Robust Differences in p16-Dependent Oropharyngeal Squamous Cell Carcinoma Distant Metastasis: Implications for Targeted Therapy.

OBJECTIVE: Historically, head and neck squamous cell carcinoma (HNSCC) has been earmarked a lymphatic malignancy. Recently, this has been called into question. Our study aims to (1) illustrate the robust differences in distant metastases between p16+ and p16- oropharyngeal squamous cell carcinoma (OPSCC) and (2) provide support that p16+ OPSCC has a predilection toward vasculature invasion and hematogenous spread. STUDY DESIGN: Multi-institutional, case series with chart review. SETTING: Four academic institutions. SUBJECTS AND METHODS: Within a group of 1113 patients with primary OPSCC who received treatment between 1979 and 2013, those who developed distant metastasis (DM) were divided into 2 cohorts based on p16 status. Intergroup and intragroup univariate analysis was performed as well as descriptive analysis of end-organ sites. RESULTS: Of the 1058 patients included, 89 developed DM. Thirty were p16- and 59 were p16+. Of the p16- patients with DM, only 10% had disseminated disease (distant metastases at ≥2 sites) compared with 74% of p16+ patients. Distant disease in p16+ patients included brain, abdomen, and a distinct pattern of pulmonary metastases. CONCLUSION: Our large, multi-institutional study supports published reports that p16+ OPSCC metastasizes with a unique phenotype that is hematogenous and widely disseminated with atypical end-organ sites. Our data suggest that p16+ OPSCC has a predilection toward active vasculature invasion as evidenced by the results and illustrative radiologic and pathohistologic examples. These findings may have implications for future targeted therapy when treating p16+ OPSCC.

Multi-institutional investigation of the prognostic value of lymph nodel yield in advanced-stage oral cavity squamous cell carcinoma.

BACKGROUND: Although existing literature provides surgical recommendations for treating occult disease (cN0) in early-stage oral cavity squamous cell carcinoma (SCC), a focus on late-stage oral cavity SCC is less pervasive. METHODS: The medical records of 162 patients with late-stage oral cavity SCC pN0 who underwent primary neck dissections were reviewed. Lymph node yield as a prognosticator was examined. RESULTS: Despite being staged pN0, patients that had a higher lymph node yield had an improved regional/distant control rates, disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). Lymph node yield consistently outperformed all other standard variables as being the single best prognostic factor with a tight risk ratio range (RR = 0.95-0.98) even when correcting for the number of lymph nodes examined. CONCLUSION: The results of this study showed that lower regional recurrence rates and improved survival outcomes were seen as lymph node yield increased for advanced T classification oral cavity SCC pN0. This suggests that increasing lymph node yield with an extended cervical lymphadenectomy may result in lower recurrence rates and improved survival outcomes for this advanced stage group.

Recurrent post-tympanostomy tube otorrhea secondary to aerobic endospore-forming bacilli: a case report and brief literature review.

We report a unique case in which a 57-year-old man with an 8-year history of late recurrent post-tympanostomy tube otorrhea (PTTO) was found to harbor Bacillus subtilis, an aerobic endospore-forming bacillus that is typically resistant to chemical and physical agents because of its unique life cycle. Removal of the patient's tympanostomy tube resulted in complete resolution of his long-standing otorrhea. We also review the etiologies of and treatment strategies for early, late, chronic, and recurrent PTTO. We conclude that regardless of the etiology, a patient with persistent or recurrent PTTO should consider undergoing removal of the ventilation tube.

Etiologic causes of late osteocutaneous free flap failures in oral cavity cancer reconstruction.

