Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer.

The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined HNSCC subtypes by their malignant and stromal composition and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.

Cell-free human papillomavirus DNA kinetics after surgery for human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). METHODS: To determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24 hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45. RESULTS: In patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1 copy/mL by POD 1 (n = 8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350 copies/mL) and remained elevated until adjuvant treatment (n = 3/3). Patients with intermediate POD 1 ctHPVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n = 9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1 mm (P = .0481) and with increasing lymph nodes involved (P = .0453) and were further associated with adjuvant treatment received (P = .0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2 months earlier than clinical detection. CONCLUSIONS: POD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. LAY SUMMARY: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1 day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.

Multispecialty surgical management of carotid body tumors in the modern era.

OBJECTIVE: The objective of this study was to assess the perioperative and long-term outcomes of carotid body tumor (CBT) resection with a multispecialty (head and neck surgery/vascular surgery) approach. METHODS: Our institutional data registry was queried for Current Procedural Terminology codes (60600, 60605) pertaining to CBT excision. These patient records and operative reports were individually reviewed to determine laterality, preoperative tumor embolization, operative time, estimated blood loss, need for intraoperative transfusion, intraoperative electroencephalogram changes, intraoperative division of the external carotid artery, carotid artery repair, resection of the carotid bifurcation, tumor volume, final pathology, cranial nerve injury, stroke, death, and clinical or radiographic evidence of recurrence. RESULTS: From 1996 to 2018, 74 CBT resections were identified in 68 patients (41 [60%] females; mean age, 50.83 years). The mean tumor volume was 9.92 ± 14.26 cm3 (range, 0.0250-71.0627 cm3). Embolization was performed by a neurointerventional specialist in 27 CBT resections (36%) based on size (embolization 14.27 ± 16.84 cm3 vs 7.17 ± 11.86 cm3; P = .063) and superior extension. This practice resulted in one asymptomatic vertebral dissection, which postponed the surgery. There was a trend toward greater blood loss in the embolization group (embolization 437 ± 545 mL vs 262 ± 222 mL; P = .17); however, no transfusions were required in any patient. The mean operative time was also significantly longer in the embolization group (198.33 ± 61.13 minutes vs 161.5 ± 55.56 minutes; P = .03). Three resections had reversible intraoperative electroencephalogram changes, one of which occurred during carotid clamping. These changes resolved with shunting. Eight external carotid resections (11%) and 6 carotid reconstructions (8.1%; two primary, two patch, and two primary anastomosis) were required. Malignancy was identified in four tumors (5.4%), accounting for four of the six carotid reconstructions. There were no postoperative cranial nerve injuries, no strokes, no reexplorations, and no deaths. One patient developed transient dysphagia from pharyngeal tumor infiltration. Long-term follow-up (mean, 43 ± 54 months), available in 61 of the 68 patients (89.7%), revealed three (4.4%) recurrences. CONCLUSIONS: This large, single-institution series demonstrates that a multispecialty team combining two surgical skill sets for the treatment of this rare, challenging condition yields unparalleled low complication rates with short operative times. This approach, including long-term surveillance for recurrent disease, should be considered to optimize outcomes of CBT resection.

Nasal and paranasal sinus mucosal melanoma: Long-term survival outcomes and prognostic factors.

OBJECTIVE: To determine prognostic factors and survival patterns for different treatment modalities for nasal cavity (NC) and paranasal sinus (PS) mucosal melanoma (MM). METHODS: Patients from 1973 to 2013 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier method and multivariable cox proportional hazard modeling were used for survival analyses. RESULTS: Of 928 cases of mucosal melanoma (NC = 632, PS = 302), increasing age (Hazard Ratio [HR]:1.05/year, p < 0.001), T4 tumors (HR: 1.81, p = 0.02), N1 status (HR: 6.61, p < 0.001), and PS disease (HR: 1.50, p < 0.001) were associated with worse survival. Median survival length was lower for PS versus NC (16 versus 26 months, p < 0.001). Surgery and surgery + radiation therapy (RT) improved survival over non-treatment or RT alone (p < 0.001). Adding RT to surgery did not yield a survival difference compared with surgery alone (p = 0.43). Five-year survival rates for surgery and surgery + RT were similar, at 27.7% and 25.1% (p = 0.43). CONCLUSION: Surgery increased survival significantly over RT alone. RT following surgical resection did not improve survival.

Submental flap practice patterns and perceived outcomes: A survey of 212 AHNS surgeons.

