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Radiation therapy, a mainstay of treatment for head and neck cancer, is not always curative due to the development of treatment resistance; additionally, multi-institutional trials have questioned the efficacy of concurrent radiation with cetuximab, the epidermal growth factor receptor (EGFR) inhibitor. We unraveled a mechanism for radiation resistance; that is, radiation induces EGFR, which phosphorylates TRIP13 (thyroid hormone receptor interactor 13) on tyrosine 56. Phosphorylated (phospho-)TRIP13 promotes non-homologous end joining (NHEJ) repair to induce radiation resistance. NHEJ is the main repair pathway for radiation-induced DNA damage. Tumors expressing high TRIP13 do not respond to radiation but are sensitive to cetuximab or cetuximab combined with radiation. Suppression of phosphorylation of TRIP13 at Y56 abrogates these effects. These findings show that EGFR-mediated phosphorylation of TRIP13 at Y56 is a vital mechanism of radiation resistance. Notably, TRIP13-pY56 could be used to predict the response to radiation or cetuximab and could be explored as an actionable target.

Purpose Microvascular free tissue transfer (MFTT) is a reliable reconstructive option with variation in perioperative care and a general lack of clinical practice guidelines. Oral and maxillofacial surgeons’ (OMSs) current MFTT perioperative practices in the United States have not been described. This study describes these practices including surgeon practice environment, operative practices, perioperative management, and success. Methods The study design is cross sectional. The sample is composed of OMSs who completed an Oral/Head and Neck Oncologic and Microvascular Surgery Fellowship prior to 2018 in the United States. Data were collected by means of a survey of the study sample. Descriptive statistics were reported. Results Forty surgeons responded to the survey for a response rate of 33.9%. Respondents were 97.5% (n = 39) male and worked in private (n = 8), combination (n = 10), and academic practices (n = 23). Surgeons in private and academic practice performed an average of 23.3 (SD 13.9) and 48.6 (SD 28.6) flaps per year, respectively. The 2-team approach was used by 88.2% of surgeons. Immediate dental implants were placed in osteocutaneous free flaps by 28.6% (n = 2) of private practice surgeons and 70% (n = 14) of academic surgeons. Postoperatively, most patients went to an intensive care unit (ICU) (82.7%, average duration 2.6 days). Anticoagulation or antiplatelet medications were routinely used with the most common choice being aspirin (77.4%, n = 24). Antibiotics were universally administered, often for 3 days or longer (74.2%, n = 23). Self-reported success rates were 95.3% (SD 4.1) and 96.0% (SD 1.7) in private and academic settings, respectively. Conclusion This is the first report of practice trends by microvascular OMSs in the United States. The results of this study suggest that there is variation in MFTT operative and perioperative practices by individual surgeons and practice environment with minimal variation in self-reported success rates.

Depth of invasion (DOI) is an independent predictor of regional metastasis in oral squamous cell carcinoma. Measurement criteria for DOI were modified in the American Joint Committee on Cancer (AJCC) eighth edition. The purpose of this study was to compare DOI AJCC seventh (DOI7) and eighth (DOI8) edition criteria on frozen section accuracy for decisions regarding elective neck dissection (END) in cT1N0 oral squamous cell carcinoma.A blinded, retrospective, comparative study of patients who underwent ablative surgery at the University of Michigan was completed. The predictor variable was criteria for DOI measurement. The outcome variables were concordance between DOI7 and DOI8 measurements and accuracy using thresholds for END. Effect of tumor growth pattern and worst pattern of invasion, and the difference between DOI8 on frozen and permanent specimen were assessed.A total of 30 specimens of T1N0 oral squamous cell carcinoma (16 tongue, 5 alveolus, 5 floor of mouth, 4 buccal mucosa) were included. DOI7 versus DOI8 on frozen and permanent specimen were significantly different (P .05) but clinically insignificant and highly correlated (r 0.99, P .001). One hundred percent concordance between DOI7 and DOI8 was noted on frozen specimen in predicting the need for END when compared with permanent pathology DOI. There was no significant impact of tumor growth pattern or worst pattern of invasion on measurements and no significant difference in DOI on frozen and permanent specimen for DOI8 (P = .68). Excellent agreement between pathologists for all measurements was observed (ICC0.99, P 0001).High concordance between DOI measurements by AJCC seventh and eighth edition criteria suggests that guidelines for DOI thresholds for END in patients with T1N0 tumors developed using the AJCC seventh edition can be safely applied using AJCC eighth edition criteria. DOI measurement by AJCC 8 criteria on frozen specimen can be used to guide decision-making regarding END, given the high correlation to AJCC 8 permanent DOI measurement.

