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Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are follicular-patterned thyroid neoplasms defined by nuclear atypia and indolent behavior. They harbor RAS mutations, rather than BRAFV600E mutations as is observed in papillary thyroid carcinomas with extensive follicular growth. Reliably identifying NIFTPs aids in safe therapy de-escalation, but has proven to be challenging due to interobserver variability and morphologic heterogeneity. The genomic scoring system BRS (BRAF-RAS score) was developed to quantify the extent to which a tumor’s expression profile resembles a BRAFV600E or RAS-mutant neoplasm. We proposed that deep learning prediction of BRS could differentiate NIFTP from other follicular-patterned neoplasms. A deep learning model was trained on slides from a dataset of 115 thyroid neoplasms to predict tumor subtype (NIFTP, PTC-EFG, or classic PTC), and was used to generate predictions for 497 thyroid neoplasms within The Cancer Genome Atlas (TCGA). Within follicular-patterned neoplasms, tumors with positive BRS (RAS-like) were 8.5 times as likely to carry an NIFTP prediction than tumors with negative BRS (89.7% vs 10.5%, P

To report functional outcomes for patients with human papillomavirus-positive oropharyngeal cancer treated on a phase 2 protocol of risk- and induction chemotherapy response-adapted dose and volume de-escalated radiation therapy (RT)/chemoradiation (CRT).Patients were stratified as low risk (LR) or high risk (HR) according to T/N-stage and smoking history. Induction chemotherapy was followed by radiographic response assessment. LR patients with ≥50% response received 50 Gy RT (RT50), whereas LR patients with 30% to 50% response or HR patients with ≥50% response received 45 Gy CRT (CRT45). All other patients received 75 Gy CRT (CRT75) with RT limited to the first echelon of uninvolved nodes. Pre- and post-RT/CRT modified barium swallow studies were performed. Percutaneous endoscopic gastrostomy (PEG) tube placement, body mass index (BMI), and narcotic use were recorded. Statistical comparisons used linear or logistic regression, the Mann-Whitney U test, the χTwenty-eight LR and 34 HR patients were enrolled; 49 completed RT50/CRT45 and 11 completed CRT75. PEG-tube dependency at the end of RT/CRT and 3 months post-RT/CRT significantly differed according to risk and treatment groups (all P.05). Treatment intensity was independently associated with 3-month PEG status while adjusting for risk group (P = .002). The CRT75 group had a median -8.42% change from baseline BMI at 1 year post-RT/CRT versus -2.54% for the RT50/CRT45 group (P = .01). At the end of RT/CRT, CRT75 patients were less likely to tolerate a normal diet, more likely to have swallowing performance status scale scores ≥4, more likely to have Rosenbek's penetration-aspiration scores ≥7, more likely to have developed trismus, and more likely to require narcotics2 months (all P.05).Induction chemotherapy followed by risk- and response-adapted dose and volume de-escalated RT/CRT is associated with clinically meaningful functional outcomes including (1) improved swallowing function, (2) higher BMI, and (3) shorter narcotic use for patients receiving de-escalation.

Aneurysmal bone cysts (ABCs) are benign lesions which most frequently occur in the long bones of pediatric patients. Long thought to be reactive, recent molecular advances have demonstrated that the majority of primary ABCs harbor rearrangements of the USP6 gene, confirming their neoplastic nature. Secondary ABCs arising from other lesions do not demonstrate this recurrent genetic anomaly. ABCs rarely occur in the craniofacial bones, and sinonasal ABCs are exceedingly rare. We report a case of a primary ABC arising the maxillary sinus of a 14-year-old female, which was found to harbor USP6 rearrangement. We describe the clinical, radiologic, and pathologic features of this case, and review the current literature on craniofacial ABCs. Careful histologic evaluation and genetic studies are warranted in order to confirm the rare occurrence of a primary sinonasal ABC.

Objectives Definitive chemoradiation (CRT) for oral cavity squamous cell carcinoma (OC-SCC) is often criticized for poor efficacy or toxicity. We describe a favorable 20-year experience of primary CRT for locally-advanced OC-SCC. Materials and Methods Patients with locally-advanced, stage III/IV OC-SCC receiving primary concomitant CRT on protocols from 1994 to 2014 were analyzed. Chemotherapy included fluorouracil and hydroxyurea with other third agents. Radiotherapy (RT) was delivered once or twice daily to a maximum dose of 70–75 Gy. Intensity-modulated RT (IMRT) was exclusively used after 2004. Progression-free survival (PFS), overall survival (OS), locoregional control (LRC), and distant control (DC) were calculated by the Kaplan-Meier method and compared across treatment decades using the log-rank test. Rates of osteoradionecrosis (ORN) requiring surgery were compared across treatment decades using the Chi-square test. Results 140 patients with locally-advanced OC-SCC were treated with definitive CRT. Of these, 75.7% had T3/T4 disease, 68.6% had ≥N2 nodal disease, and 91.4% had stage IV disease. Most common primary sites were oral tongue (47.9%) and floor of mouth (24.3%). Median follow-up was 5.7 years. Five-year OS, PFS, LRC, and DC were 63.2%, 58.7%, 78.6%, and 87.2%, respectively. Rates of ORN and long-term feeding tube dependence were 20.7% and 10.0%, respectively. Differences in LRC (P = 0.90), DC (P = 0.24), PFS (P = 0.38), OS (P = 0.10), or ORN (P = 0.38) were not significant across treatment decades. Conclusion Definitive CRT is a viable and feasible strategy for organ preservation for patients with locally-advanced OC-SCC.