OBJECTIVES/HYPOTHESIS: To evaluate perioperative complications in a homogeneous cohort undergoing microvascular osteocutaneous free flap (OCFF) reconstruction following segmental mandibulectomy for advanced oral cancer and to identify the causes of late OCFF failures. STUDY DESIGN: Retrospective chart review. METHODS: The records of 65 adults who underwent a segmental mandibulectomy for primary oral cavity cancer followed by single-stage reconstruction OCFF were reviewed. Early and late complications were identified and their associations to patients' independent variables and to each other were analyzed to assess etiologic causes of late OCFF failure. RESULTS: The incidence of early and late complications mirrored each another at 29%, and a 95% early-success rate was achieved. An early complication did predict an early infection (odds ratio [OR], 63.3; 95% confidence interval [CI], 6.8-585.3). Furthermore, an early perioperative infection impacted the incidence of late complications (OR, 4.8; 95% CI, 1.3-18.3), and moreover severely impacted the incidence of osteomyelitis/osteoradionecrosis (OR, 8.8; 95% CI, 1.8-41.9) and late failures (OR, 12.8; 95% CI, 1.9-84.5). CONCLUSIONS: Mandibular reconstruction following segmental mandibulectomy provides immediate restoration but is often plagued with perioperative complications that are difficult to predict. Early perioperative infections impact patient long-term morbidity by increasing the risk of late graft failure by almost 13-fold. Consequently, it is felt that early aggressive treatment of these infections may reduce the incidence and severity of late complications and improve patient outcomes.

Postlaryngectomy dysphagia masking as velopharyngeal insufficiency: a simple solution for an anterior neopharyngeal diverticulum.

Postlaryngectomy dysphagia is a common occurrence and can be a source of emotional distress that results in a decrease in quality of life among a patient population that is already exposed to considerable morbidity. One etiologic source that is less commonly reported as a source for postlaryngectomy dysphagia, and perhaps overlooked, is an anterior neopharyngeal diverticulum. Herein, we describe a postlaryngectomy dysphagia caused by a neopharyngeal diverticulum masking as velopharyngeal insufficiency of liquids. The liquid dysphagia was immediately relieved via transoral endoscopic approach using the Harmonic scalpel to resect and simultaneously coagulate the posterior wall.

Inner ear effects of canal wall down mastoidectomy.

OBJECTIVE: To evaluate the inner ear effects of canal wall down (CWD) mastoidectomy without ossiculoplasty in the treatment of chronic otitis media (COM) with regard to sensorineural hearing loss (SNHL) and reported tinnitus and dizziness-related disability. SETTING: Tertiary care academic medical center. SUBJECTS AND METHODS: Prospective study of 86 patients treated by CWD mastoidectomy without ossiculoplasty for COM with or without cholesteatoma. Standard patient workup included preoperative audiogram and completion of 2 surveys: Dizziness Handicap Inventory (DHI) and Tinnitus Handicap Inventory (THI). Patients underwent repeat audiogram, DHI, and THI surveys at 4 to 6 months postoperatively. Preoperative and postoperative data were analyzed. RESULTS: No significant SNHL occurred after CWD mastoidectomy. Thirteen patients (13/34 [38%]) had DHI improvement greater than 18 points, indicating a significant improvement in dizziness-related disability. Three patients developed new-onset postoperative dizziness complaints. Twenty patients (20/43 [46.5%]) had THI improvement greater than 7 points, indicating a significant improvement in tinnitus-related disability. Five patients developed new-onset postoperative tinnitus complaints. The odds ratio for improving DHI and THI scores after surgery was 6.6 (1.8 to 25.0) and 4.2 (95% confidence interval, 1.45% to 12.2%), respectively. CONCLUSION: In this study, CWD mastoidectomy without ossiculoplasty in the treatment of COM did not cause significant SNHL. In addition, using the DHI and THI measures, patient-perceived disability from dizziness and tinnitus, respectively, was shown to decrease after mastoid surgery.

Obstructing encephaloceles presenting as chronic rhinosinusitis: lessons learned from a case series.

We present a unique anatomic cause of encephalocele, and describe appropriate diagnosis. Two patients underwent stereotactic image-guided sinus surgery for presumed chronic rhinosinusitis with intraoperative findings of a sinus encephalocele. The first patient underwent a conservative 2-stage management that included an initial cerebrospinal fluid (CSF) leak repair followed by encephalocele resection. The second patient underwent a 1-stage encephalocele resection and CSF leak repair with a septal graft. The sinus surgeon needs to consider the possibility of encephalocele when the ethmoid, sphenoid, or, rarely, frontal sinuses present with an isolated opacification that does not improve with conservative medical therapy.

Evolving treatment strategies in thin cutaneous head and neck melanoma: 1 institution's experience.