OBJECTIVES: To describe American Head and Neck Society (AHNS) surgeon submental flap (SMF) practice patterns and to evaluate variables associated with SMF complications. METHODS: The design is a cross-sectional study. An online survey was distributed to 782 AHNS surgeons between 11/11/16 and 12/31/16. Surgeon demographics, training, practice patterns and techniques were characterized and evaluated for associations with frequency of SMF complications. RESULTS: Among 212 AHNS surgeons, 108 (50.9%) reported performing SMFs, of whom 86 provided complete responses. Most surgeons who performed the SMF routinely reconstructed oral cavity defects with the flap (86.1%, n = 74). Thirty-seven surgeons (43.0%) experienced "very few" complications with the SMF. Surgeons who practiced in the United States versus internationally (p = 0.003), performed more total career SMFs (p = 0.02), and routinely reconstructed parotid and oropharyngeal defects (p = 0.04 and p < 0.001) with SMFs were more frequently perceived to have "very few" complications. SMF surgeons reported more perceived complications with the SMF compared to pectoralis major (p = 0.001) and radial forearm free flaps (p = 0.01). However, similar perceived complications were reported between all three flaps when surgeons performed >30 SMF. Among 94 surgeons not performing SMFs, 71.3% had interest in a SMF training course. CONCLUSIONS: Practice patterns of surgeons performing SMFs are diverse, although most use the flap for oral cavity reconstruction. While 43% of surgeons performing the SMF reported "very few" complications, overall complication rates with the SMF were higher compared to other flaps, potentially due to limited experience with the SMF. Increased training opportunities in SMF harvest and inset are indicated.

Predictive factors for prolonged operative time in head and neck patients undergoing free flap reconstruction.

PURPOSE: Defining the predictive factors associated with prolonged operative time may reduce post-operative complications, improve patient outcomes, and decrease cost of care. The aims of this study are to 1) analyze risk factors associated with prolonged operative time in head and neck free flap patients and 2) determine the impact of lengthier operative time on surgical outcomes. METHODS: This retrospective cohort study evaluated 282 head and neck free flap reconstruction patients between 2011 and 2013 at a tertiary care center. Perioperative factors investigated by multivariate analyses included gender, age, American Society of Anesthesiologists class, tumor subsite, stage, flap type, preoperative comorbidities, and perioperative hematocrit nadir. Association was explored between operative times and complications including flap take back, flap survival, transfusion requirement, flap site hematoma, and surgical site infection. RESULTS: Mean operative time was 418.2 ± 88.4 (185-670) minutes. Multivariate analyses identified that ASA class III (beta coefficient + 24.5, p = .043), stage IV tumors (+34.8, p = .013), fibular free flaps (-44.8, p = .033 for RFFF vs. FFF and - 67.7, p = .023 for ALT vs FFF) and COPD (+36.0, p = .041) were associated with prolonged operative time. History of CAD (-43.5, p = .010) was associated with shorter operative time. There was no statistically significant association between longer operative time and adverse flap outcomes or complications. CONCLUSION: As expected, patients who were medically complex, had advanced cancer, or underwent complex flap reconstruction had longer operative times. Surgical planning should pay special attention to certain co-morbidities such as COPD, and explore innovative ways to minimize operative time. Future research is needed to evaluate how these factors can help guide planning algorithms for head and neck patients.

The Difficult Secondary Tracheoesophageal Puncture: A Technique for Safe Insertion.

BACKGROUND/AIMS: The tracheoesophageal prothesis (TEP) has become the primary modality for laryngeal communication after total laryngectomy due to high success rates, minimal morbidity, and more natural pulmonary driven speech. Fibrosis, kyphosis, and post-radiation contracture may preclude TEP placement through rigid esophagoscopy, and certain patients may not tolerate an in-office awake procedure. For such patients, a technique for flexible esophageal stenting and TEP placement is necessary. METHODS: We performed a retrospective review of 3 patients who underwent TEP placement through endotracheal-tube esophageal stenting at the Massachusetts Eye and Ear Infirmary. RESULTS: All 3 patients underwent laryngectomy after prior chemoradiotherapy for laryngeal cancer with resulting neck contracture and fibrosis preventing rigid esophagoscopy. All patients underwent successful TEP placement through endotracheal stenting without complication and developed excellent tracheoesophageal speech. Specific technical details are highlighted. CONCLUSIONS: In patients with anatomical constraints preventing traditional TEP placement through rigid esophagoscopy, fiberoptic guidance through an endotracheal tube stent provides a safe and efficient approach for TEP placement.

