation between planned and actual reconstruction: intercondylar distance = 2.10 mm (SD: 2.2); intergonial distance = 2.23 mm (SD: 1.9); anterior-posterior distance (APD) = 1.76 mm (SD: 1.5); gonial angle (GA) = 3.11 degrees (SD: 2.4). Mean change in donor-bone segment length inferiorly was 2.67 mm (SD: 2.6) and superiorly 3.27 mm (SD: 3.2). Higher number of donor-bone segments was associated with decreased accuracy in GA (p = .023) and longer donor-bone length was associated with decreased accuracy in APD (p = .031). Conclusion: To our knowledge this is the largest series assessing surgical accuracy of VSP/3Dprinted-guide/plate for osseous-free-flap mandibular reconstruction. We demonstrate highly accurate results, with increased number of donor-bone segments and donor-bone length associated with decreased accuracy. Our findings further support VSP/3Dprinted-guide/plate as a reliable and accurate tool for mandibular reconstruction. Level of Evidence: Level 4.

Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition [anti-PD-1, nivolumab (N), and anti-KIR, lirilumab (L)] before and after salvage surgery to improve disease-free survival (DFS). PATIENTS AND METHODS: In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling. RESULTS: Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response (P = 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8-71.7) and 1-year OS was 85.7% (95% CI, 66.3-94.4). Two-year DFS and OS were 64% and 80% among pathologic responders. CONCLUSIONS: (Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted.See related commentary by Sacco and Cohen, p. 435.

Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial.

Importance: Novel approaches are needed to improve outcomes in patients with squamous cell carcinoma of the oral cavity. Neoadjuvant immunotherapy given prior to surgery and combining programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitors are 2 strategies to enhance antitumor immune responses that could be of benefit. Design, Setting, and Participants: In this randomized phase 2 clinical trial conducted at 1 academic center, 29 patients with untreated squamous cell carcinoma of the oral cavity (≥T2, or clinically node positive) were enrolled between 2016 to 2019. Interventions: Treatment was administered with nivolumab, 3 mg/kg, weeks 1 and 3, or nivolumab and ipilimumab (ipilimumab, 1 mg/kg, given week 1 only). Patients had surgery 3 to 7 days following cycle 2. Main Outcomes and Measures: Safety and volumetric response determined using bidirectional measurements. Secondary end points included pathologic and objective response, progression-free survival (PFS), and overall survival. Multiplex immunofluorescence was used to evaluate primary tumor immune markers. Results: Fourteen patients were randomized to nivolumab (N) and 15 patients to nivolumab/ipilimumab (N+I) (mean [SD] age, 62 [12] years; 18 men [62%] and 11 women [38%]). The most common subsite was oral tongue (n = 16). Baseline clinical staging included patients with T2 (n = 20) or greater (n = 9) T stage and 17 patients (59%) with node-positive disease. Median time from cycle 1 to surgery was 19 days (range, 7-21 days); there were no surgical delays. There were toxic effects at least possibly related to study treatment in 21 patients, including grade 3 to 4 events in 2 (N), and 5 (N+I) patients. One patient died of conditions thought unrelated to study treatment (postoperative flap failure, stroke). There was evidence of response in both the N and N+I arms (volumetric response 50%, 53%; pathologic downstaging 53%, 69%; RECIST response 13%, 38%; and pathologic response 54%, 73%, respectively). Four patients had major/complete pathologic response greater than 90% (N, n = 1; N+I, n = 3). With 14.2 months median follow-up, 1-year progression-free survival was 85% and overall survival was 89%. Conclusions and Relevance: Treatment with N and N+I was feasible prior to surgical resection. We observed promising rates of response in both arms, supporting further neoadjuvant studies with these agents. Trial Registration: ClinicalTrials.gov Identifier: NCT02919683.

Chemotherapy after immune checkpoint blockade in patients with recurrent, metastatic squamous cell carcinoma of the head and neck.