PURPOSE/OBJECTIVES Broken appointments are an important cause of waste in health care. Patients who fail to attend incur costs to providers, deny trainees learning opportunities, and impact their own health as well as that of other patients who are waiting for care. METHODS A total of 410,000 appointment records over 3 years were extracted from our electronic health record. We conducted exploratory data analysis and assessed correlations between appointment no-shows and other attributes of the appointment and the patient. The University of Michigan Medical School's Committee on Human Research reviewed the study and deemed that no Institutional Review Board oversight was necessary for this quality improvement project that was, retrospectively, turned into a study with previously de-identified data. RESULTS The patient's previous attendance record is the single most significant correlation with attendance. We found that patients who said they are "scared" of dental visits were 62% as likely to attend as someone reporting "no problem." Patients over 65 years of age have better attendance rates. There was a positive association between receiving email/text confirmation and attendance. A total of 94.9% of those emailed a reminder and 92.2% of those who were texted attended their appointment. CONCLUSION(S) We were able to identify relationships of several variables to failed and attended appointments that we were previously unknown to us. This knowledge enabled us to implement interventions to support better attendance at Dental Clinics at the University of Michigan, improving patient health, student training, and efficient use of resources.

We investigated the overall survival (OS), disease-specific survival (DSS), and disease-free survival among patients with oral lichen planus-associated oral cavity squamous cell carcinoma (OLP-OCSCC). The secondary objective was to assess the annual risk of tumor recurrence or second primary tumor (SPT).A comparative retrospective study was performed of patients with OLP-OCSCC presenting between June 2007 and December 2018 to the Department of Oral and Maxillofacial Surgery, Michigan Medicine (Ann Arbor, MI) and patients with OCSCC in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database (1973 to 2015).A total of 87 patients with OLP-OCSCC met the inclusion criteria, and 55,165 patients with OCSCC from the SEER database were included. The proportion of women was greater in the OLP group than in the SEER group (56.3 vs 38.0%; P .001). In the OLP group, 47.1% had no smoking history and 43.7% had no alcohol history. Most patients in the OLP group had presented with stage I disease (46.0%) compared with 31.7% in the SEER group (P = .004). Overall, the OS and DSS were significantly greater in the OLP group than in the SEER group at all points from 1 to 5 years (P ≤ .01). In the OLP group, 46 patients (52.9%) had at least 1 recurrence or SPT. At 10 years, the predicted mean number of recurrences was 1.93 per patient (95% confidence interval, 1.56 to 2.39).OLP-OCSCC frequently affects women, nonsmokers, and nondrinkers and presents with localized disease at a high frequency. Patients with OLP-OCSCC have increased OS and DSS and a greater risk of tumor recurrence or SPT compared with OCSCC in the general population. Lifelong, frequent surveillance is recommended for patients with OLP-OCSCC owing to the risk of late recurrence. Future studies are needed to understand the pathophysiology of OLP-OCSCC.

Purpose First branchial cleft fistula/sinus is a rare congenital developmental deformity that can sometimes be acquired from incision and drainage of a branchial cleft cyst. The aim of the present study was to explore the clinical manifestations, diagnosis, and surgical management of first branchial cleft fistula/sinus in both a large patient series and a review of the pertinent literature. Materials and Methods The data from 31 cases diagnosed from February 2004 to April 2019 as first branchial cleft fistula/sinus were retrospectively reviewed. The patient demographic data and outcomes were explored. In addition, we performed a literature review of studies reported from 1923 to 2018 for first branchial cleft fistula/sinus and summarized those results. Results The present study included 31 patients (15 males, 16 females) with a median age of 4 years. All the patients reviewed had presented with a unilateral first branchial cleft fistula/sinus. The parotid region was the most frequent site of presentation (41.9%) in these cases. The fistula/sinus had occurred on the left side in 13 patients (41.9%) and on the right side in 18 patients (58.1%). Of the 31 patients, 24 (77.4%) had acquired the disease from infection of an existing brachial cleft cyst or incomplete previous excision. Of the 31 cases, 28 (90%) had an intimate relationship between the tract and the facial nerve. Despite this close association, no patient developed postoperative facial nerve palsy. Of the 31 operations, 30 (97%) successfully accomplished complete resection with no recurrence postoperatively. Only 1 patient with a history of multiple recurrences experienced a subsequent recurrence, which was successfully treated with a second surgery. Conclusions First branchial cleft fistula/sinus is a frequently misdiagnosed and, therefore, undertreated entity, which leads to recurrence. It is closely associated with the facial nerve and extra auditory canal. The correct diagnosis and meticulous removal can be effectively achieved with minimal risk to the facial nerve.