Background Favorable prognosis for Human papillomavirus-associated (HPV+) oropharyngeal cancer (OPC) led to investigation of response-adaptive de-escalation, yet long-term outcomes are unknown. We present expanded experience and follow-up of risk/response adaptive treatment de-intensification in HPV+ OPC. Methods A phase 2 trial (OPTIMA) and subsequent cohort of sequential off-protocol patients treated from September 2014 to November 2018 at the University of Chicago were reviewed. Eligible patients had T3-T4 or N2-3 (AJCC 7th edition) HPV+ OPC. Patients were stratified by risk: High-risk (HR) (T4, ≥N2c, or >10PYH), all others low-risk (LR). Induction chemotherapy (IC) included 3 cycles of carboplatin and nab-paclitaxel (OPTIMA) or paclitaxel (off-protocol). LR with ≥50% response received low-dose radiotherapy (RT) alone to 50 Gy (RT50). LR with 30–50% response and HR with ≥50% response received intermediate-dose chemoradiotherapy (CRT) to 45 Gy (CRT45). All others received full-dose CRT to 75 Gy (CRT75). Results 91 patients consented and 90 patients were treated, of which 31% had >10PYH, 34% had T3/4 disease, and 94% had N2b/N2c/N3 disease. 49% were LR and 51% were HR. Overall response rate to induction was 88%. De-escalated treatment was administered to 83%. Median follow-up was 4.2 years. Five-year OS, PFS, LRC, and DC were 90% (95% CI 81,95), 90% (95% CI 80,95), 96% (95% CI 90,99), and 96% (88,99) respectively. G-tube placement rates in RT50, CRT45, and CRT75 were 3%, 33%, and 80% respectively (p Conclusion Risk/response adaptive de-escalated treatment for an inclusive cohort of HPV+ OPC demonstrates excellent survival with reduced toxicity with long-term follow-up.

Histologically benign airway strictures are frequently misdiagnosed as asthma or COPD and may present with severe symptoms including respiratory failure. A clear understanding of pathophysiology and existing classification systems is needed to determine the appropriate treatment options and predict clinical course. Clinically significant airway strictures can involve the upper and central airways extending from the subglottis to the lobar airways. Optimal evaluation includes a proper history and physical examination, neck and chest computed tomography, pulmonary function testing, endoscopy and serology. Available treatments include medical therapy, endoscopic procedures and open surgery which are based on the stricture's extent, location, etiology, morphology, severity of airway narrowing and patient's functional status. The acuity of the process, patient's co-morbidities and operability at the time of evaluation determine the need for open surgical or endoscopic interventions. The optimal management of patients with benign airway strictures requires the availability, expertise and collaboration of otolaryngologists, thoracic surgeons and interventional pulmonologists. Multidisciplinary airway teams can facilitate accurate diagnosis, guide management and avoid unnecessary procedures that could potentially worsen the extent of the disease or clinical course. Implementation of a complex airway program including multidisciplinary clinics and conferences ensures that such collaboration leads to timely, patient-centered and evidence-based interventions. In this article we outline algorithms of care and illustrate therapeutic techniques based on published evidence.

This article is a continuation of the "Do You Know Your Guidelines" series, an initiative of the American Head and Neck Society's Education Committee to increase awareness of current best practices pertaining to head and neck cancer. The National Comprehensive Cancer Network (NCCN) guidelines for primary and adjuvant treatment of cancer of the glottic larynx are reviewed here in a systematic fashion according to stage.

Background. Salivary gland secretory carcinoma is usually a low-grade neoplasm. However, high-grade transformation can occur and has important implications for clinical outcome. Methods. A patient presented with an enlarging buccal mass. Magnetic resonance imaging (MRI) showed a tumor with a biphasic appearance along the right parotid duct. Local excision and histopathologic examination confirmed the diagnosis of secretory carcinoma with high-grade transformation. ETV6-NTRK3 translocation and loss of CDKN2A/B were identified. Results. The patient subsequently presented with cough and dyspnea and was found to have pleural metastases. Carboplatin and paclitaxel exacerbated the symptoms. Crizotinib resulted in initial symptomatic and radiographic improvement; however, the patient soon succumbed to progressive intrathoracic disease. Conclusions. High-grade salivary gland secretory carcinoma can have a biphasic appearance on MRI. Diagnosis is confirmed by the histologic appearance and associated ETV6-NTRK3 fusion. Additional molecular genetic events leading to transformation are unknown; however, loss of CDKN2A/B may have contributed. Treatment with multimodal chemotherapy was of limited benefit.

Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy, but categorization is complicated by variability in grading systems and uncertain prognostic significance of MAML2 rearrangement. The aims of this study were to determine the prognostic significance of MEC grading systems and MAML2 rearrangement status. Fifty-three carcinomas originally diagnosed as MEC (45 primary; 8 recurrent) of major and minor salivary glands were graded according to modified Healey, Brandwein, AFIP, and Katabi systems. Fluorescence in-situ hybridization for MAML2 rearrangement was performed. Clinical features and outcomes were recorded. Twenty-five (47%) carcinomas scored the same in all grading systems. The most common histologic feature leading to a diagnosis of intermediate grade was isolated solid growth. Brandwein assigned the highest percentage of high grade (29%) and AFIP the highest percentage of low grade (80%). MAML2 was rearranged in 37/46 (80%) cases. Forty-three (81%) were morphologically compatible with MEC, and these were more likely to be low-intermediate grade and MAML2-rearranged. Of primary carcinomas, 6 (13%) recurred. Statistically significant univariate risk factors for recurrence included non-MEC morphology, stage T4, and high Brandwein grade. Margin status, MAML2 rearrangement, and isolated solid growth were not predictive of recurrence. A binary grading system (Brandwein high versus low-plus-intermediate) could be considered to better reflect biologic behavior in MEC. Our study confirms that MAML2 wildtype tumors more likely represent high grade non-MECs, and prior studies demonstrating worse prognosis in MAML2-non-rearranged MECs may be diluted by high grade non-MECs.

WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.).

6011 Background: Despite the success of anti-PD-1 in recurrent/metastatic head and neck cancer, incorporation in the curative setting with induction therapy has yet to be investigated. Favorable prognosis of human papillomavirus associated (HPV+) oropharyngeal cancer (OPC) has led to interest in treatment de-escalation. OPTIMA 2 evaluated nivolumab (nivo) with nab-paclitaxel and carboplatin followed by risk/response adaptive de-intensified treatment for locoregionally advanced HPV+ OPC. We report the primary analysis and outcomes. Methods: OPTIMA 2 enrolled locoregionally advanced HPV+ OPC. Nivo, nab-paclitaxel, and carboplatin were administered for 3 cycles. High-risk (HR) included any of the following: T4, N2c-N3 (AJCC 7th edition), > 20 pack year smoking history, non-HPV16 subtype; All others were low-risk (LR). Arm A included LR with ≥50% post-induction shrinkage by RECIST received single-modality de-escalation with low-dose radiation (RT) alone (50 Gy) or transoral robotic surgery (TORS). Arm B included HR with ≥50% shrinkage or LR with

This article is a continuation of the "Do You Know Your Guidelines" series, an initiative of the American Head and Neck Society's Education Committee to increase awareness of current best practices pertaining to head and neck cancer. The National Comprehensive Cancer Network guidelines for the management of nasopharyngeal cancer are reviewed here in a systematic fashion. These guidelines outline the workup, treatment and surveillance of patients with nasopharyngeal cancer. © 2016 Wiley Periodicals, Inc. Head Neck 39: 201-205, 2017.