BACKGROUND: Although existing melanoma literature provides recommendations for thinner lesions (≤1 mm) within a heterogeneous population, a focus on the head and neck group is less pervasive. METHODS: The records of 49 node-negative individuals with thin head and neck melanoma that underwent surgical intervention ± sentinel lymph node (SLN) biopsy were reviewed. RESULTS: A significant increased Breslow thickness and mitotic rate, and a trend toward significance in Clark level ≥ IV were shown in patients that underwent an SLN biopsy versus those that did not. The total number of positive biopsies was 2 (5%). In our subset analysis using the modified American Joint Committee on Cancer recommendations by Wong and colleagues, the incidence of positive SLN biopsy would have increased to 11%. CONCLUSION: We advocate performing an SLN biopsy in thin head and neck melanomas for primary tumors > 0.75 mm, regardless of "high-risk" features as described by Wong and colleagues.

Osseointegrated implant applications in cosmetic and functional skull base rehabilitation.

This study discusses the indications, outcomes, and complications in patients that underwent osseointegrated implantation for skull base rehabilitation. We conducted a retrospective review of eight patients with skull base defects who had undergone implantation of a facial prosthetic retention device ± bone-anchored hearing aid at a tertiary academic referral center. Descriptive analysis of applications, techniques, outcomes, and complications were reviewed. The majority of patients were males (n = 6) with previously diagnosed skull base malignancy (n = 5) with an average age of 46 (range, 14 to 77). All patients received an implanted facial prosthetic device either for an aural (n = 7) or orbital (n = 1) prosthesis. There were only two complications that included infection (n = 1) and implant extrusion (n = 1). Osseointegrated implantation of abutments for anchoring prosthetic devices in patients for skull base rehabilitation provides an excellent cosmetic option with minimal complications.

A 25-year analysis of veterans treated for tonsillar squamous cell carcinoma.

OBJECTIVE: To determine the recurrence and survival outcome based on treatment date, type of treatment, stage of disease, and comorbidity and the recurrence and survival differences based on smoking status as a surrogate for human papillomavirus status in veterans treated for tonsillar squamous cell carcinoma (SCC). DESIGN: Outcome cohort study. SETTING: Tertiary care Department of Veterans Affairs hospital. PATIENTS: A consecutive sample from 1981 through 2006 of 683 patients treated for oropharyngeal SCC was screened, and 141 patients with tonsillar SCC without distant metastatic spread and a minimum of 2 years of follow-up were included. MAIN OUTCOME MEASURES: Disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). RESULTS: Disease-free survival was significantly better in cohort II (treated during or after 1997) compared with cohort I (treated before 1997) (2- and 5-year DFS, 82% vs 64% and 67% vs 48%; P = .02). Disease-specific survival was better in the surgical vs nonsurgical group (2- and 5-year DSS, 77% vs 46% and 67% vs 30%; P < .001), as was the OS (2- and 5-year OS, 66% vs 41% and 45% vs 23%; P = .005). In subjects with early-stage disease, OS and DSS were not different regardless of treatment type. In subjects with late-stage disease treated most recently (time cohort II), there was significantly better DSS in those receiving surgical vs nonsurgical treatment (2-year DSS, 70% vs 43%; P = .045). Nonsmokers had better OS (94 months vs 41 months; P = .001) and lower incidence of recurrence (8% vs 44%; P = .02). CONCLUSION: In veterans treated for tonsillar SCC, we advocate the consideration of a treatment plan that includes surgery for patients presenting with advanced-stage SCC of the tonsil, even in patients with notable comorbidities.

Radiotherapy-associated euthyroid Graves ophthalmopathy following floor-of-mouth surgery: a case report.

The thyroid gland is commonly included in the radiation field during treatment of nonthyroidal neoplastic disease of the head and neck. As a result, thyroid abnormalities sometimes occur following external irradiation. We report an unusual case of radiotherapy-associated Graves ophthalmopathy 5 months after adjuvant external irradiation of the head and neck in a euthyroid patient who had undergone wide local excision of squamous cell carcinoma from the floor of the mouth.

Cervical spine causes for referred otalgia.

OBJECTIVE: Present experience in diagnosis and treatment for referred otalgia secondary to cervical spine degenerative disease (CSDD). STUDY DESIGN: A retrospective study of 123 patients with ear pain. SUBJECTS AND METHODS: All patients had a normal otologic examination and diagnosed with unspecified otalgia. The causes for referred otalgia were categorized into Group I: otalgia from non-cervical spine disease (n = 72), and Group II: cervical spine disease-referred otalgia (n = 51). Pain relief following cervical spine physical therapy (CSPT) was assessed. RESULTS: The most common cause for referred otalgia in Group I was Temporomandibular joint (TMJ) dysfunction (46%); most common cervical spine finding in Group II was CSDD (88%). CSPT in those documented patients all reported subjective pain relief. CONCLUSION: As the population in America ages, CSDD in the elderly will begin to emerge as a major etiologic source for referred otalgia. With a targeted medical history and physical examination one can use directed studies to diagnose CSDD-referred otalgia, and this pain can be alleviated with CSPT.