The purpose of this study was to investigate the prognostic value of the family history of cancer (FHC) in predicting survival and clinicopathological features in oral squamous cell carcinoma (OSCC) patients.This single-institution study utilized data from 610 patients undergoing surgery from 2014 to 2020 that was prospectively collected and cataloged for research purposes. All patients underwent standard surgery with/without radiotherapy or chemoradiotherapy. We statistically evaluated whether FHC was associated with changes in disease-free survival (DFS) and disease-specific survival (DSS).Among 610 patients, 141 (23.1%) reported a family history of cancer. The distribution of clinicopathological characteristics was balanced between FHC-positive and FHC-negative OSCC patients. FHC-positive patients had decreased DFS (p = 0.005) and DSS (p = 0.018) compared to FHC-negative patients.FHC-positive OSCC patients have a poorer prognosis. FHC positivity is an independent predictor of negative outcomes based on DFS and DSS. FHC should be a consideration in screening, evaluating, counseling, and treating OSCC patients.

Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaws (MRONJ) - formerly referred to as bisphosphonate-related osteonecrosis of the jaws (BRONJ)-were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007, 2009 and 2014. The position papers were developed by a committee appointed by the AAOMS Board of Trustees and comprising clinicians with extensive experience in caring for these patients, as well as clinical and basic science researchers. The knowledge base and experience in addressing MRONJ continues to evolve and expand, necessitating modifications and refinements to the previous position papers. Three members of the AAOMS Committee on Oral, Head, and Neck Oncologic and Reconstructive Surgery (COHNORS) and three authors of the 2014 position paper were appointed to serve as a working group to analyze the current literature and revise the guidance as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis and management strategies and highlights the current research status. AAOMS maintains that it is vitally important for this information to be disseminated to other relevant healthcare professionals and organizations.

Purpose The purpose of this study was to describe 3 cases of tongue cancer in patients less than 21 years of age. Secondarily, a literature review was performed to examine disease presentation, risk factors, prognosis, and treatment strategies for young persons with tongue cancer. Methods The authors presented 3 cases of childhood tongue cancer between 2009 and 2020 at the University of Michigan Department of Oral and Maxillofacial Surgery (Ann Arbor, MI). An electronic literature review was conducted via PubMed, Embase, Web of Science, and MLibrary. Results Including the present case series, 64 studies reporting 108 cases were identified. Age at presentation ranged from newborn to 20 years, with a mean age of 14.5 years. The majority of patients were female (52.2%); 68.1% of patients presented with T1 or T2 disease. Nodal metastases were seen in 56.1% of patients. The most commonly identified predisposing factors included Fanconi anemia (13.9%), bone marrow transplant (9.3%), tobacco use (6.5%), and xeroderma pigmentosum (4.6%). Most patients received surgery alone (37.5%), followed by surgery with adjuvant radiation (33.8%); 60.6% underwent neck dissection. Overall survival was 60.3% at 1 year and 43.6% at 5 years. Conclusions Oral tongue cancer in the young is a rare disease with poorly understood etiology. There is a need for oncologists and maxillofacial surgeons to collaborate in the study of genetic, social, environmental, and medical risk factors contributing to the disease. All patients should undergo high-throughput genetic sequencing to expand our understanding of the disease process and allow for targeted treatment strategies.

Purpose Perineural invasion (PNI) is considered an adverse histological feature in oral squamous cell carcinoma (OSCC). Controversy exists regarding elective neck dissection (END) in cT1N0M0 OSCC with PNI as the only risk factor. The purpose of this study was to evaluate PNI as an indicator for END, as well as its utility when combined with the depth of invasion (DOI) as a second indicator. Patients and Methods cT1N0M0 (AJCC8) OSCC patients treated from August 1998 to July 2017 in the Department of Oral and Maxillofacial Surgery, University of Michigan (MI), and Beijing Stomatological Hospital, Capital Medical University (BSH) were reviewed. Data from these sites included both prospectively captured data housed in a database and retrospective data. Results 283 cT1N0M0 OSCC patients were analyzed. The tongue was the most common subsite (56.2%). Ninety-nine (99) patients received END and 184 neck observation. PNI was found in only 8 patients (2.83%) all in the tongue or inferior gingiva. END was performed in 7 of the PNI patients. The mean depth of invasion for tumors with PNI was 3.97 mm, compared to 2.54 mm in tumors without PNI. PNI was statistically correlated with nodal disease (pN+) and extranodal extension (ENE+). After using DOI as a primary indicator for END, no additional PNI patients benefited from END. In addition, only 2 patients had PNI identified preoperatively both with 5 mm DOI, and therefore, already indicated for END on the basis of DOI status. Conclusions PNI status is statistically correlated with pN+ and ENE + pathology in cT1N0M0 OSCC. After using DOI as a primary indicator for END, PNI status had no added value in decision making. Even surgeons who do not use DOI will find very limited value in PNI status with less than 1% preoperative prevalence (0.71%) in this patient population.