Mucoepidermoid Carcinoma of the Parotid: Very Close Margins and Adjuvant Radiotherapy.

BACKGROUND/AIMS: The importance of adjuvant radiotherapy in patients with close margin resections for mucoepidermoid carcinoma of the parotid gland remains unclear. METHODS: Patients who underwent parotidectomy for mucoepidermoid carcinoma with or without adjuvant radiotherapy at a single academic tertiary care center from 2000 to 2014 were identified. Included patients had negative but close (≤2 mm) surgical margins without other high-risk histopathological factors including advanced T-stage, positive nodal disease, lymphovascular or perineural invasion, or high-grade histology. RESULTS: Nineteen patients were identified, of whom 15 (79%) were observed postoperatively, while 4 (21%) underwent adjuvant radiotherapy. There were no significant differences in extent of parotidectomy, elective neck dissection, T staging, or tumor size between patients who were observed and those undergoing adjuvant radiation. There were no locoregional or distant recurrences in any patients at a mean follow up 74.3 months. Patients undergoing adjuvant radiation, however, had significantly more intermediate-grade as compared to low-grade histology (75% vs. 13%, difference 62%, 95% CI 4% to 100%). CONCLUSIONS: Patients with negative but close (≤2 mm) surgical margins without other high-risk histopathological factors have excellent long-term locoregional control with surgery alone. The effects of adjuvant radiotherapy for those who have intermediate-grade disease remain uncertain.

Composite Nasoseptal Flap for Palate Reconstruction.

Palatal fistulae represent a pathological connection from the oral cavity through the hard or soft palate to the nasal cavity and can present a significant reconstructive dilemma. Surgical correction of palatal fistulae is often limited by prior treatment, including ablative procedures and radiotherapy, or previous reconstructive attempts. In light of these challenges, the nasoseptal flap represents an excellent adjacent source of vascularized tissue which may be suitable for palatal fistula repair with minimal donor site morbidity, low associated risks, and a short recovery period. The purpose of this study was to fully understand the potential utility of this reconstructive option, including the ability to harvest a composite flap including both septal cartilage and contralateral mucoperichondrium. In this single institution prospective study consisting of a series of 5 cadaver dissections, primary outcome measures were the anterior reach of the flap as compared to the anterior nasal spine and the size of the palatal defect that the nasoseptal flap could be used to successfully reconstruct. Composite flaps were successfully harvested in continuity with a disc of septal cartilage and contralateral mucoperichondrium, providing structural integrity to the reconstruction and the ability to anchor the flap to the native hard palate mucosa. The nasoseptal flap's maximum anterior reach was within 2.0 cm (standard deviation of 0.1 cm) from the anterior nasal spine and could reliably reconstruct palate defects of 2.5 cm or less. The nasoseptal flap provides a viable regional option for reconstructing defects of the hard palate. Prospective clinical trials are needed to investigate long-term reconstructive and functional outcomes of the composite nasoseptal flap in palatal reconstruction.

National trends in inpatient parotidectomy: A fourteen-year retrospective analysis.

PURPOSE: Operating room (OR) procedures represent one quarter of hospitalizations, yet OR-related stays account for nearly 50% of hospital costs. Understanding trends in inpatient parotidectomy, associated charges, and key outcomes including length of stay is imperative in the era of evolving health reform. MATERIALS AND METHODS: The Nationwide Inpatient Sample (NIS) was queried for patients who underwent inpatient parotidectomy (ICD9-CM procedure code 26.31 and 26.32) between 2001 and 2014. Patient demographics, co-morbidities, hospital characteristics and outcomes including length of stay (LOS) and hospital charges were assessed. RESULTS: A total of 66,914 parotidectomies were performed in the inpatient setting between 2001 and 2014. The volume of inpatient parotidectomy decreased steadily by 48% over the study period (7375 procedures in 2001 to 3530 procedures in 2014). Average LOS increased from 1.8 days in 2001 to 2.5 days in 2014. Total charges increased from $17,072 in 2001 to $55,929 in 2014. In 2014, the majority of inpatient parotidectomies were performed in a teaching hospital (87%) and among patients who were older than 65 years (48.1%). In 2001, only 35.4% of patients who underwent parotidectomy were older than age 65, and relatively fewer surgeries were performed at teaching hospitals (63.1%). CONCLUSIONS: Inpatient parotidectomy in the United States has evolved over the past fourteen years. Notable trends include a nearly 50% reduction of inpatient surgery, doubling in LOS, tripling of hospital charges and predominance of elderly patients with malignant disease. These results provide insight into inpatient parotid lesion management.

