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OBJECTIVERadiation dose to the cochlea has been proposed as a key prognostic factor in hearing preservation following stereotactic radiosurgery (SRS) for vestibular schwannoma (VS). However, understanding of the predictive value of cochlear dose on hearing outcomes following SRS for patients with non-VS tumors of the lateral skull base (LSB) is incomplete. The authors investigated rates of hearing loss following high-dose SRS in patients with LSB non-VS lesions compared with patients with VS.METHODSPatients with LSB meningioma or jugular paraganglioma and serviceable pretreatment hearing who underwent SRS treatment during 2007–2016 and received a modiolus dose > 5 Gy were included in a retrospective cohort study, along with a similarly identified control group of consecutive patients with sporadic VS.RESULTSSixteen patients with non-VS tumors and a control group of 43 patients with VS met study criteria. Serviceable hearing, defined as American Academy of Otololaryngology–Head and Neck Surgery class A/B, was maintained in 13 non-VS versus 23 VS patients (81% vs 56%, p = 0.07). All 3 instances of hearing loss in non-VS patients were observed in cerebellopontine angle (CPA) meningiomas. Non-VS with preserved hearing had a median modiolus dose of 6.9 Gy (range 5.7–19.2 Gy), versus 7.4 Gy (range 5.4–7.6 Gy) in those patients with post-SRS hearing loss (p = 0.53). Sporadic VS patients received an overall median modiolus point-dose of 6.8 Gy (range 5.4–11.7 Gy).CONCLUSIONSThe modiolus dose threshold of 5 Gy does not predict hearing loss in patients with non-VS tumors undergoing SRS, suggesting that dosimetric parameters derived from VS may not be applicable to this population. Differential rates of hearing loss appear to vary by pathology, with paragangliomas and petroclival meningiomas demonstrating decreased risk of hearing loss compared to CPA meningiomas that may directly compress the cochlear nerve similarly to VS.

Background Treatment of superficial venous reflux in addition to compression therapy accelerates venous leg ulcer healing and reduces ulcer recurrence. The aim of this study was to evaluate the costs and cost-effectiveness of early versus delayed endovenous treatment of patients with venous leg ulcers. Methods This was a within-trial cost-utility analysis with a 1-year time horizon using data from the EVRA (Early Venous Reflux Ablation) trial. The study compared early versus deferred endovenous ablation for superficial venous truncal reflux in patients with a venous leg ulcer. The outcome measure was the cost per quality-adjusted life-year (QALY) over 1 year. Sensitivity analyses were conducted with alternative methods of handling missing data, alternative preference weights for health-related quality of life, and per protocol. Results After early intervention, the mean(s.e.m.) cost was higher (difference in cost per patient £163(318) (€184(358))) and early intervention was associated with more QALYs at 1 year (mean(s.e.m.) difference 0·041(0·017)). The incremental cost-effectiveness ratio (ICER) was £3976 (€4482) per QALY. There was an 89 per cent probability that early venous intervention is cost-effective at a threshold of £20 000 (€22 546)/QALY. Sensitivity analyses produced similar results, confirming that early treatment of superficial reflux is highly likely to be cost-effective. Conclusion Early treatment of superficial reflux is highly likely to be cost-effective in patients with venous leg ulcers over 1 year. Registration number: ISRCTN02335796 (http://www.isrctn.com).

The application of information technology to finance, or “fintech,” is expected to revolutionize many aspects of borrowing and lending in the future, but technology has been reshaping consumer and mortgage lending for many years. During the 1990s computerization allowed mortgage lenders to reduce loan-processing times and largely replace human-based assessment of credit risk with default predictions generated by sophisticated empirical models. Debt-to-income ratios at origination add little to the predictive power of these models, so the new automated underwriting systems allowed higher debt-to-income ratios than previous underwriting guidelines would have typically accepted. In this way, technology brought about an exogenous change in lending standards, which helped raise the homeownership rate and encourage the conversion of rental properties to owner-occupied ones, but did not have large effects on housing prices. Technological innovation in mortgage underwriting may have allowed the 2000s housing boom to grow, however, because it enhanced the ability of both borrowers and lenders to act on optimistic beliefs about future house-price growth.

Opinion statement Taste sensation is vital for a healthy body as it influences our food intake, acts as a defense mechanism and elicits pleasure. Majority of the head and neck cancer (HNC) patients undergoing radiotherapy suffer from altered taste function and often complain of inability to taste their food, reduced food intake, and weakness. However, there are not many studies conducted to assess this commonly reported side effect. Furthermore, clinical research on radiotherapy-induced taste alterations has proven to be difficult, considering a lack of reliable and validated study tools for assessing objective and subjective outcomes. Developing standardized tools for assessment of taste function and conducting prospective studies in larger population of HNC is the need of the hour. Taste sensation being critically important for sustenance, we need to focus on ways to preserve it. The physical properties of proton particle enable localization of the radiation dose precisely to the tumor and minimizing the exposure of the adjacent healthy tissues. By using Intensity-Modulated Proton Therapy in HNC patients, we anticipate preserving the taste sensation by reducing the dose of radiation to the taste buds.