Buccal squamous cell carcinoma (BSCC) is rare in the United States. Given its location, few anatomic barriers to its spread exist, and it has been found to have a high locoregional recurrence rate. The role of elective neck dissection (END) in the clinically negative neck (N0) is not clear. In the present study, we measured the effect of END on the locoregional and distant metastasis rates among patients with clinically N0 BSCC.A retrospective cohort study was conducted. The sample included subjects diagnosed with BSCC. The primary predictor variable was END status (yes vs no). The primary outcome variable was locoregional recurrence. The secondary outcome variables were distant metastasis and the 2- and 5-year survival rates. Other variables collected included demographic data, initial operation, adjuvant therapy, pathologic data, and stage. Kaplan-Meier and Cox proportional hazards statistics were computed.The sample included 20 subjects with clinical N0 BSCC and a mean age of 67 years (range 42-88); 55% were men. The disease stage was T1 in 30%, T2 in 40%, T3 in 15%, and T4 in 15%. Fifteen subjects underwent END. Of the 5 who had not undergone END, all 5 (100%) had locoregional recurrence and 1 (20%) had metastasis. Of the 15 who had undergone END, 5 (33%) had locoregional recurrence and 1 (7%) had metastasis (P = .002). The 2- and 5-year survival rates for N0 patients without END was 80% and 40%, respectively, compared with 93% and 87% for those who had undergone END.END had a therapeutic role, resulting in a lower locoregional recurrence rate. Also, the 2- and 5-year survival rates were greater for those who had undergone END.

Surgery is the primary treatment modality for oral cavity squamous cell carcinoma (OCSCC). Care team factors, patient factors, and procedure-related factors affect surgical outcomes and overall prognosis. The management of the primary tumor per oral cavity subsite, the management of the neck, and the evaluation of margin status are fundamental surgical principles. In addition, dental rehabilitation is an important functional consideration in the reconstruction following tumor ablation. The use of adjunct surgical tools including surgical navigation and virtual surgery planning allows for patient-specific and highly precise bony ablation and reconstruction. Evidence-based surgical decision-making can optimize treatment outcomes and improve survival.

Background The purpose of this study was to investigate the critical primary tumor depth of invasion in oral squamous cell carcinoma that would lead to a 20% or greater risk of nodal metastasis. Methods An institutional review board approved retrospective review of our head and neck database was performed from 2009 to 2014 and the data were statistically analyzed. Results Two hundred eighty-six patients with a diagnosis of oral squamous cell carcinoma who met our inclusion criteria underwent primary excision and neck dissection. For a depth of invasion of 1 mm or less, there were no patients with a positive node. From 1.1 mm to 2 mm of depth of invasion, there was 1 of 11 patients (9%) who had at least 1 positive node. At 2.1 mm to 3 mm, 5 of 25 patients (20%) had at least 1 positive node. Conclusion Depth of invasion and the location of the tumor are 2 important variables to consider when making treatment recommendations to patients with clinical N0 disease. © 2017 Wiley Periodicals, Inc. Head Neck 39: 974–979, 2017

Oral and Maxillofacial Surgeons have increasing opportunities to train in head and neck oncologic and reconstructive surgery. The development of a fellowship training programs within our speciality has had a transformative effect on the speciality. This survey by the commitee on Maxillofacial Oncology and Reconstructive is aimed to evaluate the impact of fellowship training on the careers of the fellows and speciality from 2005-2015.

Purpose Depth of invasion (DOI) is one predictor of nodal metastasis in oral cavity squamous cell carcinoma (OCSCC) and can facilitate the decision to complete an elective neck dissection (END) in early-stage disease with a clinically negative neck. The purpose of this study was to investigate the accuracy of DOI in intraoperative frozen specimens for T1N0 oral OCSCC. Materials and Methods To compare the accuracy of DOI in frozen versus permanent specimens, we completed a prospective, blinded study of 30 patients with cT1N0 OCSCC who presented between October 2016 and December 2017. Results DOI in frozen specimens was 96.8% accurate in predicting the need for END with a sensitivity of 90.9%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 95.2%. A strong correlation was found between DOIs in frozen and permanent specimens measured by head and neck (HN) pathologists (r = 0.96; 95% confidence interval [CI], 0.93 to 0.97), between HN pathologists using frozen specimens (r = 0.98; 95% CI, 0.95 to 0.99) and permanent specimens (r = 0.95; 95% CI, 0.91 to 0.98), and in DOIs in frozen specimens communicated intraoperatively versus measured by HN pathologist 1 (r = 0.93; 95% CI, 0.86 to 0.97) and HN pathologist 2 (r = 0.95; 95% CI, 0.89 to 0.98). Only 1 patient who did not undergo an END based on frozen specimens was undertreated owing to upgrading of the DOI in permanent specimens. Conclusions DOI in intraoperative frozen sections has an accuracy of 96.8% and may be reliably used as a clinical tool to determine the need for END in early-stage OCSCC.

