InCISE: Instrument for Comprehensive Incisional and Surgical Evaluation.

OBJECTIVE: The evaluation of healing after head and neck surgery is currently qualitative and non-standardized, limiting the quality of surgical healing assessments in clinical and research settings. We sought to develop an objective, standardized wound assessment score, and hypothesize that a reliable instrument can be developed to evaluate head and neck surgical wounds. METHODS: A prospective cohort study was conducted in a tertiary-care, academic head and neck surgery practice. Patients undergoing head and neck surgery were enrolled. A digital photograph protocol was developed for evaluating healing surgical wounds. A panel of experts developed and refined a wound healing score and established reliability, reproducibility, internal consistency, and validity of the score. RESULTS: InCISE: Instrument for comprehensive incisional and surgical evaluation was created. The utility of our wound healing score was assessed using classical test theory. We performed the major steps of establishing reliability in head and neck surgeons: (1) internal consistency (Cronbach's α = 0.81), (2) inter-observer reliability (intra-class correlation = 0.76), and (3) intra-rater reliability (intra-class correlation = 0.87), and content validity (through focus groups). Our composite measure was found to have strong internal consistency, inter-rater reliability, and intra-rater reliability. Preliminary work suggests criterion validity via associations with physical health related quality of life (SF-12). CONCLUSION: A wound healing score for head and neck surgery, InCISE, has been developed and is reliable, reproducible, and consistent. Although content validity is present and criterion validity is suggested, work continues to establish validity in this instrument to allow for expanded clinical and research use. LEVEL OF EVIDENCE: NA Laryngoscope, 133:2166-2173, 2023.

Characterization of Baseline Temperature Characteristics Using Thermography in The Clinical Setting.

BACKGROUND: Thermography is a diagnostic method based on the ability to record infrared radiation emitted by the skin and is unique in its ability to accurately show physiological and/or pathological cutaneous temperature changes in a non-invasive way. This method can be used to indirectly assess changes or impairments in cutaneous perfusion. Significant technological advancements have allowed thermography to be more commonly utilized by clinicians, yet a basic consensus of patient characteristics that may affect temperature recordings is not established. MATERIALS AND METHODS: We evaluated cutaneous temperature in a cohort of outpatients to understand what factors, including tobacco use and other high-risk characteristics, contribute to cutaneous tissue perfusion as measured by thermography. Participants were prospectively enrolled if they were a combustible cigarette smoker, an electronic cigarette (e-cigarette) user, or a never smoker. Standardized thermographic images of the subject's facial profiles, forearms, and calves were taken and demographic characteristics, medical comorbidities, and tobacco product use were assessed. These variables were statistically tested for associations with temperature at each anatomic site. RESULTS: We found that gender had a significant effect on thermographic temperature that differed by anatomic site, and we found a lack of significant difference in thermographic temperature by race. Our regression analysis did not support significant differences in thermographic temperatures across smoking groups, while there was a trend for decreased perfusion in smokers relative to non-smokers and e-cigarette users relative to non-smokers. CONCLUSION: Thermographic imaging is a useful tool for clinical and research use with consideration of sex and other perfusion-affecting characteristics.

Excessive inflammation portends complications: Wound cytokines and head and neck surgery outcomes.