BACKGROUND Surgical resection is typically cited as the optimal treatment of patients with Spetzler-Martin Grade I-II arteriovenous malformation (AVM). OBJECTIVE To report our experience with single-fraction stereotactic radiosurgery (SRS) for Spetzler-Martin Grade I-II AVM. METHODS A prospectively maintained registry was reviewed for patients with nonsyndromic Spetzler-Martin Grade I-II AVM having SRS from 1990 to 2011. Patients with

To determine whether N-acetylcysteine rinse was safe and could improve thickened secretions and dry mouth during and after radiotherapy.We designed a prospective pilot double-blind, placebo-controlled randomized clinical trial (Alliance MC13C2). Adult patients (age ≥18 years) were enrolled if they underwent chemoradiotherapy (≥60 Gy). Patients initiated testing rinse within 3 days of starting radiotherapy. With swish-and-spit, they received 10% N-acetylcysteine (2500 mg daily) or placebo rinse solution 5 times daily during radiotherapy and 2 weeks postradiotherapy. The primary aim was to evaluate N-acetylcysteine in improvement of saliva viscosity with the Groningen Radiotherapy-Induced Xerostomia questionnaire. Secondary aims included evaluating xerostomia improvement by the same questionnaire and with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck-35 Questions survey and adverse-event profiles. The type I error rate was 20%.Thirty-two patients undergoing chemoradiotherapy were enrolled. Baseline characteristics were balanced for placebo (n=17) and N-acetylcysteine (n=15). N-acetylcysteine was better for improving sticky saliva (area under curve, P=.12). Scores of multiple secondary end points favored N-acetylcysteine, including sticky saliva daytime (P=.04), daytime and total xerostomia (both P=.02), pain (P=.18), and trouble with social eating (P=.15). Repeated measures models confirmed the findings. Taste was a major dissatisifer for N-acetylcysteine rinse; however, both testing rinses were safe and well tolerated overall.Our pilot data showed that N-acetylcysteine rinse was safe and provided strong evidence of potential efficacy for improving thickened saliva and xerostomia by patient-reported outcome. A confirmatory phase 3 trial is required.clinicaltrials.gov Identifier: NCT02123511.

Background Past research established that surgery plus adjuvant radiotherapy (S + AR) improves overall survival (OS) in esthesioneuroblastoma (ENB). However, it is unknown if the addition of adjuvant chemotherapy (AC) further improves survival. The primary objective of this study was to compare survival among patients treated with S + AR alone to patients who underwent S + AR + AC. Methods Retrospective review of patient records. Results Thirty-eight patients met inclusion criteria for either S + AR or S + AR + AC treatment groups. The S + AR + AC group contained more patients with Kadish stage D disease, dural invasion, and positive histologic margins postsurgery. All S + AR + AC patients received platinum-based regimens, combined with etoposide in 67%. OS and recurrence-free survival did not differ between the two groups, even when restricting the analysis to patients with Kadish stages B and C disease. Conclusion Patients who received platinum-based AC did not exhibit improved survival compared to S + AR alone. Further investigation, preferably prospective, into the optimal use of systemic therapy in ENB is warranted.

PURPOSE: To study the effects of metastasis-directed stereotactic body radiation therapy (mdSBRT) on CD8(+) T-cell subpopulations and to correlate post-mdSBRT immunophenotypic responses with clinical outcomes in patients with oligometastatic prostate cancer (OPCa). METHODS AND MATERIALS: Peripheral blood mononuclear cells (PBMCs) were prospectively isolated from 37 patients with OPCa (≤3 metastases) treated with mdSBRT. Immunophenotyping identified circulating CD8(+) T-cell subpopulations including: Tumor-Reactive (T(TR)), Effector Memory (T(EM)), Central Memory (T(CM)), Effector (T(EF)), and Naïve (T(N)) T-cells from samples collected before and after mdSBRT. Univariate Cox proportional hazards regression was used to assess whether changes in these T-cell subpopulations were potential risk factors for death and/or progression. Kaplan-Meier method was used for survival. Cumulative incidence for progression and new distant metastasis was estimated considering death as a competing risk. RESULTS: Median follow-up was 39 months (IQR 34–43). Overall survival at 3 years was 78.2%. Cumulative incidence for local progression and new distant metastasis at 3 years was 16.5% and 67.6%, respectively. Between baseline and day 14 after mdSBRT, an increase in the T(CM) cell subpopulation was associated with the risk of death (HR 1.22 [95%CI, 1.02–1.47]; P=0.033), and an increase in the T(TR) cell subpopulation was protective against the risk of local progression (HR 0.80 [95%CI, 0.65–0.98]; P=0.032). CONCLUSIONS: An increase in the T(TR) cell subpopulation was protective against the risk of disease progression while an increase in the T(CM) cell subpopulation was associated with the risk of death in patients with OPCa treated with mdSBRT. Disease control may be further improved by better understanding the CD8(+) T-cell subpopulations, and by enhancing their anti-tumor effect.