OBJECTIVES: Given that immune checkpoint inhibitors (ICIs) are now preferred agents in first-line treatment of recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN), we retrospectively studied outcomes on post-ICI therapies. MATERIALS AND METHODS: We collected data from the medical records of 60 patients with R/M SCCHN who received ICIs followed by at least one further line of cytotoxic or biologic therapy at our institution from 2014 to 2019. We also compared outcomes with those of historical trials in the ICI-naïve, second-line or greater setting. RESULTS: Patients who received platinum-based regimens as their post-ICI therapies experienced improved overall response (ORR) (50% versus 10%, p < 0.01) and improved overall survival (OS) (15.1 months versus 7.3 months, HR 0.46, p = 0.04) compared to the rest of the cohort. Patients receiving platinum re-challenge were more likely to respond than all other patients in the cohort (OR 8.37, p = 0.01). The ORR for patients on 5-fluorouracil (5-FU)-containing regimens (63%) was also higher than other patients in the cohort (p = 0.03). Immunotherapy-based regimens compared favorably to historical data of first exposure to ICIs (disease control rate 54% versus 36%). Singlet regimens were associated with shorter OS than other regimens (HR = 2.38, p = 0.01). CONCLUSIONS: Platinum- and 5-FU-based doublet or triplet regimens may be superior options in the post-ICI setting. Immunotherapy re-challenge following ICI therapy may also be a reasonable option.

Complications, Mortality, and Functional Decline in Patients 80 Years or Older Undergoing Major Head and Neck Ablation and Reconstruction.

Importance: Data regarding outcomes after major head and neck ablation and reconstruction in the growing geriatric population (specifically ≥80 years of age) are limited. Such information would be extremely valuable in preoperative discussions with elderly patients about their surgical risks and expected functional outcomes. Objectives: To identify patient and surgical factors associated with 30-day postoperative complications, 90-day mortality, and 90-day functional decline; to explore whether an association exists between the type of reconstructive procedure and outcome; and to create a preoperative risk stratification system for these outcomes. Design, Setting, and Participants: This retrospective, multi-institutional cohort study included patients 80 years or older undergoing pedicle or free-flap reconstruction after an ablative head and neck surgery from January 1, 2015, to December 31, 2017, at 17 academic centers. Data were analyzed from February 1 through April 20, 2019. Main Outcomes and Measures: Thirty-day serious complication rate, 90-day mortality, and 90-day decline in functional status. Preoperative comorbidity and frailty were assessed using the American Society of Anesthesiologists classification, Adult Comorbidity Evaluation-27 score, and Modified Frailty Index. Multivariable clustered logistic regressions were performed. Conjunctive consolidation was used to create a risk stratification system. Results: Among 376 patients included in the analysis (253 [67.3%] men), 281 (74.7%) underwent free-flap reconstruction. The median age was 83 years (range, 80-98 years). A total of 193 patients (51.3%) had 30-day serious complications, 30 (8.0%) died within 90 days, and 36 of those not dependent at baseline declined to dependent status (11.0%). Type of flap (free vs pedicle, bone vs no bone) was not associated with these outcomes. Variables associated with worse outcomes were age of at least 85 years (odds ratio [OR] for 90-day mortality, 1.19 [95% CI 1.14-1.26]), moderate or severe comorbidities (OR for 30-day complications, 1.80 [95% CI, 1.34-2.41]; OR for 90-day mortality, 3.33 [95% CI, 1.29-8.60]), body mass index (BMI) of less than 25 (OR for 30-day complications, 0.95 [95% CI, 0.91-0.99]), high frailty (OR for 30-day complications, 1.72 [95% CI, 1.10-2.67]), duration of surgery (OR for 90-day functional decline, 2.94 [95% CI, 1.81-4.79]), flap failure (OR for 90-day mortality, 3.56 [95% CI, 1.47-8.62]), additional operations (OR for 30-day complications, 5.40 [95% CI, 3.09-9.43]; OR for 90-day functional decline, 2.94 [95% CI, 1.81-4.79]), and surgery of the maxilla, oral cavity, or oropharynx (OR for 90-day functional decline, 2.51 [95% CI, 1.30-4.85]). Age, BMI, comorbidity, and frailty were consolidated into a novel 3-tier risk classification system. Conclusions and Relevance: Important demographic, clinical, and surgical characteristics were found to be associated with postoperative complications, mortality, and functional decline in patients 80 years or older undergoing major head and neck surgery. Free flap and bony reconstruction were not independently associated with worse outcomes. A novel risk stratification system is presented.

Incidence and Demographic Burden of HPV-Associated Oropharyngeal Head and Neck Cancers in the United States.

BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal head and neck squamous cell carcinoma (OPSCC) is increasing in the United States. Current epidemiologic assessments of the national burden of HPV-positive OPSCC are needed. METHODS: The Surveillance Epidemiology and End Results HPV Status Database included 12,017 patients with head and neck squamous cell carcinoma of pharyngeal subsites, including OPSCC and non-OPSCC head and neck cancer subsites (hypopharynx, nasopharynx, and "other pharynx"), diagnosed from 2013 to 2014. Age-adjusted incidence rates per 100,000 persons by HPV status were calculated. An exploratory Fine-Gray competing-risks regression determined the associations between HPV status and cancer-specific mortality. RESULTS: From 2013 to 2014, the U.S. incidence of HPV-positive OPSCC was 4.62 [95% confidence interval (CI), 4.51-4.73] versus 1.82 (95% CI, 1.75-1.89) per 100,000 persons for HPV-negative OPSCC. The incidence of HPV-positive versus negative non-OPSCC of the head and neck was 0.62 (95% CI, 0.58-0.66) versus 1.38 (95% CI, 1.32-1.44). White race (5.47) and male sex (8.00) had the highest incidences of HPV-positive OPSCC, with a unimodal age incidence distribution peaking at ages 60 to 64 years (27.23). HPV positivity was associated with lower cancer-specific mortality than HPV-negative disease for OPSCC [adjusted HR (aHR), 0.40; P < 0.001], but not non-OPSCC (aHR, 1.08; P = 0.81), P interaction = 0.002. CONCLUSIONS: The U.S. incidence of HPV-positive OPSCC was 4.62 per 100,000 persons. Most cases were found in white male patients younger than 65 years, where it represents the sixth most common incident nonskin cancer. The favorable prognosis associated with HPV appears to be limited to the oropharynx. IMPACT: This large population-based epidemiologic assessment of the U.S. population defines the incidence and demographic burden of HPV-positive OPSCC.

Guide design in virtual planning for scapular tip free flap reconstruction.

BACKGROUND: Virtual surgical planning (VSP), intraoperative cutting guides and stereolithographic models, provides the head and neck reconstructive surgeon with powerful tools for complex reconstruction planning. Despite its use in fibular osteocutaneous reconstruction, application to the scapular tip has not been as widely reported. METHODS: From 2013 to 2014, four cases of either mandibular or maxillary reconstruction were completed with the scapular tip osseous free flap. All four cases underwent preoperative VSP with patient-specific guide design. RESULTS: Patient-specific guides were generated for scapular tip harvest. Guide placement was improved using a stabilizing flange and bracket design. With minimal disruption of the overlying periosteum a wedge osteotomy was successfully implemented in one case. CONCLUSIONS: Unlike the fibula and iliac crest donor sites, the scapular tip has overlying muscle attachments that make intraoperative osteotomies challenging. Attention to key aspects of scapular anatomy, including the fibrous tip and extensive overlying muscle, permits effective guide design. LEVEL OF EVIDENCE: 4.

TMEM16A/ANO1 suppression improves response to antibody-mediated targeted therapy of EGFR and HER2/ERBB2.

TMEM16A, a Ca2+ -activated Cl- channel, contributes to tumor growth in breast cancer and head and neck squamous cell carcinoma (HNSCC). Here, we investigated whether TMEM16A influences the response to EGFR/HER family-targeting biological therapies. Inhibition of TMEM16A Cl- channel activity in breast cancer cells with HER2 amplification induced a loss of viability. Cells resistant to trastuzumab, a monoclonal antibody targeting HER2, showed an increase in TMEM16A expression and heightened sensitivity to Cl- channel inhibition. Treatment of HNSCC cells with cetuximab, a monoclonal antibody targeting EGFR, and simultaneous TMEM16A suppression led to a pronounced loss of viability. Biochemical analyses of cells subjected to TMEM16A inhibitors or expressing chloride-deficient forms of TMEM16A provide further evidence that TMEM16A channel function may play a role in regulating EGFR/HER2 signaling. These data demonstrate that TMEM16A regulates EGFR and HER2 in growth and survival pathways. Furthermore, in the absence of TMEM16A cotargeting, tumor cells may acquire resistance to EGFR/HER inhibitors. Finally, targeting TMEM16A improves response to biological therapies targeting EGFR/HER family members.