OBJECTIVES/HYPOTHESIS: Postoperative wound-healing complications can be devastating after head and neck surgery. Whereas many patients are expected to have more complications, few objective indicators predict these poorer outcomes. We evaluated wound healing in this population by studying the association between biomarkers and surgical outcomes. STUDY DESIGN: Prospective cohort study. METHODS: A study was performed of head and neck surgery patients at our tertiary care center, from 2012 to 2015. Postsurgical drain fluid was collected 24 hours postoperatively. Biomarkers of wound healing were assayed. These included interleukin (IL)-1, -6, and -8; tumor necrosis factor (TNF)-α; transforming growth factor ß; epidermal growth factor; fibroblast growth factor; C-reactive protein (CRP); vascular endothelial growth factor (VEGF); soluble fms-like tyrosine kinase-1; and placental growth factor. Patient characteristics and clinical outcomes were recorded. Two-sample, two-sided t tests evaluated differences in cytokine levels by clinical outcomes. RESULTS: Twenty-eight patients were enrolled with drain fluid collection. IL-1ß, IL-8, and matrix metalloproteinase (MMP)-9 were significantly higher in the wound fluid of subjects with complications. Patients with longer length of stay in days had statistically higher levels of TNF-α (P = .011), IL-6 (P = .021), IL-8 (P = .004), IL-1ß (P = .004), MMP-1 (P = .002), MMP-2 (P = .022), VEGF-A (P = .038), and CRP (P < .001), and longer length of stay was associated with malignancy. There were no statistically significant associations between baseline clinical characteristics and post-operative complications. CONCLUSIONS: In this head and neck surgical cohort, higher IL-1ß, IL-8, and MMP-9 levels in wound fluid were associated with postoperative complications, and elevation of multiple proinflammatory cytokines was associated with longer length of stay. These findings suggest excessive inflammation in early wound healing may portend poorer clinical outcomes after head and neck surgery. LEVEL OF EVIDENCE: 2b Laryngoscope, 129:E238-E246, 2019.

Tobacco exposure and wound healing in head and neck surgical wounds.

OBJECTIVE: Smoking impairs wound healing, yet the underlying pathophysiological mechanisms are unclear. We evaluated tobacco-altered healing in head and neck surgery by studying the association between biomarkers and tobacco exposure, as well as cutaneous perfusion by smoking status. STUDY DESIGN: Prospective cohort study, tertiary/academic care center, 2011 to present. METHODS: Patients who required head and neck surgery were enrolled prospectively. Postsurgical drain fluid was collected 24 hours postoperatively. Biomarkers associated with postulated mechanisms of smoking-impaired healing were assayed. These included interleukin-1, -6, and -8; tumor necrosis factor- alpha; transforming growth factor-beta; epidermal growth factor (EGF); basic fibroblastic growth factor (bFGF); C-reactive protein; vascular endothelial growth factor; soluble FMS-like tyrosine kinase-1 (sFLT-1); and placental growth factor. Tobacco exposure and clinical outcomes were recorded. Two sample two-sided t tests evaluated the differences in cytokine levels by tobacco exposure. In a second cohort, cutaneous vascular assessment via indocyanine green angiography was compared by smoking status. RESULTS: Twenty-eight patients were enrolled with drain fluid collection. Twenty-one subjects were current/former smokers, whereas seven were never smokers. EGF was higher in never smokers than smokers in a statistically significant manner (P = 0.030). Likewise, sFLT-1 was significantly higher in never smokers (P = 0.011). Cutaneous angiography revealed nonsmokers to have significantly higher cutaneous perfusion than smokers. CONCLUSION: In this head and neck surgical cohort, significantly higher EGF and sFLT-1 levels in wound fluid were associated with never smoking, suggesting that smoking has adverse effects on the inflammatory phase of wound healing. Cutaneous angiography supports the detrimental effect of smoking on skin perfusion. These findings suggest the need for further study as well as therapeutic targets for smokers undergoing surgery. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:618-625, 2018.

Association of Oral Cavity and Oropharyngeal Cancer Biomarkers in Surgical Drain Fluid With Patient Outcomes.