Intensity-modulated proton therapy minimizes the incidental irradiation of normal tissues in patients with head and neck cancer relative to intensity-modulated photon (x-ray) therapy and has been associated with lesser treatment-related toxicity and improved quality of life. A phase II/III randomized trial sponsored by the US National Cancer Institute is currently underway to compare deintensification treatment strategies with intensity-modulated proton therapy vs intensity-modulated photon (x-ray) therapy for patients with advanced-stage oropharyngeal tumors. After significant input from numerous stakeholders, the phase III portion of the randomized trial was redesigned as a noninferiority trial with progression-free survival as the primary endpoint. The process by which that redesign took place is described here.

The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma.

Background Factors predicting locoregional relapse after surgery for oropharyngeal squamous cell carcinoma (SCC) were identified in the pre-human papillomavirus (HPV) era. We examined whether traditional indications for adjuvant radiotherapy (RT) or adjuvant chemoradiotherapy (CRT) still correlate with locoregional relapse in HPV-positive patients after transoral robotic surgery (TORS). Methods Retrospective review of oropharyngeal SCC cases identified patients with HPV-positive tumors who did not receive adjuvant therapy after TORS despite intermediate or high-risk features. Results Median follow-up was 26.7 months (range, 4.9–73.1 months). Five of 25 eligible patients (20%) relapsed at a median 4.8 months (range, 3.2–7.8 months). Two of 18 (11%) intermediate and 3 of 7 (43%) high-risk patients relapsed. Kaplan–Meier 2-year locoregional relapse-free survival estimates for intermediate and high-risk patients were 88% and 57% (p = .078), respectively. Conclusion Traditional indications for adjuvant RT or CRT were associated with high risk of locoregional relapse in HPV-positive patients treated with TORS alone. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

The purpose of this study was to evaluate the impact of offline rotational corrections and assess intrafraction motion for head and neck (HN) cancer patients immobilized with and without a custom neck cushion.Fifty HN cancer patients were immobilized and imaged with pretreatment and posttreatment cone beam computed tomography (CBCT) for each treatment fraction. Of these patients, 25 had a custom neck cushion added to their immobilization. Each CBCT was registered to the simulation computed tomography offline. Registrations were performed with automatching tools and a matching volume of interest that consisted of a 5-mm expansion around the mandible, occipital bone, C1/C2, and C7/T1. To determine positioning accuracy, the registration was inspected to confirm these bony anatomy structures were contained within a 3- or 5-mm expansion of the simulation position. If not, the registration was repeated with rotational corrections included and re-evaluated. For each fraction, intrafraction motion was also quantified through the difference between the pretreatment and posttreatment CBCT registration coordinates.For translational registrations, the bony anatomy in pretreatment imaging was outside the 3-mm or 5-mm expansion structure, respectively, for 49% and 15% of fractions on average for patients without a custom headrest and for 48% and 13% of fractions on average for patients with a custom headrest. The addition of rotational corrections reduced these numbers to 21% and 4% and to 28% and 6%, respectively. Intrafraction motion was significantly lower for patients immobilized with the addition of a custom neck cushion: 1.0 ± 0.5 mm compared with 1.8 ± 1.6 mm for patients with the standard headrest only (P = .02). This was reflected in posttreatment positioning accuracy, which was significantly reduced in the case of the standard headrest compared with pretreatment imaging (P values of.001 to .048).Rotational corrections significantly improved pretreatment patient positioning accuracy (P.001). Intrafraction motion was reduced significantly through the addition of a custom neck cushion and resulted in an increase in posttreatment positioning accuracy for these patients.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (HN the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