3D-printed tracheoesophageal puncture and prosthesis placement simulator.

OBJECTIVES: A tracheoesophageal prosthesis (TEP) allows for speech after total laryngectomy. However, TEP placement is technically challenging, requiring a coordinated series of steps. Surgical simulators improve technical skills and reduce operative time. We hypothesize that a reusable 3-dimensional (3D)-printed TEP simulator will facilitate comprehension and rehearsal prior to actual procedures. METHODS: The simulator was designed using Fusion360 (Autodesk, San Rafael, CA). Components were 3D-printed in-house using an Ultimaker 2+ (Ultimaker, Netherlands). Squid simulated the common tracheoesophageal wall. A Blom-Singer TEP (InHealth Technologies, Carpinteria, CA) replicated placement. Subjects watched an instructional video and completed pre- and post-simulation surveys. RESULTS: The simulator comprised 3D-printed parts: the esophageal lumen and superficial stoma. Squid was placed between components. Ten trainees participated. Significant differences existed between junior and senior residents with surveys regarding anatomy knowledge(p<0.05), technical details(p<0.01), and equipment setup(p<0.01). Subjects agreed that simulation felt accurate, and rehearsal raised confidence in future procedures. CONCLUSIONS: A 3D-printed TEP simulator is feasible for surgical training. Simulation involving multiple steps may accelerate technical skills and improve education.

Tip-on-Tip Scapular (TOTS) Flap for Reconstruction of Combined Palatectomy and Rhinectomy Defects.

Combination anterior palatectomy and rhinectomy defects result in complete loss of midface and nasal support and present a significant reconstructive challenge. A novel use of the scapular tip free flap-the tip-on-tip scapula flap-was developed to provide both palatal repair and restoration of intrinsic nasal support. The scapular tip bone is split into a large proximal segment for the anterior palate and a smaller distal bone segment for nasal framework reconstruction. Two patients undergoing reconstruction of both total palatectomy and partial rhinectomy defects at a single academic tertiary care center were reviewed. In both cases, the larger proximal segment of the scapular tip flap, used for the palatal defect, was based on the angular artery. The distal bone segment, used for nasal framework repair, was vascularized in one of two ways. In the osteomyogenous serratus-scapular tip variant, the serratus arterial branch provided periosteal blood supply to the bone through a cuff of attached serratus muscle. In the split-scapular tip variant, the periosteum of the scapular tip was kept in continuity with the distal bone segment and fed through the periosteal vascular arcade from the angular branch. In both patients, the distal bone segment demonstrated robust intraoperative vascularity and both flaps healed without complication. Both patients were able to resume oral diets and had good nasal breathing.

Repair of complex pharyngocutaneous fistula using a staged temporoparietal fascial flap.

INTRODUCTION: PCF is the most common major complication after salvage total laryngectomy (TL), especially for previously irradiated patients with laryngeal or hypopharyngeal cancer. METHODS/RESULTS: A 65-year-old woman presented with recurrent bilateral supraglottic SCC requiring salvage TL 5.5years after initial T1N0M0 epiglottic SCC resection. Her post-operative course was complicated by PCF development one month post-operatively and surgical fistula closure was delayed for adjuvant chemoradiotherapy. The fistula persisted despite local wound therapy, several primary closures, pectoralis flap reconstruction with multiple revisions, and extensive hyperbaric oxygen treatments. Given her prior history, she underwent a staged right temporoparietal fascial flap reconstruction for persistent complex fistula, with second-stage flap takedown and complete inset of the TPFF skin island into the PCF. CONCLUSION: This case demonstrates the utility of staged TPFF in complex PCF repair, with minimal morbidity, especially in a patient with prior irradiation and flap use that complicates tissue availability.

A Collaborative Clinical Learning Initiative to Improve Perioperative Head and Neck Cancer Care.