The role of cetuximab in the treatment of locoregionally advanced head and neck squamous cell cancer (LA-HNSCC) remains poorly defined. In this phase 2 randomized study, we investigated the addition of cetuximab to both induction chemotherapy (IC) and hyperfractionated or accelerated chemoradiation.Patients with LA-HNSCC were randomized to receive 2 cycles of weekly IC (cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (concurrent cetuximab, 5-fluorouracil, hydroxyurea, and 1.5 Gy twice-daily radiation therapy every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated radiation therapy with delayed concomitant boost to 72 Gy in 42 fractions). The primary endpoint was progression-free survival (PFS), with superiority compared with historical control achieved if either arm had 2-year PFS ≥70%.110 patients were randomly assigned to either Cetux-FHX (n=57) or Cetux-PX (n=53). The overall response rate to IC was 91%. Severe toxicity on IC was limited to rash (23% grade ≥3) and myelosuppression (38% grade ≥3 neutropenia). The 2-year rates of PFS for both Cetux-FHX (82.5%) and Cetux-PX (84.9%) were significantly higher than for historical control (P.001). The 2-year overall survival (OS) was 91.2% for Cetux-FHX and 94.3% for Cetux-PX. With a median follow-up time of 72 months, there were no significant differences in PFS (P=.35) or OS (P=.15) between the treatment arms. The late outcomes for the entire cohort included 5-year PFS, OS, locoregional failure, and distant metastasis rates of 74.1%, 80.3%, 15.7%, and 7.4%, respectively. The 5-year PFS and OS were 84.4% and 91.3%, respectively, among human papillomavirus (HPV)-positive patients and 65.9% and 72.5%, respectively, among HPV-negative patients.The addition of cetuximab to IC and chemoradiation was tolerable and produced long-term control of LA-HNSCC, particularly among poor-prognosis HPV-negative patients. Further investigation of cetuximab may be warranted in the neoadjuvant setting and with non-platinum-based chemoradiation.

6575 Background: Human papilloma virus (HPV) associated oropharyngeal cancer is associated with a favorable prognosis, but standard multimodality treatment is associated with substantial treatment related toxicity. A de-escalation treatment paradigm that optimizes oncologic outcomes while reducing toxicity is needed. We sought to further expound on our published OPTIMA data with long-term follow-up and additional pts subsequently treated using the OPTIMA treatment paradigm. Methods: Long-term follow-up of our institutional de-escalation OPTIMA trial (NCT02258659) and retrospective review of additional patients treated subsequently per OPTIMA outline was performed. Pts were classified as low-risk (LR) (≤T3, ≤N2B, ≤10PYH) or high-risk (HR) (T4, ≥N2c, > 10PYH). Pts received induction chemotherapy (IC) of 3 cycles of dose dense carboplatin and nab-paclitaxel (OPTIMA) or paclitaxel (subsequently treated). LR with ≥50% response received low-dose radiotherapy (RT) to 50 Gy. LR with 30-50% response or HR with ≥50% response received intermediate-dose chemoradiotherapy (CRT) to 45Gy. All others received full-dose CRT to 75Gy. Results: 108 pts consented and 107 were treated (61 on study; 46 subsequently) from October 2014 through November 2019. 1 pt transferred care post-enrollment. Median follow-up was 36 months (interquartile range 17-45). Median age was 63 years (range 33-84) and 95% were male. 47% were LR and 53% were HR. ≥50% tumor shrinkage occurred in 78/107 (73%) of pts overall, and 37/51 (73%) among LR; 41/56 (73%) among HR. 82% of pts received de-escalated (C)RT. Overall, 94% of pts were alive at last follow-up (98% LR; 89% HR). 3 pts (2 HR and 1 LR) developed disease recurrence (2.7%), with 2 local recurrences and 1 distant recurrence. Likelihood of G-tube placement was 3% in low-dose RT, 35% in intermediate-dose CRT, and 84% in full-dose CRT. Conclusions: IC followed by risk-adapted dose and volume de-escalated treatment for HPV+ oropharyngeal cancer demonstrates excellent oncologic and functional outcomes with long-term follow-up. Supported by Celgene, Alinea benefit supported by Grant Achatz/Nick Kokonas, and National Cancer Institute of the National Institutes of Health (NIH) through Grant Number P30 CA14599. Clinical trial information: NCT02258659 .

There are many types of cutaneous malignant neoplasms and associated conditions that can involve the head and neck regions. This chapter reviews the characteristic clinicopathological and imaging findings of basal cell carcinoma, squamous cell carcinoma, melanoma, cutaneous lymphomas, dermatofibrosarcoma protuberans, Kaposi sarcoma, Merkel cell carcinoma, microcystic adnexal carcinoma, sebaceous carcinoma, adenoid cystic carcinoma, angiosarcoma, and metastases.

Background Patients with HPV+ oropharyngeal squamous cell carcinoma were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment-related toxicity while preserving efficacy. Patients and methods Patients were classified as low-risk (≤T3, ≤N2B, ≤10 pack-year history) or high-risk (T4 or ≥N2C or >10 PYH). After three cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30%–50% response or high-risk patients with ≥50% response received 45 Gy CRT (CRT45). Patients with lesser response received standard-of-care 75 Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary end point was 2-year progression-free survival compared with a historic control of 85%. Secondary end points included overall survival and toxicity. Results Sixty-two patients (28 low risk/34 high risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% noninferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (P = 0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (P Conclusions Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified. Clinical trial registration Clinical trials.gov identifier: NCT02258659.