Importance: Survival rates for head and neck cancer have been relatively stable for several decades. Individualized prognostic indicators are needed to identify patients at risk for poorer outcomes. Objective: To determine whether biomarker levels in surgical drain fluid of patients with head and neck cancer are associated with poor cancer outcomes. Design, Setting, and Participants: This prospective cohort study enrolled patients with squamous cell carcinoma (SCC) of the oral cavity and oropharynx who required surgical treatment from April 1, 2011, to February 1, 2016, at a tertiary or academic care center. Twenty patients, including 14 with stage IV disease, had complete specimen collection. Differences in cytokine and MMP levels by disease outcomes were evaluated. Interventions: Patients underwent surgical treatment with drain placement as dictated by the standard of care. Drain fluid samples were collected every 8 hours postoperatively until drains were removed because of clinical criteria. Levels of cytokines and matrix metalloproteinases (MMPs) were measured using electrochemiluminescent, patterned array, multiplex technology. Main Outcomes and Measures: The primary clinical outcome measures were survival outcome and recurrence. The biomarkers measured included the cytokines basic fibroblastic growth factor, vascular endothelial growth factor isoform A, soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PIGF) and MMP-1, MMP-3, and MMP-9. Other clinical and pathologic cancer characteristics were recorded. Results: In this cohort of 20 patients with SCC (15 men and 5 women; mean [SD] age, 63.5 [9.9] years), a significant association with recurrence was found for levels of MMP-1 (relative difference between groups, 2.78; 95% CI, 1.23-6.29), MMP-3 (relative difference between groups, 5.29; 95% CI, 2.14-13.05), and sFlt-1 (relative difference between groups, 3.75; 95% CI, 1.84-7.65). No biomarkers were associated with disease outcome. Vascular endothelial growth factor isoform A was associated with nodal metastasis (relative difference between groups, 1.98; 95% CI, 1.12-3.51), and basic fibroblastic growth factor was associated with lymphovascular invasion (relative difference between groups, 1.74; 95% CI, 1.02-2.97). Conclusions and Relevance: In this pilot sample of patients with SCC of the oral cavity and oropharynx, MMP-1, MMP-3, and sFlt-1 levels in wound fluid were associated with poor clinical cancer outcomes in the form of recurrence. This finding is consistent with the literature of tumor microenvironment in saliva, serum, and tumor tissue biomarkers. To our knowledge, this report is the first of such findings in surgical drain fluid, an easily accessible means of cytokine measurement. Measurement of these biomarkers in surgical fluid potentially represents a novel means of assessing cancer prognosis in this population.

Comparison of Neurovascular Characteristics of Facial Skin in Patients After Primary and Revision Rhytidectomies.

IMPORTANCE: Wound healing influences both the cosmetic and functional outcomes of facial surgery. Study of cutaneous innervation may afford insight into patients' preoperative wound healing potential and aid in their selection of appropriate surgical procedures. OBJECTIVE: To present the quantitative and qualitative differences of epidermal nerve fibers (ENFs), neurotransmitters, vasculature, and mast cells in facial skin among patients after primary and revision rhytidectomies. DESIGN, SETTING, AND PARTICIPANTS: This pilot study collected cutaneous specimens from 8 female patients aged 42 to 66 years who underwent primary rhytidectomy (n = 5) and revision rhytidectomy (n = 3) at Centennial Lakes Surgery Center, Edina, Minnesota, from July 2010 to March 2014. Tissue was processed for confocal/epifluorescence microscopy and indirect immunofluorescent localization of several neural and tissue antigens as well as basement membrane and mast cell markers. INTERVENTION: Primary rhytidectomy vs revision rhytidectomy with selection of a small area of redundant, otherwise disposed of tissue anterior to the tragus for ENF study. MAIN OUTCOMES AND MEASURES: Demographic characteristics included smoking status; 10-point rating scales for facial sensation, pain, and paresthesias; and confocal/epifluorescence microscopy to quantify ENFs, neurotransmitters, vasculature, and mast cells. RESULTS: Patients in the primary rhytidectomy group had a mean (SD) of 54.4 (31.6) ENFs/mm (range, 14.2-99.2 ENFs/mm), and those in the revision rhytidectomy group had a mean (SD) of 18.6 (5.8) ENFs/mm (range, 13.8-25.0 ENFs/mm). A patient in the primary rhytidectomy group was a 25-pack-year smoker and had 14.2 ENFs/mm, the lowest in both groups. In addition to these structural neural changes, functional neural changes in revision rhytidectomy samples included qualitative changes in normal neural antigen prevalence (substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide). Capillary loops appeared less robust and were less common in dermal papilla among samples from both the primary and revision groups, and mast cells were more degranulated. No differences were found in subjective, self-reported postoperative facial sensation. CONCLUSIONS AND RELEVANCE: Previous skin elevation was associated with decreased epidermal nerve fiber density and qualitative changes in dermal nerves, capillaries, and mast cells in a clinical sample of patients undergoing rhytidectomy. Future research is needed to determine whether histological findings predict wound healing and to better understand the effects of surgery on regenerative capacity of epidermal nerve fibers. LEVEL OF EVIDENCE: NA.