Our aim was to assess the long-term results, complications, and factors associated with failure of mandibular reconstructions among wounded Iraqi civilians with mandibular defects. Success was measured by the quality of bony union, and assessed radiographically and by physical examination. Failures were defined as loss of most or all of the bone graft, or inability to control infection. During the 6-year period (2006-2011), 35 Iraqi patients (30 men and 5 women, mean age 33 years, range 15-57) had residual mandibular defects reconstructed by iliac crest bone grafts. The causes were bullets (n=29), blasts (n=3), and shrapnel (n=3). The size of the defect was more than 5cm in 19 cases. Along the mandible the defect was lateral (n=14), central/lateral (n=5), lateral/central/lateral in continuity (n=6), and central in continuity (n=10). The mean time from injury to operation was 548 days (range 45-3814). All but 2 patients had infected lesions on admission. Bony fixation was ensured by locking reconstruction plates (n=27), non-locking reconstruction plates (n=6), and miniplates (n=2). Complications were associated with the reconstruction plate in 2 cases, and donor-site morbidity in 5. After a mean follow-up of 17 months (range 6-54), bony union was achieved in 28 (80%). The quality of the bone was adequate for dental implants in 23 cases (66%). Our results suggest that war-related mandibular defects can be reconstructed with non-vascularised bone grafts by multistage procedures with good results, provided that the soft tissues are in good condition, infection is controlled, and the method of fixation is appropriate. Further studies are needed to assess the role of vascularised free flaps in similar conditions.

The cross ratio is a well known and useful invariant in Euclidean and projective geometries. Since it is invariant under Mobius transformations, it extends to spherical and hyperbolic geometries. I...

Controversy exists regarding the predictive ability of a negative sentinel lymph node biopsy (SLNB) and the use of adjuvant radiation in Merkel cell carcinoma (MCC). Retrospective study of patients with MCC undergoing SLNB at Mayo Clinic from 1995 to 2011. Cumulative incidence (CI) of regional recurrence and death from MCC, respectively, were estimated taking into account the competing risk of death from other causes and compared between groups using Gray’s test. A total of 111 (74 %) of 150 SLNB were negative and comprised our study group. There were 15 regional recurrences, and the CI of a regional recurrence was 5.1, 15.0, and 16.6 % at 1, 3, and 5 years, respectively, after initial surgery. Nine patients (8 % of all patients) experienced a same nodal basin recurrence after a negative SLNB. Among 14 patients who received nodal radiation, the CI of a regional recurrence was 0 and 9.1 % at 1 and 3 years, respectively, compared to 5.8 and 15.5 %, respectively, among the 97 who did not receive nodal radiation (p = 0.45). Male sex was the only characteristic predictive of regional recurrence after a negative SLNB; the CI at 3 years was 21.3 versus 0 % in men and women, respectively (p = 0.007). Head and neck location was not associated with a higher risk of recurrence or an improvement in regional recurrences after radiation. Same nodal basin recurrences are uncommon after SLNB in MCC, and regional nodal irradiation can be avoided in the setting of successful sentinel lymph node mapping and a negative SLNB.

BACKGROUND The purpose of this study was to determine the clinical outcomes and review the management strategies for metastatic esthesioneuroblastoma. METHODS We conducted a systematic review and meta-analysis. RESULTS Forty-eight studies totaling 118 patients met inclusion criteria. Chemotherapy in combination with surgery and/or radiation exhibited the best overall survival when compared to monotherapy and no treatment (P < .001). However, most patients (66%) received either monotherapy or no therapy. The number and location of metastases among the 3 treatment groups did not significantly differ (P = .85). Treatment modality remained significantly associated with overall survival on multivariable analysis (P < .001). Platinum-based chemotherapy was most commonly utilized but did not provide a survival benefit when compared with all other regimens (P = .88). CONCLUSION Distant metastases with esthesioneuroblastoma portend a poor prognosis. Chemotherapy in combination with surgery and/or radiation was associated with improved overall survival. Further research into the optimal systemic therapeutic regimen for patients with distant metastases is critical.

The contemporary treatment paradigm for jugular paraganglioma focuses on the preservation of neurologic function. For this reason, non-invasive means of achieving tumor control with minimal morbidity have been adopted as first line therapeutic options. Conventional radiation therapy is utilized for large, inoperable tumors but carries a small risk of local tissue injury and must be delivered over several weeks. In contrast, stereotactic radiosurgery and radiotherapy, with steep radiation falloff gradients, permits the delivery of a high dose of focused radiation in a single treatment or hypofractionated fashion to arrest tumor growth with reduced collateral injury. In the absence of prior treatment, these modalities achieve tumor control rates of greater than 90% in most series. Radiosurgery for recurrent disease, or in an adjuvant fashion following subtotal tumor resection, has been demonstrated to yield similar tumor control while avoiding cranial nerve damage that may occur with attempts at gross total tumor resection. Patients may experience an attendant decrease in symptoms such as pulsatile tinnitus, making this an attractive treatment option when the risk associated with surgery is high.