Background: Discharge anticoagulation counseling is important for ensuring patient comprehension and optimizing clinical outcomes. As pharmacy resources become increasingly limited, the impact of informational videos on the counseling process becomes more relevant. Objective: To evaluate differences in pharmacist time spent counseling and patient comprehension (measured by the Oral Anticoagulation Knowledge [OAK] test) between informational videos and traditional face-to-face (oral) counseling. Methods: This prospective, open, parallel-group study at an academic medical center randomized 40 individuals—17 warfarin-naïve (“New Start”) and 23 with prior warfarin use (“Restart”)—to receive warfarin discharge education by video or face-to-face counseling. “Teach-back” questions were used in both groups. Results: Although overall pharmacist time was reduced in the video counseling group ( P < 0.001), an interaction between prior warfarin use and counseling method ( P = 0.012) suggests the difference between counseling methods was smaller in New Start participants. Following adjustment, mean total time was reduced 8.71 (95% CI = 5.15-12.26) minutes (adjusted P < 0.001) in Restart participants and 2.31 (−2.19 to 6.81) minutes (adjusted P = 0.472) in New Start participants receiving video counseling. Postcounseling OAK test scores did not differ. Age, gender, socioeconomic status, and years of education were not predictive of total time or OAK test score. Conclusion: Use of informational videos coupled with teach-back questions significantly reduced pharmacist time spent on anticoagulation counseling without compromising short-term patient comprehension, primarily in patients with prior warfarin use. Study results demonstrate that video technology provides an efficient method of anticoagulation counseling while achieving similar comprehension.

SummaryBackgroundPhotodynamic therapy with aminolevulinic acid (ALA PDT) for oral leukoplakia has shown promising effects in regression of oral leukoplakia. Although ALA has been extensively studied and is an ideal photosensitizer, the optimal light dose for treatment of oral leukoplakia has not been determined. We conducted a phase I study to determine MTD and DLT of PDT in patients treated with ALA for leukoplakia.MethodsPatients with histologically confirmed oral leukoplakia received a single treatment of ALA PDT in cohorts with escalating doses of light (585nm). Clinical, histologic, and biologic markers were assessed.ResultsAnalysis of 11 participants is reported. No significant toxicity from ALA PDT was observed in patients who received ALA with a light dose of up to 4J/cm2. One participant experienced transient grade 3 transaminase elevation due to ALA. One participant had a partial clinical response 3months after treatment. Biologic mucosal risk markers showed no significant associations. Determination of MTD could not be accomplished within a feasible timeframe for completion of the study.ConclusionsALA PDT could be safely administered with a light dose up to 4J/cm2 and demonstrated activity. Larger studies are needed to fully elucidate the MTD and efficacy of ALA-PDT.

Background The purpose of this study was to determine the prognostic value of lymph node density in head and neck cancer. Methods We utilized a prospective, multicenter database of 223 patients with head and neck cancer to identify patients who underwent lymph node dissection before chemoradiation to assess the prognostic significance of lymph node density. Results In 38 patients who met study criteria, lymph node density ≤0.20 predicted for improved overall survival (OS; 79% vs 50%; p = .04). Lymph node density was also associated with a trend toward improved 3-year locoregional control (96% vs 79%; p = .14) and distant metastasis–free survival (93% vs 78%; p = .13). In the patients with treatment failure distantly or locoregionally, that failure was earlier in patients with lymph node density >0.20 than in patients with lymph node density ≤0.20 (median, 12.7 months vs 5.2 months; p = .004). Conclusion Our data suggest that lymph node density predicts for OS in patients with head and neck cancer and that the difference in OS may be because of differences in time to failure. © 2013 Wiley Periodicals, Inc. Head Neck 36: 266–272, 2014

Summary Purpose Current standard therapy for nasopharyngeal carcinoma (NPC) is concurrent chemoradiation based on randomized data. However, limited randomized data exist to support the addition of induction chemotherapy (ICT). Methods 58 Patients with NPC were treated from 1990 to 2010. All patients received platinum-based ICT. All 58 patients were treated with chemoradiation, 57 in a week-on/week-off (WOWO) fashion. Concurrent chemotherapy included hydroxyurea/5-fluorouracil for all patients. Median radiation dose was 70 Gy. No patient received adjuvant chemotherapy. Results AJCC 2009 stage was II = 13, III = 21, IVa = 13, and IVb = 11. Median follow-up for surviving patients was 66 months. Response to ICT was complete response (CR) 17% and partial response (PR) 64%. The CR rate after chemoradiation was 96%. Five-year actuarial freedom from local failure (FFLF), freedom from distant failure (FFDF), cause-specific survival (CSS), and overall survival (OS) was 98%, 90%, 90%, and 76%, respectively. Analysis of pediatric patients ( n = 9) demonstrated 5-year actuarial FFLF, FFDF, CSS, and OS of 100%, 88%, 80%, and 80%, respectively. Conclusions ICT followed by concurrent chemoradiation demonstrates excellent FFLF, FFDF, CSS, and OS with tolerable toxicity. Induction chemotherapy followed by concurrent chemoradiation for patients with NPC should be explored further in a randomized setting.

Background AdGV.EGR.TNF.11D (TNFerade™ Biologic) is a replication-deficient adenoviral vector expressing human tumor necrosis factor alpha (TNF-α) under the control of the chemoradiation-inducible EGR-1 promoter. TNF-α has been shown to function as a radiation sensitizer. We conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of TNFerade™ Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC). Methods TNFerade™ Biologic was injected intratumorally on day 1 of each 14-day cycle and dose-escalated in log increments from 4 × 109 to 4 × 1011 PU. Daily radiation, infusional 5-fluorouracil (5-FU), and hydroxyurea were given on days 1–5 for seven cycles (FHX). Tumor biopsies were obtained before, during, and after treatment. Results Fourteen patients were treated. DLT was reached at a dose level of 3 (4 × 1011 PU) with three thrombotic events. The response rate was 83.3%. The median survival was 9.6 months. One patient (7.1%) remained alive 3 years after treatment. Biopsies were obtained in 90% of patients. Nearly all tumors expressed adenovirus receptors, TNF-α, and TNF-α receptors. Adenoviral DNA was detected in three biopsies from one patient. Conclusions TNFerade™ Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 × 1010 PU. Monitoring for thrombotic events is indicated.