Purpose Buccal squamous cell carcinoma (BSCC) is rare in the United States. Given its location, few anatomic barriers to spread exist and it has been found to have a high locoregional recurrence rate. The role of elective neck dissection (END) in patients with clinically negative neck (N0) is not clear. This study aims to answer the following research question: Among patients with N0 BSCC, does END improve locoregional control rates, distant metastasis rates, and 2- and 5-year survival rates? Materials and Methods A retrospective cohort study was conducted. The sample included patients who received a diagnosis of BSCC. The primary predictor variable was END status (yes or no). Five institutions participated between June 2001 and June 2011: University of Washington, University of Michigan, University of Tennessee, North Memorial Oral and Maxillofacial Surgery in Minnesota, and Head and Neck Surgical Associates (Portland, OR). The primary outcome variable was locoregional recurrence. Secondary outcome variables were distant metastasis and 2- and 5-year survival rates. Other variables collected were demographic characteristics, initial operation, adjuvant therapy, clinical and pathologic data, and staging. Kaplan-Meier and Cox proportional hazards statistics were computed. Results The sample was composed of 98 patients with clinical N0 BSCC. The mean age was 66 years (range, 30-88 years), and 54% were men. Of the patients, 74 (76%) underwent END. The locoregional recurrence–free rate was 61% for END versus 38% for no END (P = .042). The distant metastasis rate was 4% for END versus 9% for no END. The 2- and 5-year disease-free survival rates were 91% and 75% (P = .042), respectively, for END and 85% and 63% (P = .019), respectively, for no END. Conclusions END had a therapeutic effect, as evidenced by a lower locoregional recurrence rate, lower distant metastasis rate, and improved 2- and 5-year survival rates.

In reconstructive surgery, tissue perfusion/vessel patency is critical to the success of microvascular free tissue flaps. Early detection of flap failure secondary to compromise of vascular perfusion would significantly increase the chances of flap salvage. We have developed a compact, clinically-compatible monitoring system to enable automated, minimally-invasive, continuous, and quantitative assessment of flap viability/perfusion. We tested the system’s continuous monitoring capability during extended non-recovery surgery using an in vivo porcine free flap model. Initial results indicated that the system could assess flap viability/perfusion in a quantitative and continuous manner. With proven performance, the compact form constructed with cost-effective components would make this system suitable for clinical translation

Purpose A variety of modalities has been suggested for treatment of keratocystic odontogenic tumor (KOT), including Carnoy's solution (CS) and modified Carnoy's (without chloroform) solution (MC). The purpose of the present study was to investigate the effect of CS versus MC as it relates to the KOT recurrence rates when used in conjunction with simple enucleation and curettage (EC hazard ratio 6.9). Conclusion In the present retrospective study, the recurrence rate of KOTs treated by E&C with application of CS is significantly lower than that of MC. The data provided could be considered by the Food and Drug Administration for a clinical trial of CS in patients with KOT.

Purpose Despite data showing worse outcomes and aggressive disease behavior, perineural invasion (PNI) has not been well characterized in terms of tumor location, histopathologic features, or cervical lymph node status. The specific aims of this study were to measure correlations between PNI, tumor location, and other known histopathologic characteristics used to define aggressive disease. Materials and Methods This was a retrospective cohort study of adult patients with primary squamous cell carcinoma of the oral cavity who underwent neck dissection. We excluded patients whose neck was previously treated with surgery or radiation therapy. Demographic and histopathologic variables of interest were obtained from patient charts. The primary outcome of interest was PNI, and the predictors of interest included tumor location, histopathologic tumor characteristics, and cervical lymph node status. For continuous variables, mean differences were compared by t tests. For categorical variables, the differences in the distribution of the proportions were analyzed with the χ2 test. All variables were entered simultaneously into a multivariate logistic regression model to control for possible confounding. Statistical significance for the study was set at P Results Three hundred sixty-eight patients met the study criteria. PNI showed statistically significant correlations with lymph node status, tumor depth, and specific primary tumor location. PNI was more likely to be seen in tumors located in the tongue or floor of the mouth. Tumors with PNI had a deeper depth of invasion: 15.9 ± 10.9 mm versus 10.2 ± 10.0 mm (P Conclusions PNI is statistically correlated with tongue and floor-of-the-mouth subsites within the oral cavity, as well as larger tumors, deeper tumors, and disease that has progressed to the lymph nodes. Whether this correlation represents causation in either direction remains unknown.