Purpose To characterize the changes in the use of radiation therapy (RT), specifically proton beam radiation therapy (PBRT), among adult and pediatric patients over a 11-year period in a very large population of insured patients. Methods and Materials We conducted a retrospective analysis of the OptumLabs Data Warehouse claims database of more than 100 million insured US enrollees. Descriptive analyses were undertaken to evaluate the characteristics of patients receiving RT from 2002 to 2012. Results There were 474,533 patients treated with RT from 2002 to 2012. The percentage of patients treated with 3-dimensional conformal radiation therapy, 2-dimensional RT/brachytherapy, intensity modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and PBRT was 34.5%, 63.4%, 2.1%, 0.0%, and 0.1% and 40.4%, 36.0%, 21.9%, 1.1%, and 0.6% in 2002 and 2012, respectively. The greatest increase in utilization was of IMRT for prostate cancer, growing from 3.5% to 64.0%. For non–prostate cancer adults, IMRT use grew from 1.7% to 16.4%. For children, PBRT utilization increased from 0.3% to 9.7%. For prostate cancer patients, PBRT increased from 0.0% to 2.6%. For all patients, advanced technology (SBRT and PBRT) use was very low at Conclusions This is the largest and most geographically diverse description of RT utilization. Proton beam RT utilization remains very low and has had little impact on overall RT utilization compared with IMRT. The largest shift has occurred in IMRT for prostate cancer. Our findings indicate that overall utilization of proton therapy has been low and that its use has likely had little impact on national expenditures on cancer care in the current environment.

OBJECTIVEThe morbidity of gross-total resection of jugular paraganglioma (JP) is often unacceptable due to the potential for irreversible lower cranial neuropathy. Stereotactic radiosurgery (SRS) has been used at the authors’ institution since 1990 for the treatment of JP and other benign intracranial tumors. Conventional means of assessing tumor progression using linear measurements or elliptical approximations are imprecise due to the irregular shape and insinuating growth pattern of JP. The objective of this study was to assess long-term tumor control in these patients by using slice-by-slice 3D volumetric segmentation of serial MRI data.METHODSRadiographic data and clinical records were reviewed retrospectively at a single, tertiary-care academic referral center for patients treated from 1990 to 2017. Volumetric analyses by integration of consecutive tumor cross-sectional areas (tumor segmentation) of serial MRI data were performed. Tumor progression was defined as volumetric growth of 15% or greater over the imaging interval. Primary outcomes analyzed included survival free of radiographic and clinical progression. Secondary outcomes included new or worsened cranial neuropathy.RESULTSA total of 85 patients were treated with Gamma Knife radiosurgery (GKRS) for JP at the authors’ institution over the last 27 years. Sixty patients had pretreatment and serial posttreatment contrast-enhanced MRI follow-up suitable for volumetric analysis. A total of 214 MR images were analyzed to segment tumor images in a slice-by-slice fashion to calculate integral tumor volume. The median follow-up duration was 66 months (range 7–202 months). At 5 years the tumor progression-free survival rate was 98%. Three tumors exhibited progression more than 10 years after GKRS. Estimated survival free of radiographic progression rates (95% confidence interval [CI]; n = number still at risk) at 5, 10, and 15 years following radiosurgery were 98% (95% CI 94%–100%; n = 34), 94% (95% CI 85%–100%; n = 16), and 74% (95% CI 56%–98%; n = 6), respectively. One patient with tumor progression required treatment intervention using external beam radiation therapy, constituting the only case of clinical progression. Two patients (3%) without preexisting lower cranial nerve dysfunction developed new ipsilateral vocal fold paralysis following radiosurgery.CONCLUSIONSSRS achieves excellent long-term tumor control for JP without a high risk for new or worsened cranial neuropathy when used in primary, combined modality, or recurrent settings. Long-term follow-up is critical due to the potential for late radiographic progression (i.e., more than 10 years after SRS). As none of the patients with late progression have required salvage therapy, the clinical implications of this degree of tumor growth have yet to be determined.

Purpose: Charged particle facility design and operation presents numerous challenges, both technical and operational. The Mayo Clinic Proton Beam Therapy Program (PBTP) will consist of 2 proton radiation therapy facilities, each with 4 treatment gantries and 1 fixed beam room, located in Rochester, MN and Phoenix, AZ, respectively, operating under a single organizational structure. The proton facilities will open in 2015 and treat approximately 2,400 patients per year when fully operational. Materials and Methods: To facilitate development of a unified organizational culture for the Mayo Clinic PBTP, a survey consisting of open ended queries regarding facility design and organizational culture was sent to 36 charged particle treatment facilities worldwide and analyzed using McKinsey's 7-S model of organizational values. The survey was also given to the Mayo PBTP planning group. Results: The survey revealed the external respondents felt that aspects of organizational culture involving management s...