Early steroid withdrawal therapy in renal transplant recipients: a steroid-free sirolimus and CellCept-based calcineurin inhibitor-minimization protocol.

BACKGROUND: Maintenance steroid therapy is associated with significant morbidity and mortality in renal transplant recipients. Elimination of the many long-term side effects of corticosteroids, including those that impinge on cardiovascular risk, remains a laudable goal in designing immunosuppressive protocols. However, concern persists that prednisone-free maintenance immunotherapy in kidney transplant recipients will result in an increase incidence of acute rejections, renal dysfunction and ultimate graft loss. METHODS: From 24 March 2003 to 1 December 2004, 84 kidney transplant recipients (61 deceased donor, 23 living donors) discontinued prednisone on post-operative day 6. Immunotherapy consisted of polyclonal antibody induction (thymoglobulin) for five d and prednisone intraoperatively with a rapid taper over the next six d. Maintenance therapy consisted of a sirolimus and CellCept-based calcineurin inhibitor-minimization protocol. Tacrolimus and mycophenolate mofetil (CellCept) were initiated on day 0. Sirolimus immunotherpay was started on post-operative day 6 concomitant with the cessation of steroids. We compared outcomes with that of our historical controls, treated with sirolimus and tacrolimus, who did not discontinue steroids. In addition, we analyzed outcomes independently for recipients of living and deceased donors in the steroid-free protocol. RESULTS: The recipients on prednisone-free maintenance immunosuppression had excellent 2.5-yr actuarial patient survival (97%), graft survival (93%), and acceptable acute rejection-free graft survival (89%). The mean serum creatinine level (+/-SD) at one yr was 1.5 +/- 0.6 mg/dL and at two yr was 1.5 +/- 0.6 mg/dL. We noted that 5% of recipients developed cytomegalovirus (CMV) syndrome; 1%, polyoma nephropathy; 1%, post-transplant lymphoproliferative disorder (PTLD), and 5% developed post-transplant diabetes mellitus (PTDM). In all, 91% of kidney recipients with functioning grafts remain steroid-free as of 31 December 2005. When compared with historical controls, the recipients on the early steroid-withdrawal (ESW) protocol had comparable graft survival, acute rejection-free survival, graft function, but significantly better patient actuarial survival (p = 0.048). In addition, recipients on the steroid-free protocol had decreased prevalence of four risk factors for cardiovascular disease when compared with historical controls: hypertension (p = 0.008), hyperlipidemia (p = 0.003), weight gain (p = 0.024), and incidence of PTDM (p = 0.015). CONCLUSION: Early steroid-withdrawal in renal transplant recipients with a sirolimus and CellCept-based calcineurin inhibitor-minimimization protocol can effectively reduce many of the steroid-related side effects, decrease risk factors for cardiovascular disease, and is associated with improved recipient survival without compromising graft function.

Synthesis and structure revision of calyxin natural products.

Tandem Prins cyclization and Friedel-Crafts reaction with an electron-rich aromatic ring were used to prepare the core structures of calyxin natural products. The proposed structure of epicalyxin F was prepared and shown to be incorrect. Several calyxin natural products, including calyxin F and L, were synthesized, and the structures were reassigned on the basis of NMR data and synthetic correlations.

Synthesis of (-)-centrolobine by Prins cyclizations that avoid racemization.

[formula: see text] The segment-coupling Prins cyclization avoids two of the problems common to other Prins cyclization protocols: side-chain exchange and partial racemization by reversible 2-oxonia Cope rearrangement. Model studies demonstrate the stereochemical fidelity of Prins cyclizations using alpha-acetoxy ethers compared with direct aldehyde-alcohol Prins reactions. Furthermore, we propose a mechanism for the racemization observed in some intermolecular Prins cyclizations. Two straightforward syntheses of optically pure (-)-centrolobine highlight the utility of Prins cyclizations.