The need for oral and maxillofacial surgeons to replace and reconstruct defects of the head and neck is common. Trauma, pathology, and congenital etiologies may all lead to the necessity of pedicled or free vascularized flaps. These procedures are a growing part of the specialty and have become important skills in the armamentarium of many maxillofacial surgeons. Although there is plenty of literature in the method of harvest and the usage of each flap, the day-to-day care of these flaps and the perioperative considerations have not been as frequently outlined. In this chapter, we will discuss perioperative management of patients with flap reconstruction.

In reconstructive surgery, the ability to detect blood flow interruptions to grafted tissue represents a critical step in preventing postsurgical complications. We have developed and pilot tested a compact, fiber-based device that combines two complimentary modalities-diffuse correlation spectroscopy (DCS) and diffuse reflectance spectroscopy-to quantitatively monitor blood perfusion. We present a proof-of-concept study on an in vivo porcine model (n=8). With a controllable arterial blood flow supply, occlusion studies (n=4) were performed on surgically isolated free flaps while the device simultaneously monitored blood flow through the supplying artery as well as flap perfusion from three orientations: the distal side of the flap and two transdermal channels. Further studies featuring long-term monitoring, arterial failure simulations, and venous failure simulations were performed on flaps that had undergone an anastomosis procedure (n=4). Additionally, benchtop verification of the DCS system was performed on liquid flow phantoms. Data revealed relationships between diffuse optical measures and state of occlusion as well as the ability to detect arterial and venous compromise. The compact construction of the device, along with its noninvasive and quantitative nature, would make this technology suitable for clinical translation.

Head and neck squamous cell carcinomas (HNSCC) contain a small subpopulation of stem cells endowed with unique capacity to generate tumors. These cancer stem cells (CSC) are localized in perivascular niches and rely on crosstalk with endothelial cells for survival and self-renewal, but the mechanisms involved are unknown. Here, we report that stromal interleukin (IL)–6 defines the tumorigenic capacity of CSC sorted from primary human HNSCC and transplanted into mice. In search for the cellular source of Interleukin-6 (IL-6), we observed a direct correlation between IL-6 levels in tumor-associated endothelial cells and the tumorigenicity of CSC. In vitro, endothelial cell-IL-6 enhanced orosphere formation, p-STAT3 activation, survival, and self-renewal of human CSC. Notably, a humanized anti-IL-6R antibody (tocilizumab) inhibited primary human CSC-mediated tumor initiation. Collectively, these data demonstrate that endothelial cell-secreted IL-6 defines the tumorigenic potential of CSC, and suggest that HNSCC patients might benefit from therapeutic inhibition of IL-6/IL-6R signaling. Stem Cells 2014;32:2845–2857

In reconstructive surgery, impeded blood flow in microvascular free flaps due to a compromise in arterial or venous patency secondary to blood clots or vessel spasms can rapidly result in flap failures. Thus, the ability to detect changes in microvascular free flaps is critical. In this paper, we report progress on in vivo pre-clinical testing of a compact, multimodal, fiber-based diffuse correlation and reflectance spectroscopy system designed to quantitatively monitor tissue perfusion in a porcine model’s surgically-grafted free flap. We also describe the device’s sensitivity to incremental blood flow changes and discuss the prospects for continuous perfusion monitoring in future clinical translational studies.

In reconstructive surgery, tissue perfusion/vessel patency is critical to the success of microvascular free tissue flaps. Early detection of flap failure secondary to compromise of vascular perfusion would significantly increase the chances of flap salvage. We have developed a compact, clinically-compatible monitoring system to enable automated, minimally-invasive, continuous, and quantitative assessment of flap viability/perfusion. We tested the system's continuous monitoring capability during extended non-recovery surgery using an in vivo porcine free flap model. Initial results indicated that the system could assess flap viability/perfusion in a quantitative and continuous manner. With proven performance, the compact form constructed with cost-effective components would make this system suitable for clinical translation.

The tongue and floor of the mouth represents an anatomically small compartment within the head and neck, but it is a complex collision of tissue types and function. This area is perhaps often overlooked in the hierarchy of importance due to the concealment of the overlying lips and maxillomandibular complexes, but nonetheless demands the utmost attention to the reconstructive surgeon. There are numerous tissues of distinct embryologic origins that interface with one another. Applying a thorough understanding of the relevant surgical anatomy, reconstructive options, and scientific information can lead to individually tailored approaches which optimize surgical outcomes. The focus of this chapter will be on reconstruction of the tongue and floor of the mouth defects that are compositely less than or equal to a hemiglossectomy. There will be a systematic and straightforward approach that both the neophyte and seasoned surgeon alike can glean from.