SLC44A2 single nucleotide polymorphisms, isoforms, and expression: Association with severity of Meniere's disease?

SLC44A2 was discovered as the target of an antibody that causes hearing loss. Knockout mice develop age related hearing loss, loss of sensory cells and spiral ganglion neurons. SLC44A2 has polymorphic sites implicated in human disease. Transfusion related acute lung injury (TRALI) is linked to rs2288904 and genome wide association studies link rs2288904 and rs9797861 to venous thromboembolism (VTE), coronary artery disease and stroke. Here we report linkage disequilibrium of rs2288904 with rs3087969 and the association of these SLC44A2 SNPs with Meniere's disease severity. Tissue-specific isoform expression differences suggest that the N-terminal domain is linked to different functions in different cell types. Heterozygosity at rs2288904 CGA/CAA and rs3087969 GAT/GAC showed a trend for association with intractable Meniere's disease compared to less severe disease and to controls. The association of SLC44A2 SNPs with VTE suggests that thrombi affecting cochlear vessels could be a factor in Meniere's disease.

Effects of topical copper tripeptide complex on wound healing in an irradiated rat model.

OBJECTIVES: To evaluate clinical and immunohistopathological effects of topical glycyl-histidyl-lysine-copper (GHK-Cu) on in vivo irradiated rat wounds. DESIGN: Animal model. SETTING: Academic institution. SUBJECTS AND METHODS: After dorsal irradiation and a 28-day recovery period, 2 × 8 cm cranially based dorsal flaps were created in Sprague-Dawley rats. Twice daily GHK-Cu gel (test) or aquaphilic ointment (control) was applied for 10 days. Animals were euthanized, digital images of flaps were taken, and harvested tissues were immunohistochemically stained for a vascular endothelium marker, caveolin-1, and vascular endothelial growth factor (VEGF). Digital image analysis was used for outcome measures. Unpaired t-tests were used for statistical analyses; significance of P < .01 accounted for multiple comparisons. RESULTS: By digital analysis of clinical images, 13 test and 10 control animals showed mean ischemic areas of 5.0 cm(2) (SD = 0.9) for tests and 3.8 cm(2) (SD = 1.1; P = .011) for controls. Whole slide digitized images allowed quantification of caveolin-1-stained blood vessels and VEGF expression in fibroblasts at the interface of healing flaps. Caveolin-1 analyses showed a mean of 209.0 vessels (SD = 111.1) and a mean vessel luminal area of 525.7 um(2) (SD = 191.0) in tests and 207.4 vessels (SD = 109.4; P = .973) and 422.8 um(2) (SD = 109.7; P = .118) in controls. VEGF quantified as the percentage of pixels exceeding a colorimetric threshold, with higher fractions of positive pixels indicating more intense staining, showed a mean intensity score of 0.34 (SD = 0.19) in tests and 0.54 (SD = 0.41; P = .169) in controls. CONCLUSIONS: Irradiated dorsal rat flaps treated with topical GHK-Cu gel demonstrated no difference in flap ischemia, blood vessel number or area, or VEGF expression compared to controls.

The effect of young age on outcomes in head and neck cancer.