Gefitinib has activity in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) and skin toxicity has been postulated to be a predictor of response and improved outcome.This open-label, multi-institution, phase II study evaluated the activity of gefitinib at individually escalated doses up to 750 mg to achieve the skin toxicity grade ≥2.Forty four patients were enrolled. Only twenty-three (52%) experienced skin rash grade ≥2. Of 44 patients, partial responses were noted in 3 (7%), stable disease in 8 (18%) and progressive disease in 33 patients. Median progression-free survival was 1.9 months (95% CI 1.6-2.2) and median overall survival was 5.1 months (95% CI 2.4-7.8). Grade of skin rash was not associated with response rate (p=0.169) nor tumor control rate (p=0.284); however, higher gefitinib trough levels were associated with disease control. Of the 11 tissue samples analyzed for EGFR gene copy by FISH, 7 were EGFR FISH positive, but this was not associated with improved tumor control or survival.Gefitinib has clinical activity as monotherapy in SCCHN. Dose escalation of gefitinib is feasible and may increase skin toxicity, but our data do not support increased activity.

Background Patients with T4 laryngeal cancers, including those with large-volume (cartilage or tongue-base invasion) lesions, are often excluded from organ-preservation trials due to expectations of inferior outcome in terms of survival and function. We hypothesize that such patients indeed have acceptable survival and function when treated with organ-preservation strategies. Methods Retrospective analysis of prospectively collected data of a cohort of patients with T4 laryngeal cancer was carried out. Follow-up ranged from 0.18 to 15.6 years. All T4 laryngeal cancer patients who were enrolled in the University of Chicago concomitant chemoradiotherapy protocols from 1994 to the present were reviewed. This study was composed of 80 newly diagnosed T4 laryngeal cancer patients. Efficacy of treatment was determined through evaluations of survival and function. Survival was evaluated via Kaplan–Meier methods. Swallowing function was evaluated by an oropharyngeal motility (OPM) study and swallowing scores were assigned. Higher scores reflected increasing swallowing dysfunction. Results Fifty-five of 80 patients (∼69%) had documented large-volume tumor. Two- and 5-year overall survivals were 60.0% and 48.7%, respectively. Disease-specific 2- and 5-year survivals for the group were 80.1% and 71.3%, and 79.4 and 74.3%, respectively, for the 55 patients with large volume status. Progression-free survival rates were 52.6% and 47.6%. Forty-four of 65 patients (∼68%) with OPM data had a Swallowing Performance Status Scale (SPSS) score of ≤5, indicating various degrees of swallowing abnormalities not requiring a gastrostomy tube. This is a functional-preservation rate of 67.7%. Conclusions Chemoradiation for patients with T4 laryngeal cancer appears to be an effective and reasonable option, particularly in light of the satisfactory survival and function-preservation rates. © 2011 Wiley Periodicals, Inc. Head Neck, 2012

Background Concurrent chemoreirradiation therapy (CRRT) offers a therapeutic option for patients with locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that response to induction chemotherapy (IC) would improve outcome and predict increased survival. Patients and methods Subjects with recurrent SCCHN not amenable to standard therapy were eligible. IC consisted of two 28-day cycles of gemcitabine and pemetrexed on days 1 and 14, followed by surgical resection, if appropriate, and/or CRRT consisting of carboplatin, pemetrexed, and single daily fractionated radiotherapy. Results Thirty-five subjects were enrolled, 31 were assessable for response, with 11 responders [response rate = 35%; 95% confidence interval (CI) 19.2–54.6]. Among 24 subjects who started CRRT, 11 were assessable for radiographic response, 4 complete response, 2 partial response, and 5 progressive disease. Median progression-free survival and overall survival (OS) were 5.5 months (95% CI 3.6–8.3) and 9.5 months (95% CI 7.2–15.4), respectively. One-year OS was 43% (95% CI 26% to 58%). Subjects who responded to IC had improved survival (P = 0.02). Toxic effects included mucositis, dermatitis, neutropenia, infection, hemorrhage, dehydration, and pain. Conclusions The combination of pemetrexed plus gemcitabine was active and well tolerated in recurrent SCCHN. Response to IC may help stratify prognosis and offer an objective and dynamic metric in recurrent SCCHN patients being considered for CRRT.

Introduction We conducted a randomized phase II study to evaluate the impact of adding bevacizumab (B) to 5-fluorouracil (5-FU), hydroxyurea (HU), and radiotherapy (FHX) for intermediate-stage and select T4 head and neck squamous cell cancers (HNSCC). Patients and methods Eligible patients had newly diagnosed HNSCC. Randomization was 2:1 in favor of BFHX. All patients received 500 mg HU p.o. b.i.d., 600 mg/m2/day continuous infusion 5-FU, and b.i.d. radiotherapy with or without bevacizumab 10 mg/kg administered on day 1 of each 14-day cycle. Patients received five cycles consisting of chemoradiotherapy for 5 days followed by 9 days without therapy. Results Twenty-six patients were enrolled (19 BFHX and 7 FHX). The study was halted following unexpected locoregional progression. Two-year survival was 68%; 89% treated with FHX and 58% (95% confidence interval 33% to 78%) treated with BFHX. Two-year locoregional control was 80% after chemoradiotherapy and 85% after surgical salvage. All locoregional progression occurred in T4 tumors randomized to BFHX. Two patients receiving BFHX died during therapy, and one died shortly after therapy. No catastrophic bleeding events were seen. Conclusions Locoregional progression seen in T4N0-1 tumors treated with BFHX was unexpected and led to study termination. The addition of bevacuzimab to chemoradiotherapy for HNSCC should be limited clinical trials.

Objectives: To report outcomes of oral cavity cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy (chemoIMRT). Methods: Between 2001 and 2004, 21 patients with oral cavity squamous cell carcinoma underwent definitive chemoIMRT. Sites included were oral tongue (n = 9), floor of mouth (n = 6), buccal mucosa (n = 3), retromolar trigone (n = 2), and hard palate (n = 1). Most had stage III-IV disease (n = 20). The most common regimen was 5 days infusional 5-fluorouracil (600 mg/m2/d × 5 days), hydroxyurea (500 mg, PO BID), and 1.5 Gy twice-daily irradiation to 72 to 75 Gy. Results: The median follow-up for surviving patients was 60 months. Treatment failure occurred as follows: local-1, regional-1, and distant metastases-2. The 2- and 5-year estimates of locoregional progression-free survival, disease-free survival, and overall survival were 90% and 90%, 71% and 71%, and 76% and 76%, respectively. Late complications included osteoradionecrosis (3 patients, 14%). Conclusions: Concurrent chemoIMRT results in promising locoregional control for oral cavity squamous cell carcinomas with acceptable toxicity.