Successful Implementation of a Clinical Care Pathway for Management of Epistaxis at a Tertiary Care Center.

OBJECTIVE: We compare the management of patients with severe epistaxis before and after the implementation a clinical care pathway (CCP) to standardize care, minimize hospital stay, and decrease cost. STUDY DESIGN: Single prospective analysis with historical control. SETTING: Tertiary academic hospital. SUBJECTS AND METHODS: Patients treated for epistaxis between October 2012 to December 2013 were compared with a prospective analysis of patients treated for severe epistaxis after implementation of a CCP from June 2014 to February 2015. Severe epistaxis was defined as nasal bleeding not able to be controlled with local pressure, topical vasoconstrictors, or simple anterior packing. RESULTS: Severe epistaxis was similar in the pre- and post-CCP cohorts: 24.7% (n = 42) vs 18.9% (n = 22), respectively. Implementation of early sphenopalatine artery ligation resulted in decreased number of days packed (3.2 ± 1.6 to 1.4 ± 1.6; P = .001), decreased hospital stay (5.2 ± 3.9 to 2.1 ± 1.3 days; P < .001), an increased percentage of sphenopalatine artery ligations (31.0% vs 54.5%; P = .035), admission to an appropriate hospital location with access to key resources (41.7% vs 83.3%; P = .007), and decreased overall cost of hospitalization by 66% ($9435 saved). No patients received embolization after the CCP was implemented. CONCLUSIONS: Implementation of a CCP decreased hospital stay and days of packing, facilitated definitive care in patients with severe epistaxis, improved patient safety, and decreased cost. The results of this study can serve as a model for the management of severe epistaxis and for future quality improvement measures.

Oncologic outcomes of surgically treated early-stage oropharyngeal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to characterize oncologic outcomes in early (T1-T2, N0) and intermediate (T1-T2, N1) oropharyngeal squamous cell carcinoma (SCC) after surgery. METHODS: Patients with oropharyngeal SCC treated with surgery were identified from 2 academic institutions. RESULTS: Of 188 patients, 143 met the inclusion criteria. Eighty-six (60%) had T1 to T2 N0 and 57 (40%) had T1 to T2 N1 disease. Sixty-five patients (45%) underwent a robotic-assisted resection, whereas the remaining had transoral (n = 60; 42%), mandible-splitting (n = 11; 8%), or transhyoid approaches (n = 7; 5%). Human papillomavirus (HPV) status was known for 97 patients (68%), and 54 (55%) were HPV positive. Three-year recurrence-free survival (RFS) was 82% (95% confidence interval [CI] = 0.75-0.89). Since 2008, HPV infection was protective of recurrence (log-rank p = .0334). A single node did not increase the risk of recurrence (p = .467) or chance of a second primary (p = .175). CONCLUSION: Complete surgical resection is effective therapy for early and intermediate oropharyngeal SCC. HPV-negative patients were at increased risk for locoregional recurrence or second primary disease. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1471, 2016.

Intraoral midline mandibulotomy improves laryngeal access for transoral resection of laryngeal cancer.

Intraoral midline mandibulotomy is a technique that can be used to increase exposure for transoral endoscopic laser microsurgery (TLS). We describe the case of a 51 year old male with persistent T1 glottic carcinoma. At initial diagnosis, he had been referred for curative radiotherapy as laryngeal access was not sufficient for TLS. For treatment of his recurrence, we describe the technique of performing a midline mandibular osteotomy to improve access to the larynx allowing for safe and effective transoral endoscopic laser microsurgery. Surgical access to the larynx was greatly improved, and we were able to perform TLS in a case that would have otherwise not been amenable to TLS. An intraoral midline mandibulotomy can improve access to the larynx and allow for successful transoral resection of laryngeal cancer in patients with otherwise inaccessible tumors.

Using 3D computer planning for complex reconstruction of mandibular defects.

For complex reconstruction of osseous defects of the head and neck, three-dimensional (3D) computer planning has been available for over 20 years. However, despite its availability and recent refinements, it is a technology that has not been widely adopted. While 3D computer planning has been proposed to improve surgical precision, reduce operating time and enhance functional outcomes, the objective evidence supporting these claims is limited. Here we review the recent literature that supports the use of 3D computer planning for complex osseous defects of the mandible. We highlight a case example where 3D modeling played a critical role, particularly during the virtual surgical planning stage. Finally, we propose that routine post-operative 3D analysis become an essential element in determining operative success. Critical evaluation of outcomes will better define its use in complex reconstruction of osseous defects.