OBJECTIVES/HYPOTHESIS: Many head and neck surgeons believe that young patients with head and neck cancer (HNCA) have poorer outcomes than older patients, whereas the evidence in the literature is mixed. We sought to review our HNCA population to evaluate for survival differences between young and older patients. STUDY DESIGN: Matched pair retrospective cohort study. METHODS: A matched pair retrospective cohort study was completed of mucosal HNCA patients at our academic center (2003-2008). Patients aged 45 or less when diagnosed were identified as cases and matched one-to-one to controls by site of tumor, stage of disease, and gender. Risk factors, disease and treatment variables, and survival outcomes were compared between groups. In addition, a subset survival analysis was completed with oropharyngeal cancer patients and nonoropharyngeal cancer patients. RESULTS: There were 87 cases matched to 87 controls. Despite no difference in T and N stage between groups, cases more frequently underwent neck dissection. On Kaplan-Meier and multivariate analysis, overall survival was marginally better for all young patients, whereas disease-free survival was significantly better. Within the subgroup analysis, the statistically significant disease-free survival advantage was lost for young patients with oropharyngeal cancer but maintained for all other sites. CONCLUSIONS: In this cohort, young HNCA patients had mildly improved overall survival but statistically greater disease-free survival. There was no statistically significant survival difference between young and older patients with oropharyngeal cancer, potentially secondary to a human papillomavirus effect.

Squamous cell carcinoma involving the temporal bone: lateral temporal bone resection as primary intervention.

OBJECTIVE: To provide an up-to-date review of treatment and outcomes of patients with squamous cell carcinoma (SCCA) involving the temporal bone. DESIGN: Retrospective cohort study of all patients treated at our institution for SCCA of the temporal bone between 1995 and 2007 with follow-up until 2011. Factors evaluated were demographics, presenting findings, follow-up time, previous treatment, workup, stage, surgical intervention, adjuvant therapy, histopathologic findings, recurrence, and survival. SETTING: Tertiary care academic medical center. PATIENTS: Thirty patients with SCCA of the temporal bone, originating from the external auditory canal and adjacent sites. INTERVENTION: Surgical resection ± adjuvant therapy. Lateral temporal bone resection was the primary and most aggressive procedure performed. MAIN OUTCOME MEASURES: Disease-free survival. RESULTS: The overall disease free survival for this series when considering both external auditory canal and adjacent site SCCAs was 70%. When evaluated by tumor stage, disease-free survival was as follows: T1 tumors = 100%, T2 tumors = 100%, T3 tumors = 67%, and T4 tumors = 56%. Aggressive tumors of this series originating at periauricular sites behaved in a similar manner to primary canal tumors. Need for surgical resection of CN VII was associated with diminished survival on multivariate analysis. CONCLUSION: Lateral temporal bone resection provides comparable disease free survival rates to more radical surgical therapy. Such resection is appropriate for many SCCAs of the external auditory canal and adjacent sites, as these tumors are similar in disease progression and prognosis. CN VII involvement portends a poor outcome.

The effect of treating institution on outcomes in head and neck cancer.

OBJECTIVE: Factors leading patients with head and neck cancer (HNCA) to seek radiation or chemoradiation in an academic center versus the community are incompletely understood, as are the effects of site of treatment on treatment completion and survival. STUDY DESIGN: Historical cohort study. SETTING: Tertiary academic center, community practices. METHODS: A historical cohort study was completed of patients with mucosal HNCA identified by International Classification of Disease, Ninth Revision (ICD-9) codes receiving consultation at the authors' institution from 2003 to 2008. Patients who received primary and adjuvant radiation at an academic center or in the community were included. The authors compared treatment completion rates and performed univariate and multivariate analyses of treatment outcomes. RESULTS: Of 388 patients, 210 completed treatment at an academic center and 145 at a community center (33 excluded, location unknown). Patients with HNCA undergoing radiation at an academic site had more advanced disease (P = .024) and were more likely to receive concurrent chemotherapy. Academic hospitals had a higher percentage of noncurrent smokers, higher median income, and higher percentage of oropharyngeal tumors. There was no significant difference in the rate of planned treatment completion between community and academic centers (93.7% vs 94.7%, P > .81) or rate of treatment breaks (22.4% vs 28.4%, P > .28). On Kaplan-Meier analysis, the 5-year survival rate was 53.2% (95% confidence interval [CI], 45.3%-61.1%) for academic centers and 32.8% (95% CI, 22.0%-43.6%) for community hospitals (P < .001). CONCLUSION: In this cohort, although treatment completion and treatment breaks were similar between academic and community centers, survival rates were higher in patients treated in an academic setting.