Background Stereotactic radiosurgery is widely applied to deliver additional dose to head and neck tumors. However, its safety and efficacy remains equivocal. Methods One hundred eighty-four patients with primary head and neck cancers treated between January 1990 and August 2012 with Gamma Knife stereotactic radiosurgery were retrospectively reviewed. Results Two hundred fifteen sites were treated with Gamma Knife stereotactic radiosurgery among 184 patients. Fifty-one percent of patients received concurrent external beam radiotherapy (EBRT), 72% had prior surgery, and 46% received chemotherapy. Most (44%) had squamous cell carcinoma and most patients (65%) were treated for recurrent disease. With a median follow-up of 17.3 months, 12-month local control was 82%. Late effects occurred in 59 patients with the most common being temporal lobe necrosis (15 patients). Conclusion Radiosurgery can provide tumor control for patients with head and neck cancers involving the skull base. Long-term follow-up is important in survivors to identify late effects. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1557–1562, 2015

Purpose Painful oral mucositis (OM) is a significant toxicity during radiotherapy for head and neck cancers. The aim of this randomized, double-blind, placebo-controlled trial was to test the efficacy of doxepin hydrochloride in the reduction of radiotherapy-induced OM pain. Patients and Methods In all, 155 patients were randomly allocated to a doxepin oral rinse or a placebo for the treatment of radiotherapy-related OM pain. Patients received a single dose of doxepin or placebo on day 1 and then crossed over to receive the opposite agent on a subsequent day. Pain questionnaires were administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes. Patients were then given the option to continue doxepin. The primary end point was pain reduction as measured by the area under the curve (AUC) of the pain scale using data from day 1. Results Primary end point analysis revealed that the AUC for mouth and throat pain reduction was greater for doxepin (−9.1) than for placebo (−4.7; P < .001). Crossover analysis of patients completing both phases confirmed that patients experienced greater mouth and throat pain reduction with doxepin (intrapatient changes of 4.1 for doxepin-placebo arm and −2.8 for placebo-doxepin arm; P < .001). Doxepin was associated with more stinging or burning, unpleasant taste, and greater drowsiness than the placebo rinse. More patients receiving doxepin expressed a desire to continue treatment than did patients with placebo after completion of each of the randomized phases of the study. Conclusion A doxepin rinse diminishes OM pain. Further studies are warranted to determine its role in the management of OM.

Summary Objectives Standard treatment for patients with poor-risk, resected head and neck squamous cell carcinoma (HNSCC) is adjuvant radiation therapy combined with high-dose cisplatin. Many patients are treated with weekly cisplatin; it is not known whether weekly and high-dose cisplatin are equivalent. This study compares the outcomes of patients with locally-advanced HPV-negative HNSCC and HPV/p16-positive oropharynx HNSCC treated with adjuvant chemoradiation therapy with either high-dose or weekly cisplatin. Materials and methods Retrospective review of patients with Stage III/IV HNSCC who had surgery followed by adjuvant chemoradiation therapy at Mayo Clinic, Rochester. HPV and/or p16 status was available for all oropharynx patients. Results 104 Patients (51 high-dose, 53 weekly) were analyzed. The 3-year overall survival was 84% and 75% for patients who received high dose and weekly cisplatin, respectively ( p = 0.30). The 3-year recurrence free survival was 71% and 74% in the high dose and weekly cisplatin group, respectively ( p = 0.95). Patients with HPV/p16-positive oropharynx cancer who received adjuvant chemoradiation therapy with high-dose and weekly cisplatin had three-year overall survival rates of 91% and 86% ( p = 0.56), and 3-year recurrence free survival of 84% and 82% ( p = 0.93). Extracapsular extension did not affect prognosis in either group. Conclusions No significant survival difference was seen between patients with locally advanced HNSCC treated with adjuvant chemoradiation therapy with high-dose or weekly cisplatin, although there was a trend for improved survival with high-dose cisplatin. Weekly cisplatin in the adjuvant setting may be a better treatment for patients with HPV-positive oropharynx cancer to preserve survival and minimize toxicity.