Quantification of maxillary sinus accessibility via a middle meatal antrostomy.

OBJECTIVE: To quantify maxillary sinus volume and mucosal surface area (SA) that is accessible endoscopically via a middle meatal antrostomy and to explore the financial implications of using multiple disposable instruments for this procedure. METHODS: Eight cadaver maxillary sinuses configured with image guidance software were evaluated. In each sinus, a standard middle meatal antrostomy was created, through which curved microdebriders of 15, 40, 70, and 120° were placed. The SA and volume of the region accessible by each microdebrider tip was calculated. RESULTS: Mean maxillary sinus volume was 16.5 ± 2.5 cm(3) and mean SA was 31.0 ± 2.3 cm(2). The 15, 40, 70 and 120° microdebriders accessed an average of 10, 25, 41, and 66%, respectively, of the SA, and of 2, 9, 17, and 36%, respectively, of the volume. There was a trend toward improved accessibility of the superior half versus the inferior half of the maxillary sinus. When instruments of different degrees were combined to maximize accessibility, 81% of the SA of the sinus could be accessed. CONCLUSIONS: Microdebriders with increasing curvatures allowed for greater access of the maxillary sinus mucosa through an middle meatal antrostomy. No single microdebrider curvature or combination of curvatures reached the entirety of the maxillary sinus wall. Knowledge about the area of reach for these blades can lead to lower per procedure costs.

Adenosquamous carcinoma of the head and neck: Molecular analysis using CRTC-MAML FISH and survival comparison with paired conventional squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Adenosquamous carcinoma (ASC) is a rare variant of head-and-neck squamous cell carcinoma (HNSCC) generally thought to be uniformly aggressive with poor prognosis. However, it remains unknown how overall survival compare with conventional HNSCC. Here we report for the first time that ASC does not necessarily indicate a worse prognosis than conventional HNSCC. STUDY DESIGN: Case-control retrospective study. METHODS: Forty-two primary tumors of the head and neck, treated with curative intent, were identified. Next, 2:1 matching of HNSCC was performed using the following matching criteria: gender, site, pathologic tumor stage, and pathologic node stage. Successful matching was performed for 32 of 42 tumors. Additionally, 20 samples were sent for break-apart FISH testing to evaluate for the presence of the CRTC1-MAML2 translocation. RESULTS: There was a 1.8:1 male to female ratio, with a mean age of 62 years (range 38-84). The layrnx was the most common site (26%), followed by oropharynx (24%), oral cavity (19%), and sinonasal (17%). Kaplan-Meier analysis of adenosquamous and matched HNSCC showed similar survival curves. Median survival times for ASC and HNSCC were 4 and 6 years, respectively. A random-effects Cox model with Gamma frailty revealed no statistical difference between the two groups (P=0.25). All cases of ASC were negative for the CRTC1-MAML2 translocation. CONCLUSION: This study directly compares primary ASC with HNSCC. No difference in overall survival was detected in contradistinction to the previously thought uniformly poor prognosis. We also highlight the importance of the CRTC1-MAML2 translocation in distinguishing ASC from mucoepidermoid carcinoma. LEVEL OF EVIDENCE: 3b.

Silent plateau potentials, rhythmic bursts, and pacemaker firing: three patterns of activity that coexist in quadristable subthalamic neurons.

Subthalamic neurons display uncommon intrinsic behaviors that are likely to contribute to the motor and cognitive functions of the basal ganglia and to many of its disorders. Here, we report silent plateau potentials in these cells. These plateau responses start with a transient burst of action potentials that quickly diminish in amplitude because of spike inactivation and current shunt. The resulting interruption of spiking reveals a stable depolarization (up state) that clamps the cell membrane potential near -40 mV for several seconds. These plateau potentials coexist in single subthalamic neurons with more familiar patterns of burst and pacemaker firing. Within a narrow range of baseline membrane potentials (-67 to -60 mV), depolarization abruptly switches single cells from bistable to rhythmic bursts or tonic firing modes, thus selecting entirely distinct algorithms for integrating cortical and pallidal synaptic inputs.