Introduction The care of head and neck cancer patients is complex and requires the expertise of professionals from across the allied health spectrum. Perioperative nurses play a crucial role in ensuring that head and neck cancer patients receive high-quality care, but are not afforded the opportunity to witness preoperative and postoperative management decisions. We hypothesized that shadowing a senior head and neck surgeon in an outpatient setting would result in improved understanding of clinical decision making and pathophysiology with the ultimate goal of improving patient care. Methods Nurses who specialize in perioperative care at the author's home institution spent one day in the outpatient clinic with the senior author. Educational goals included improving understanding of clinical decision making and pathophysiology and answering any questions participants posed. A structured questionnaire that included Likert-type scale questions was given to all participants to assess whether the initiative achieved its goals. Results Twenty-seven perioperative nurses participated in the exercise. Twenty-five of the 27 participants (92%) agreed that the experience would allow them "to provide better care to head and neck patients,", and 24 (89%) agreed that the experience helped improve "[their] understanding of the complex nature of4he care needed for head and neck patients." All participants would recommend the experience to a colleague. Conclusion Multidisciplinary care forms the foundation of head and neck cancer care, and therefore collaboration is an essential component for achieving high-quality care. Perioperative health professionals form a crucial part of the broader multidisciplinary team. We found that an interprofessional educational exercise between a senior surgeon and perioperative nurses resulted in an improved degree of comfort in the care and understanding of head and neck cancer. Future efforts should attempt to better understand the effect of similar collaborations on team dynamics and patient outcomes.

Placement of a 16-French voice prosthesis at the time of secondary tracheoesophageal voice restoration.

PURPOSE: Tracheoesophageal voice restoration (TEVR) has traditionally been described with fistula tract creation, catheter placement, and prosthesis placement. Prosthesis placement at the time of tracheoesophageal puncture (TEP) utilizing 20-French prostheses has been previously described. Smaller initial prostheses may allow fluent speech with reduced long-term complications, such as widening of the fistula and peri-prosthesis leakage. This study evaluates the safety and efficacy of the 16-French prostheses placement at the time of secondary TEP. METHODS: All cases of 16-French tracheoesophageal voice prosthesis (TEVP) placement at the time of secondary TEP were reviewed from 1/2011 through 12/2013 at a large academic medical center. Perioperative complications attributable to device placement were recorded, including inability to place prosthesis, intraoperative complications, post-operative infection, prosthesis dislodgement, prosthesis leakage, and inability to obtain voice. RESULTS: Twenty-one patients received placement of a 16-French TEVP at the time of secondary TEP. All prostheses were placed without intraoperative complications. The proportion of patients who had minor complications within the first postoperative month was 23.8%, including leakage through the prosthesis (3 of 21), granulation tissue near the prosthesis (1 of 21), retained sheath (1 of 21) and prosthesis displacement (1 of 21). Leakage and displacement were addressed with change and replacement, respectively. Fluent voicing was achieved in 85.7% patients, with a median time to voicing of 18.5days. CONCLUSIONS: Placement of 16-French TEVPs is effective and safe, with an acceptable rate of minor complications attributable to the prosthesis. Therefore, a smaller prosthesis may be primarily placed at the time of secondary TEP and is our preference.

Modified Technique for Retrograde Placement of the Tracheoesophageal Voice Prosthesis in the Office.

For total laryngectomy patients with tortuous tracheoesophageal puncture (TEP) tracts, anterograde placement of the voice prosthesis can be challenging. This article describes an updated and straightforward technique for in-office retrograde placement of the voice prosthesis in patients with such challenging TEP tracts. Laryngoscope, 2024.

Salvage surgery for recurrent or residual hypopharyngeal squamous cell carcinoma: A systematic review.

BACKGROUND: This systematic review aggregates the data of studies that include site-specific analyses of patients undergoing salvage surgery for residual or recurrent hypopharyngeal squamous cell carcinoma. METHODS: The primary outcomes are disease-free, disease-specific, and overall survival (DFS, DSS, and OS, respectively). Secondary outcomes include complications and postoperative feeding requirements. RESULTS: Fifteen studies met the inclusion criteria with a total of 442 patients. Two-year DFS is reported from 30.0 to 50.0% and 5-year DFS ranges from 15.0 to 57.1%. Five-year DSS ranges from 28.0 to 57.1%. Two-year OS ranges from 38.8 to 52.0% and 5-year OS ranges from 15.5 to 57.1%. Complications include pharyngocutaneous fistula (0.0-71.4%), carotid artery rupture (2.9-13.3%), and stomal stenosis (4.2-20.0%). Complete oral feeding achieved following surgery ranges from 61.9 to 100.0%, while complete gastrostomy tube dependence ranges from 0.0 to 28.6%. CONCLUSIONS: Salvage surgery for residual or recurrent hypopharyngeal squamous cell carcinoma has a relatively high complication rate and should be offered to patients with the understanding of a guarded prognosis.