Background Management of neurofibromatosis type 2 (NF2)-associated vestibular schwannomas (VSs) remains controversial. Stereotactic radiosurgery (SRS) with conventional dosing is less effective for NF2-related VS compared with sporadic lesions. Objective To evaluate optimal SRS dose parameters for NF2-related VS and to report long-term outcomes. Methods A prospective database was reviewed and outcome measures, including radiographic progression, American Academy of Otolaryngology-Head and Neck Surgery hearing class, and facial nerve function, were analyzed. Progression-free survival was estimated with Kaplan-Meier methods. Associations between tumor progression and radiosurgical treatment parameters, tumor volume, and patient age were explored with the use of Cox proportional hazards regression. Results Between 1990 and 2010, 26 patients with 32 NF2-related VSs underwent SRS. Median marginal dose and tumor volume were 14 Gy and 2.7 cm, respectively. Twenty-seven tumors (84%) showed no growth (median follow-up, 7.6 years). Kaplan-Meier estimates for 5- and 10-year progression-free survival were 85% and 80%, respectively. Cox proportional hazards demonstrated a significant inverse association between higher marginal doses and tumor progression (hazard ratio, 0.49; 95% confidence interval, 0.17-0.92; P = .02). Audiometric data were available in 30 ears, with 12 having class A/B hearing before SRS. Only 3 maintained serviceable hearing at the last follow-up. Four underwent cochlear implantation. Initially, 3 achieved open-set speech recognition, although only 1 experienced long-term benefit. Facial nerve function remained stable in 50% of cases. Conclusion Higher marginal doses than commonly prescribed for sporadic VS were associated with improved tumor control in patients with NF2. Hearing outcomes were poor even when contemporary reduced marginal doses were used. However, SRS allows an anatomically preserved cochlear nerve and may permit hearing rehabilitation with cochlear implantation. Further consideration should be given to optimum dosing to achieve long-term control while maximizing functional outcomes. Abbreviations HB, House-BrackmannNF2, neurofibromatosis type 2SRS, stereotactic radiosurgeryVS, vestibular schwannoma.

Background To assess the risk of cerebrovascular accidents (CVAs) and second brain tumors (SBTs) in patients with pituitary adenoma after surgery or radiotherapy. Methods A cohort of 143 people from Olmsted County, who were diagnosed with pituitary adenoma between 1933 and 2000, was studied. Only patients from Olmsted County were included because of the unique nature of medical care in Olmsted County, which allows the ascertainment of virtually all cases of pituitary adenoma for this community's residents and comparisons to the general population in the county. Surgical resection was performed in 76 patients, 29 patients underwent radiotherapy (with 21 undergoing both surgery and radiotherapy), 5 patients were reirradiated, and 59 patients were managed conservatively and observed. Results Median follow-up was 15.5 years. There was no difference in CVA-free survival between treatment groups. On univariate analysis age > 60 years (hazard ratio [HR], 11.93; 95% CI, 6.26–23.03; P < .001); male sex (HR, 3.67; 95% CI, 2.03–6.84; P < .001), and reirradiation (HR, 3.41; 95% CI, 1.05–9.68; P = .04) were associated with worse CVA-free survival. In multivariate analysis, only age > 60 years was associated with worse CVA-free survival. Compared with the general population, there was a 4-fold increase in the rate of CVAs in pituitary adenoma patients (HR, 4.2; 95% CI, 2.8–6.1). Two patients developed SBT (an irradiated patient and a surgically managed patient). Conclusion CVA is a significant risk for patients with pituitary tumors, but treatment does not seem to impact the risk. Even with long-term follow-up, SBTs are a rare event regardless of treatment modality.

6010 Background: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations and speciation stratifies head and neck squamous cell carcinoma (HNSCC) patients bearing TP53 missense mutations as high-risk (high, EAp53≥75), associated with poor outcomes, or low-risk (low), with similar outcomes as TP53 wild-type (wt), and has been validated as a reliable prognostic marker. This study is designed to further validate prior findings that EAp53 is a prognostic marker for locally advanced HNSCC patients, and assess its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy. Methods: Eighty one resection specimens from patients treated surgically for stage III or IV human papillomavirus-negative (HPV(-)) HNSCC with high-risk pathologic features, who received either Arm 1) radiotherapy(RT)+cetuximab(CTX)+cisplatin or Arm 2) RT+CTX+docetaxel, as adjuvant treatment in a phase II randomized clinical trial (RTOG 0234) underwent TP53 targeted sequencing, and EAp53 scoring. The EAp53 scores were correlated with clinical outcomes. Due to limited sample sizes, patients were combined into 2 EAp53 groups: wt/low and high/other. Results: At median follow-up of 10 years, there was a significant interaction between treatment and EAp53 group for overall survival (OS) (p = 0.008), disease-free survival (DFS) (p = 0.05) and distant metastasis (DM) (p = 0.004). Within arm 2, high/other showed worse OS [HR 4.69 (1.52-14.50)], DFS [HR 2.69 (1.16-6.21)], and had higher DM [HR 11.71 (1.50-91.68)] than wt/low. Within arm 1, there was no significant difference by EAp53 in OS, DFS and DM. Within the wt/low group, arm 2 had better OS [HR 0.11 (0.03-0.36)], DFS [HR 0.24 (0.09-0.61)], and DM [HR 0.04 (0.01-0.31)] than arm 1 but this was not found in high/other. Conclusions: High/other EAp53 scores were associated with worse survival for patients in arm 2. Arm 2 is associated with better survival than arm 1 for patients with wt/low EAp53. This benefit appears to be largely driven by a reduction in DM. Further validation is required to determine whether EAp53 can be used for personalized post-operative treatment decisions in HPV(-) HNSCC.