The desire to target therapies to specific cancers while leaving the host unharmed remains an ongoing quest for scientists, surgeons, radiation oncologists, and medical oncologists. In recent years, great scientific progress has been made in targeted therapies. Although many modalities remain in preclinical validation, some advances affect patient care today. This article summarizes the concepts of targeting and explores current examples of successful targeting and emerging targeting technologies in head and neck oncology.

Extranodal non-Hodgkin lymphoma (NHL) in the oral region can present similarly to diseases of odontogenic origin. The objective of this report was to describe a rare case of maxillary and mandibular NHL that presented similarly to and concurrently with lesions of odontogenic origin.A unique case of extranodal NHL, which presented at the apices of maxillary and mandibular teeth in conjunction with lesions of odontogenic origin in a 68-year-old white man, is described. The patient sought care because of a lesion in the right maxillary paranasal region that caused him paresthesia. Radiographically, periapical radiolucencies were present along teeth #5-8, #23 and 24, and #30 and 31. Biopsies of the right maxillary and anterior mandibular lesions were completed and led to a diagnosis of NHL at the apices of teeth #5-8 extending to the hard palate and granulation tissue at the apices of teeth #23 and 24. Two years later, the patient returned because of pressure and sensitivity associated with teeth #30 and 31. Vestibular swelling was noted clinically, and a multilocular periapical radiolucency was present radiographically. Via endodontic therapy and a positron emission tomographic scan, the lesion associated with teeth #30 and 31 was determined to be of both odontogenic and nonodontogenic origin because it possessed both a sinus tract associated with tooth #30 and NHL. Lesions of odontogenic and nonodontogenic origin possess diagnostic and treatment challenges because they may present similarly and/or concurrently. Thoughtful and conservative management of odontogenic lesions with associated NHL is imperative. Interprofessional collaboration and communication among providers must be thorough and clear to properly coordinate care and prevent delays in diagnosis and treatment when these entities occur together.

The vascularization and resulting perfusion of transferred tissues are critical to the success of grafts in buried free flap transplantations. To enable long-term clinical monitoring of grafted tissue perfusion during neovascularization and endothelialization, we are developing an implantable instrument for the continuous monitoring of perfusion using diffuse correlation spectroscopy (DCS), and augmented with diffuse reflectance spectroscopy (DRS). This work discusses instrument construction, integration, and preliminary results using a porcine graft model.

Stable, relative localization of source and detection fibers is necessary for clinical implementation of quantitative optical perfusion monitoring methods such as diffuse correlation spectroscopy (DCS) and diffuse reflectance spectroscopy (DRS). A flexible and compact device design is presented as a platform for simultaneous monitoring of perfusion at a range of depths, enabled by precise location of optical fibers in a robust and secure adhesive patch. We will discuss preliminary data collected on human subjects in a lower body negative pressure model for hypovolemic shock. These data indicate that this method facilitates simple and stable simultaneous monitoring of perfusion at multiple depths and within multiple physiological compartments.

Bisphosphonate-related osteonecrosis of the jaw (ONJ) is characterized by nonhealing exposed bone in the maxillofacial region in patients who have undergone bisphosphonate treatment. The underlying etiology is unclear and may be multifactorial. The diagnosis is primarily clinical. Diagnostic tissue sampling may exacerbate the process and is typically avoided, necessitating other diagnostic approaches. The appearance of ONJ at diagnostic imaging is variable and includes sclerotic, lytic, or mixed lesions with possible periosteal reaction, pathologic fractures, and extension to soft tissues. There is a spectrum of signal intensity changes on T1- and T2-weighted magnetic resonance (MR) images with variable enhancement, findings that may correspond to the clinical and histopathologic stage of the process. Bone scintigraphy is sensitive with increased uptake in the area of the lesion. Although the imaging findings are nonspecific, there appears to be a role for imaging in the management of ONJ. Radiography is relatively insensitive but typically employed as the first line of radiologic investigation. Computed tomography and MR imaging are more precise in demonstrating the extent of the lesion. A number of imaging modalities have revealed lesions that may be associated with bisphosphonate exposure in asymptomatic individuals or in the context of nonspecific symptoms. The risk of these lesions advancing to overt clinical disease is unknown at this time. The radiologist should be aware of ONJ and include it in the differential diagnosis when evaluating patients with a history of bisphosphonate therapy without jaw irradiation, so as to avoid potentially harmful biopsies.