The effect of smoking on perioperative complications in head and neck oncologic surgery.

OBJECTIVES/HYPOTHESIS: Cigarette smoking is the most important risk factor for head and neck cancer. Conventional wisdom suggests that smoking causes increased postoperative wound healing and systemic complications in this patient population, but it is unclear if the clinical literature supports this. STUDY DESIGN: Systematic review. METHODS: The authors performed a review of the literature from 1990 to 2010 on the effect of cigarette smoking on perioperative complications in head and neck surgery. RESULTS: Thirty-six articles met eligibility criteria and were reviewed; 14 focused on extirpative surgery and 22 on reconstruction. Most of the evidence was comprised of case series and small cohort studies. We reviewed local wound healing and systemic complications, and 47% of studies supported an association between smoking and complications of surgery. CONCLUSIONS: Evidence from the existing clinical literature is inconclusive on an association between cigarette smoking and perioperative complications after head and neck surgery. The negative impact of smoking is suggested; however, the majority of articles had significant methodological weaknesses. Prospective study of tobacco-induced complications is needed.

Recalcitrant hypocalcemia in a lactating woman after total thyroidectomy for papillary thyroid carcinoma.

BACKGROUND: The risk of hypocalcemia after total thyroidectomy is well-described in the literature. Recalcitrant hypocalcemia after thyroidectomy in a lactating woman is uncommon and may require multiple strategies to correct. METHODS: We present a case report of a lactating woman with papillary thyroid carcinoma requiring total thyroidectomy and neck dissections. RESULTS: Postoperatively the patient suffered from recalcitrant hypocalcemia which necessitated multiple medical maneuvers to rectify. The medical treatment required to correct the calcium levels is described herein. CONCLUSION: With the incidence of thyroid cancer on the rise and the increased identification of thyroid lesions during pregnancy, the number of lactating women undergoing thyroidectomy will likely increase. Surgeons performing thyroid surgery in this patient population should be aware of the risk of severe hypocalcemia and the tools necessary to correct it.

Chemoselection as a strategy for organ preservation in patients with T4 laryngeal squamous cell carcinoma with cartilage invasion.

OBJECTIVES/HYPOTHESIS: High rates of overall survival (OS) and laryngeal preservation were achieved in two sequential phase II clinical trials in patients with stage III/IV laryngeal squamous cell carcinoma (SCC). Patients were treated with chemoradiation after a >50% primary tumor response to one cycle of neoadjuvant chemotherapy (IC). We analyzed outcomes for T4 patients with cartilage invasion from both studies. STUDY DESIGN: Retrospective. METHODS: Records from 36 patients with T4 SCC of the larynx with cartilage invasion alone (n = 16) or cartilage invasion and extralaryngeal spread (n = 20) were retrospectively reviewed. All were treated with one cycle of cisplatin (100 mg/m(2)) [or carboplatin (AUC 6)] and 5-fluorouracil (1,000 mg/m(2)/d for 5 days) (P+5FU). Those achieving >50% response at the primary tumor received chemoradiation (70 Gy; 35 fractions with concurrent cisplatin-100 mg/m(2) [carboplatin (AUC 6)] every 21 days for 3 cycles), followed by adjuvant P+5FU for complete histologic responders (CHR). Patients with <50% response after IC underwent total laryngectomy and postoperative radiation. RESULTS: Twenty-nine of 36 patients (81%) had >50% response following IC. Of these, 27 received definitive chemoradiation, 23 (85%) obtained CHR, with 58% laryngeal preservation rate. The 3-year OS was 78%, and the disease-specific survival was 80% (median follow-up 69 months). Following chemoradiation, 8/11 (73%) patients with an intact larynx had >75% understandable speech, 6/36 (17%) were g-tube dependent and 6/36 (17%) were tracheostomy dependent. CONCLUSIONS: Our results suggest that chemo-selection is a feasible organ preservation alternative to total laryngectomy for patients with T4 laryngeal SCC with cartilage invasion.