BACKGROUND: It has been shown that concomitant chemotherapy (C) with reirradiation (ReRT) is feasible and effective for select patients with recurrent or second primary head and neck cancer (HNC). To examine potential prognostic factors associated with survival, the authors of this report retrospectively reviewed the outcomes of patients who received CReRT. METHODS: The study cohort comprised previously irradiated patients with nonmetastatic disease from 9 consecutive phase 1 and 2 protocols for poor-prognosis HNC. For all patients, reirradiation (ReRT) was delivered with concurrent chemotherapy. Chemotherapy generally was 5-fluorouracil, hydroxyurea, and a third agent. RESULTS: One hundred sixty-six patients were identified, including 81 patients who underwent surgical resection or debulking before enrollment. The median ReRT dose was 66 gray. After a median follow-up of 53 months among surviving patients, the median overall survival (OS) was 10.3 months. The 2-year rates for OS, disease-free survival, locoregional control, and freedom from distant metastasis were 24.8%, 19.9%, 50.7%, and 61.4%, respectively. Thirty-three patients (19.9%) died of treatment-related toxicity. In subgroup analysis, survival was significantly reduced in patients who received previous concurrent chemoradiotherapy (CRT) compared with patients who were naive to CRT (2-year OS rate, 10.8% vs 28.4%; P = .0043). In multivariable analysis, prior CRT was associated independently with OS along with surgery before protocol treatment, full-dose ReRT, and radiotherapy interval. CONCLUSIONS: CReRT achieved a long-term cure for a small group of patients with recurrent or second primary HNC. Previous treatment with CRT was among the important prognostic factors for survival. Because of the associated risk of severe toxicity, CReRT should be limited only to carefully selected patients. Cancer 2011;. © 2011 American Cancer Society.

Background Patients with upper aerodigestive tract tumors can have development of airway compromise both before and during chemoradiotherapy (CRT). Tracheotomy is the classic method for securing a safe airway, but tumor debulking may also be used. Methods This was a retrospective review of locoregionally advanced tumors of the base of tongue, larynx, or hypopharynx undergoing CRT between 1995 and 2007. Results Forty-two of the 109 patients presented with signs or symptoms of airway obstruction. Of these, 28 underwent tracheotomy before CRT, and 11 had tumor debulking. Two of the 11 patients who underwent debulking required tracheotomy within 1 year after CRT for persistent edema and fibrosis. Larynx tumors were more likely to require tracheotomy or debulking than other tumors (p = .01). Conclusions Debulking is a safe and effective alternative to tracheotomy in select patients with tumor-related airway obstruction before CRT. Patients who undergo debulking should be monitored closely for recurrence of airway compromise during and after CRT. © 2011 Wiley Periodicals, Inc. Head Neck, 2012

Background and purpose Induction chemotherapy prior to definitive concurrent chemoradiotherapy (CCRT) is a promising treatment option for unresectable head and neck cancer (HNC). In the postoperative setting, the efficacy of such an approach with adjuvant chemotherapy (AdjCT) followed by postoperative CCRT is unclear. Materials and methods Forty-one postoperative patients with stage III–IV (M0) HNC enrolled on 3 consecutive phase II clinical trials were retrospectively analyzed. Twenty-five of the patients were treated on a protocol which included AdjCT with carboplatin and paclitaxel prior to postoperative CCRT (AdjCT group). Sixteen were treated on protocols with similar postoperative CCRT but without AdjCT (control group). CCRT consisted of paclitaxel, 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy. Results After a median follow-up of 72 months, there were no locoregional failures (LRF) or distant metastases (DM) in the AdjCT group. In the control group, there were 2 LRF and 2 DM. The 5-year risk of disease recurrence was 0% in the AdjCT group, compared to 28.9% in the control group ( p = 0.0074). No patients had disease progression during AdjCT, and all proceeded to postoperative CCRT without delay. Conclusions Adjuvant chemotherapy after surgery followed by CCRT may be a treatment strategy associated with favorable disease outcomes in locoregionally advanced HNC. These results pose a hypothesis which warrants further investigation.

Summary Objectives/Hypotheses This study aimed to describe the demographic characteristics of patients diagnosed with paradoxical vocal fold motion (PVFM) at Walter Reed Army Medical Center (WRAMC), and to document common medical comorbidities. The military population was expected to differ from the general population because of a presumed association between high physical demands and PVFM. Study Design Retrospective chart review of active-duty (AD) military personnel compared with a natural control group of non-AD patients. Methods Reports of asthma, allergy, gastroesophageal reflux disease (GERD), and postnasal drip (consequent to chronic sinusitis) were recorded for patients referred to the Speech Pathology Clinic at WRAMC with a diagnosis of PVFM from 1996 to 2001. Results The cohort consisted of 265 patients, 127 of whom were on AD status. The AD group was significantly younger and represented a narrower age range (17–53 years) than the non-AD patients (8–80 years), and had a more balanced sex ratio (1.2:1 vs 2.9:1). Eighty percent of all patients had at least one of the medical comorbidities surveyed, and 51% had two or more factors. GERD and allergies were reported most commonly by both groups; only asthma occurred significantly more in non-AD than AD patients. Conclusions PVFM referrals of AD personnel of the US military are characterized by younger patients and a smaller female:male ratio as compared with non-AD patients. Based on the preponderance of men in the military, the number of females in the AD group remained disproportionately large. Multiple medical comorbidities were commonly documented by both groups; the only significant difference was a greater prevalence of asthma in the non-AD group. These data reinforce the need for appropriate differential diagnosis in all patients.