6071 Background: Phase III data suggests a benefit of HDC in the adjuvant setting, but the effect of HDC and WC on long term survival and for HPV+ HNSCC is unknown. Methods: Data from a published retrospective study (Geiger Oral Onc 2013) of HDC vs WC in resected HNSCC was updated. Overall survival (OS) and recurrence-free survival (RFS) was assessed by Kaplan-Meier method for all pts and by HPV status. Multivariate analyses were performed to assess impact of HPV status, smoking, age, HDC vs WC, and cumulative cisplatin dose ( < 200mg/m2 vs ≥200 mg/m2). Results: 51 patients (pts) received HDC and 53 WC. Median follow-up was 8.7 yrs (0.8-13.7). For the whole cohort, HDC had significantly improved OS over WC (p = 0.0095; 5- and 10-yr OS 84% and 80% vs 72% and 60%). No OS benefit for HDC was seen in pts with HPV+HNSCC (5- and 10-yr OS 90% and 87% for HDC and 81% and 81% for WC; p = 0.51). For HPV-negative HNSCC, OS had borderline significance with HDC vs WC (5- and 10-yr OS 73% and 68% vs 65% and 44%; p = 0.06). For the whole cohort, there was no difference in 5- and 10-yr RFS (78% and 74% for HDC vs 72% and 62% for WC; p = 0.32). When analyzed by HPV status, there was no difference in RFS with HDC or WC for either HPV+ (p = 0.43) or HPV-negative HNSCC (p = 0.97). On multivariate analyses of OS for all pts, only HPV status was significant (p = 0.0011; HR 0.27, CI 0.12-0.62). For HPV+ HNSCC, there was no significant predictor of OS. For non-HPV HNSCC, the benefit of HDC approached significance with a decreased risk of death (HR 0.38; p = 0.07). For all pts, those who received ≥200mg/m2 had significantly improved OS (5-yr 90% vs 72% and 10-yr 86% vs 61%; p = 0.004). By HPV status, cumulative dose had no significant effect on OS. Conclusions: OS is better with HDC and with cumulative dose > 200 mg/m2 in unselected patients. The benefit of cisplatin is likely higher for non-HPV HNSCC. A difference in OS with no difference in RFS suggests non cancer-related causes of death in the WC cohort. Ability to receive HDC could be a surrogate marker of comorbidity. [Table: see text]

Objectives: We evaluated relapse patterns after transoral laser microsurgery (TLM) in squamous cell carcinoma (SCC) of the tonsil and tongue base and evaluated the indications for adjuvant irradiation. Methods: Between December 1, 1996, and December 31, 2005, 79 patients with previously untreated SCC of the tonsil or tongue base underwent TLM with or without neck dissection. Thirty-eight patients (48%) underwent postoperative irradiation (median, 62 Gy) to the primary site and the neck. Analysis of relapse patterns was performed on the basis of adverse risk factors and the presence or absence of adjuvant irradiation. Results: The median follow-up for living patients was 47 months (range, 10 to 107 months), and patients were monitored for at least 2 years or until recurrence or death. Local, regional, and distant treatment failures numbered 4, 6, and 4 for surgery alone (n = 41) and 0, 2, and 6 for adjuvant irradiation (n = 38), respectively. Patients with high-risk features (extracapsular extension or at least 2 adverse factors) had locoregional control rates at 2 or more years of 66% and 94% for TLM alone and TLM plus adjuvant irradiation, respectively. Conclusions: Adjuvant irradiation after TLM resection of oropharyngeal SCC with intermediate- or high-risk features improves locoregional control compared with TLM alone.

Christopher L. Foote of Federal Reserve Bank of Boston reviews, “The Redistribution Recession: How Labor Market Distortions Contracted the Economy” by Casey B. Mulligan. The Econlit abstract of this book begins: “Explores the decline of employment in the United States after the financial crisis and its failure to recover and considers the role of economic activity and public policy. Discusses the rise of labor productivity; the expanding social safety net; supply and demand—labor market consequences of safety net expansions; means-tested subsidies and economic dynamics since 2007; cross-sectional patterns of employment and hours changes; Keynesian and other models of safety net stimulus; recession-era effects of factor supply and demand—evidence from the seasonal cycle, the construction market, and minimum wage hikes; incentives and compliance under the federal mortgage modification guidelines; and uncertainty, redistribution, and the labor market. Mulligan is Professor of Economics at the University of Chicago.”