Epidemiologic data have shown changes in the demographic profile of patients presenting with oral cavity squamous cell carcinoma (SCC) during the past 4 decades. In particular, there has been a marked increase in the number of young women without a history of smoking presenting with SCC of the tongue. A Surveillance, Epidemiology, and End Results review of patients with head and neck cancer identified 5.3% younger than 40 years. After comparing cohorts from 1973 to 1984 with 1985 to 1997, a 60% increase in tongue cancer in patients younger 40 years was noted. Epidemiologic data also have shown that women are tending to delay childbearing to an older age. These 2 factors have resulted in an increasing prevalence of cancer diagnosed during pregnancy. If current trends continue, oral surgeons and maternal fetal medicine obstetric specialists will see an increasing number of pregnant patients presenting with malignancies. This in turn will lead to a number of complex surgical and adjuvant treatment considerations resulting in ethical and moral decisions for which limited data exist to guide best practice. The treatment chosen will affect not only the health of the patient, but also the health of the fetus and ongoing pregnancy. This report describes the case of a woman who was diagnosed with SCC of the tongue at 14 weeks' gestational age. This report presents her treatment course and a review of the literature to support her decisions related to the care given.

Lymph node density is defined as the number of positive lymph nodes per total number of excised lymph nodes. In oral and maxillofacial cancer, there are recent data showing that increased lymph node density leads to worse outcomes for patients. However, data correlating lymph node density with other known risk parameters are lacking. This study investigated whether a direct correlation exists among cervical lymph node density, depth of invasion, perineural invasion, and extracapsular tumor spread.A retrospective chart review was undertaken to include all patients who underwent neck dissection with resection of primary oral and maxillofacial squamous cell carcinoma from January 2009 through July 2014. After applying the exclusion criteria, 286 patients were identified. Primary tumor depth of invasion, perineural invasion, and lymph node status, including extracapsular spread, were obtained from the standard pathology report. Descriptive statistics were applied. The association between 2 continuous tumor characteristics was summarized with the Pearson correlation coefficient, and the association between a continuous and a binary tumor characteristic was summarized with 2-sample t test. Statistical significance for the study was set at a P value less than .05.Mean age at time of surgery was 63.9 ± 12.5 years. The final study included 169 men and 117 women (N = 286). The mean depth of invasion was 12.3 ± 11 mm (range, 1 to 69 mm). Mean lymph node density was 0.04 ± 0.1 (range, 0 to 0.81). There was a positive association between lymph node density and depth of tumor invasion (Pearson correlation coefficient, r = 0.21; P.001). Tumors with perineural invasion had a statistically significant difference in mean lymph node density (0.074 for positive vs 0.024 for negative; P.001). There also was a significant association in mean lymph node density with the presence of extracapsular spread (0.143 for positive and 0.010 for negative; P.001).Statistically relevant positive linear relations among lymph node density, depth of invasion, perineural invasion, and extracapsular spread were identified. Lymph node density could have prognostic implications, because it is statistically correlated with other known prognostic features that lead to poor outcomes. Lymph node density could be an important feature to capture in future prospective trials. Pathology standards would be crucial in this endeavor.

Squamous cell carcinoma (SCC) accounts for more than 90% of malignancies of the oral cavity and oropharynx. Globally, SCC is one of the top ten cancers with a predilection for older males. In the U.S., SCC accounts for more deaths annually than cervical cancer, malignant melanoma or Hodgkin's lymphoma and costs about 2 billion dollars in treatment expenses. The 5-year survival rate is less than 50%, a prognosis that is poorer than that of breast cancer or melanoma.2 Significant numbers of patients develop local recurrence, second primary tumors and distant metastases. Patients presenting with late stage disease resulting in poor survival, are common; in part due to inadequate screening protocols and access to care issues. In the following review article, the risk factors, current screening protocols, treatment options and biomarkers for diagnosis and prognosis of SCC, will be discussed.

The purpose of this study was to investigate the critical primary tumor depth of invasion in oral squamous cell carcinoma that would lead to a 20% or greater risk of nodal metastasis.An institutional review board approved retrospective review of our head and neck database was performed from 2009 to 2014 and the data were statistically analyzed.Two hundred eighty-six patients with a diagnosis of oral squamous cell carcinoma who met our inclusion criteria underwent primary excision and neck dissection. For a depth of invasion of 1 mm or less, there were no patients with a positive node. From 1.1 mm to 2 mm of depth of invasion, there was 1 of 11 patients (9%) who had at least 1 positive node. At 2.1 mm to 3 mm, 5 of 25 patients (20%) had at least 1 positive node.Depth of invasion and the location of the tumor are 2 important variables to consider when making treatment recommendations to patients with clinical N0 disease. © 2017 Wiley Periodicals, Inc. Head Neck 39: 974-979, 2017.