Purpose Assess efficacy and toxicity of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, added to, and in maintenance after, concurrent chemoradiotherapy (CCRT) in locally advanced head and neck cancer (LA-HNC) and correlate outcomes with EGFR gene copy number alterations. Patients and Methods Patients with stage III to IV LA-HNC received two cycles of carboplatin/paclitaxel induction chemotherapy (IC) followed by split-course CCRT with fluorouracil, hydroxyurea, twice daily radiotherapy (FHX), and gefitinib (250 mg daily) followed by continued gefitinib for 2 years total. The primary end point was complete response (CR) rate after CCRT. EGFR gene copy number was assessed by fluorescent in situ hybridization. Results Sixty-nine patients (66 with stage IV disease, 37 with oropharynx primary tumors, and 67 with performance status 0 to 1) were enrolled with a median age of 55 years. Predominant grade 3 or 4 toxicities during IC and CCRT were neutropenia (n = 20) and in-field mucositis (n = 59) and dermatitis (n = 23), respectively. CR rate after CCRT was 90%. After median follow-up of 3.5 years, 4-year overall, progression-free, and disease-specific survival rates were 74%, 72%, and 89%, respectively. To date, one patient has developed a second primary tumor in the aerodigestive tract. In 31 patients with available tissue, high EGFR gene copy number was associated with worse overall survival (P = .02). Conclusion Gefitinib can be administered with FHX and as maintenance therapy for at least 2 years, demonstrating CR and survival rates that compare favorably with prior experience. High EGFR gene copy number may be associated with poor outcome in patients with LA-HNC treated with this regimen.

WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is an autosomal dominant disease related to a mutation in the chemokine receptor CXCR4 resulting in altered immune function. An increased susceptibility in these patients to human papillomavirus (HPV) manifests as cutaneous warts and, in women, cervical dysplasia and squamous carcinoma. HPV-related squamous carcinoma in other sites has not been documented. We report the occurrence of HPV-related squamous cell carcinoma of the oral cavity in 2 siblings with WHIM syndrome, whose pedigree has previously been described.

Objectives/Hypothesis: In suspected cases of Sjogren syndome (SS), patients are often referred for a labial minor salivary gland biopsy. However, studies have shown this test to be unreliable. Pathologic misinterpretation and immunosuppressive medications may affect the results of the biopsy. As a result, it is best to perform this procedure only when necessary. The purpose of the current study was to review clinical signs and symptoms of patients who underwent a lip biopsy to determine which patients benefited most from this procedure. Study Design: Retrospective review. Methods: A retrospective chart review of patients referred to otolaryngology for a lip biopsy for the diagnosis of SS. Results: Joint pain, salivary gland swelling, and abnormal serology (anti-Sjogren syndrome A/anti-Sjogren syndrome B) were more prevalent in the positive lip biopsy group (grade = 3 or 4). Out of the 12 patients who had both sicca symptoms and positive serology, nine (75%) had a grade = 4. Presence of sicca symptoms and positive serology were predictive of a positive biopsy (P = .017). Excluding those patients who were on immunosuppression for more than 6 weeks prior to the biopsy, the correlation became stronger (P = .011). Conclusions: In this study, clinical presentation of sicca symptoms and positive serology reliably predicted the results of a lip biopsy. The results of this study suggest that patients with clear criterion for SS may not require a lip biopsy, especially those patients on immunosuppression. When physicians suspect SS, a thorough clinical and laboratory examination is necessary to determine if a patient will benefit from a minor salivary gland biopsy.

Devic’s disease is often considered as a variant of multiple sclerosis (MS). However, evidence suggests that Devic’s disease may be distinct from MS. Devic’s disease can coexist with connective tissue diseases, particularly Sjögren’s disease, but this association is rare with MS. Diagnosis of Sjögren’s disease in patients with neurological symptoms is often difficult. During early stages of Sjögren’s disease, patients may not fulfill all criteria for Sjögren’s disease. A high percentage of patients with Sjögren’s disease have inflammatory infiltrates in minor salivary glands, and this may be a reliable indicator of early or subclinical disease. We show high prevalence (80%) of salivary gland inflammation in Devic’s disease and longitudinally extensive transverse myelitis (LETM). We diagnosed 16 patients with Devic’s disease, and 2 of these satisfied criteria for Sjögren’s disease as did 2 of 9 patients with LETM. Anti-SSA/B titers were infrequently elevated. Although most did not satisfy criteria for Sjögren’s disease. 9 of 12 Devic’s disease patients and 7 of 8 LETM patients had severe salivary gland inflammation. Thus: (1) patients with Devic’s disease or with LETM who have positive labial biopsies but do not satisfy criteria for Sjögren’s disease could have subclinical Sjögren’s diseases. Alternatively, (2) as patients with Devic’s disease have elevated titers of several autoantibodies, so there may exist a set of antibodies that react with antigens in minor salivary glands and cause inflammation. Minor salivary gland biopsy is more sensitive than anti-SSA/B serology in providing histological evidence for possible Sjögren’s disease with CNS lesions.

Objective: Sjogren's syndrome (SS) is an autoimmune disease involving primarily the salivary and lacrimal glands (“sicca” symptoms) with extraglandular features including joint and nervous system involvement. In patients with a questionable diagnosis of SS but severe extraglandular symptoms, a lip biopsy is often performed to firmly establish the diagnosis of SS. This study was undertaken to identify areas of uncertainty regarding the accuracy of biopsy interpretation and the diagnostic benefits of the procedure. Study Design: Retrospective review of clinical and pathologic data. Methods: Clinical data from 47 patients referred to the otolaryngology–head and neck surgery service for lip biopsy were reviewed. Archival pathologic specimens were scored using the currently accepted grading system. Results: The grading system was incorrectly applied during initial interpretation of 45% (n = 21) of specimens. This resulted in five (10%) pathologic misdiagnoses and 16 (34%) nondiagnoses. On re-interpreting the specimens with consistent application of the grading system, 62% (n = 29) of the biopsies were definitely positive, and 36% (n = 17) were negative. Neither positive serology nor the presence of sicca symptoms predicted a positive biopsy (likelihood ratio = 0.95 and 0.96, respectively). Lip biopsy guided treatment in at least 65% (n = 31) of patients but was ignored in the presence of other clinical findings in 17% (n = 8) of patients. Conclusions: Consistent application of the grading system is essential in avoiding incorrect diagnosis and aiding clinical decisions. However, not all patients undergoing lip biopsy will derive diagnostic benefit from the procedure. In this series, clinical symptoms and serology did not predict positive lip biopsy.

The purpose of this study was to determine the maximum tolerated dose (MTD) of docetaxel based induction and concomitant chemoradiotherapy (CRT) after using the FHX platform (5 = 5-FU, H = hydroxyurea, X = Radiation). Patients with Stage III/IV locally advanced HNSCC were enrolled. Induction chemotherapy (carboplatin/docetaxel) was followed by 5 cycles of concomitant docetaxel based CRT. No DLTs were observed in dose levels 1/2 for induction and CRT. Dose level 2 was expanded. The overall survival CR rate after CRT was 79 percent. Median overall (OS) has not been reached and 2-year OS is 80.7 percent. The recommended Phase II dose of docetaxel with FHX CRT is 25 mg/m(2) and 35 mg/m(2) in combination with carboplatin induction (AUC = 6).

BACKGROUND Efforts to reduce the late toxicity associated with chemoradiation (CRT) for locally advanced head and neck squamous cell cancer (LA-HNSCC) have focused on radiotherapy (RT) dose de-escalation. In this phase I/II protocol investigating the addition of everolimus to induction chemotherapy (IC), we incorporated a novel response-adapted volume de-escalation (RAVD) approach using IC response to guide the extent of RT volume reduction. PATIENTS AND METHODS Patients with measurable LA-HNSCC received two cycles of IC (cisplatin, paclitaxel, cetuximab ± everolimus). Patients with ≥50% reduction in the sum of tumor diameters [good response (GR)] received TFHX (paclitaxel, fluorouracil, hydroxyurea, and 1.5 Gy twice daily RT every other week) to a dose of 75 Gy with the single planning target volume (PTV1) encompassing exclusively gross disease. Patients with

Purpose: The genetic differences between human papilloma virus (HPV)–positive and –negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown. To identify differential biology and novel therapeutic targets for both entities, we determined mutations and copy-number aberrations in a large cohort of locoregionally advanced HNSCC. Experimental Design: We performed massively parallel sequencing of 617 cancer-associated genes in 120 matched tumor/normal samples (42.5% HPV-positive). Mutations and copy-number aberrations were determined and results validated with a secondary method. Results: The overall mutational burden in HPV-negative and HPV-positive HNSCC was similar with an average of 15.2 versus 14.4 somatic exonic mutations in the targeted cancer-associated genes. HPV-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, PIK3CA, and NOTCH genes. HPV-positive tumors showed unique mutations in DDX3X, FGFR2/3 and aberrations in PIK3CA, KRAS, MLL2/3, and NOTCH1 were enriched in HPV-positive tumors. Currently targetable genomic alterations were identified in FGFR1, DDR2, EGFR, FGFR2/3, EPHA2, and PIK3CA. EGFR, CCND1, and FGFR1 amplifications occurred in HPV-negative tumors, whereas 17.6% of HPV-positive tumors harbored mutations in fibroblast growth factor receptor genes (FGFR2/3), including six recurrent FGFR3 S249C mutations. HPV-positive tumors showed a 5.8% incidence of KRAS mutations, and DNA-repair gene aberrations, including 7.8% BRCA1/2 mutations, were identified. Conclusions: The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes. HNSCC harbors multiple therapeutically important genetic aberrations, including frequent aberrations in the FGFR and PI3K pathway genes. Clin Cancer Res; 21(3); 632–41. ©2014 AACR. See related commentary by Krigsfeld and Chung, p. 495

Study Objective To assess the short-term efficacy and safety of an accelerated intravenous iron regimen in hospitalized patients with heart failure and iron deficiency. Design Prospective, single-arm, open-label study. Setting Large tertiary care medical center. Patients Thirteen patients with New York Heart Association class III–IV heart failure, anemia (hemoglobin level ≤ 12.0 g/dl), and iron deficiency (ferritin level

European Annals of Otorhinolaryngology, Head and Neck Diseases - Vol. 133 - N° 2 - p. 153-154

6066 Background: In this prospective phase II de-escalation study, we used induction chemotherapy to identify favorable HPV+ oropharyngeal cancer (OPC) pts, including those with high-risk tumors, and applied significantly lower radiation or chemoradiation doses than previously reported. Methods: Pts with HPV+ OPC were classified as low-risk (≤T3, ≤N2B, ≤10 PYH) or high-risk (T4 or ≥N2C or > 10 PYH). Pts received 3 cycles of carboplatin (AUC 6, D1) and nab-paclitaxel (100 mg/m2, D1/8/15). 1) Low-risk pts with ≥50% response received low-dose radiotherapy alone to 50Gy (RT50). 2) Low-risk pts with 30-50% response OR high-risk pts with ≥50% response received low-dose chemoradiotherapy to 45Gy (CRT45). 3) All other ( = poor response) pts received regular-dose CRT (CRT75). All pts also received de-escalated RT volumes limited to the first echelon of uninvolved nodes. CRT consisted of paclitaxel, 5-FU, hydroxyurea, and 1.5Gy twice daily RT every other week. Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pathologic complete response (pCR) rate and toxicity. Results: 62 pts were enrolled. 28 pts (45.2%) were low-risk and 34 pts (54.8%) were high-risk. 71.4% of low-risk pts received RT50 and 21.4% received CRT45. 70.6% of high-risk pts received CRT45. The pCR rate was 94.4% after RT50 and 92.3% after CRT45. Median follow-up is 1 year. The 2-year PFS and OS were both 100% for low-risk pts, and 91.6% and 97.0% for high-risk pts. Significant decrease in the rates of grade ≥3 mucositis (15.8% RT50, 46.4% CRT45, 60.0% CRT75, p = .033) and grade ≥3 dermatitis (0% RT50, 21.4% CRT45, 30.0% CRT75, p = .056) were observed. PEG-tube dependency was improved at 3 months (0% RT50, 14.8% CRT45, 70.0% CRT75, p < .001) and 6 months (0% RT50, 3.7% CRT45, 20.0% CRT75, p = .066) post-treatment. Conclusions: Favorable response to induction chemotherapy appears to be a powerful biomarker for dose and volume de-escalation with 50Gy RT or 45Gy CRT. Outstanding survival and high pCR rates suggest that completion neck dissection may not be necessary. Toxicity and functional outcomes are significantly improved. Clinical trial information: NCT02258659.

Background Human papillomavirus (HPV) has emerged as a causative agent and positive prognostic factor for oropharyngeal (OP) head and neck squamous cell cancer (HNSCC). This prompts inquiry into whether therapy improvements or increasing incidence of HPV drives the apparent improvements in HNSCC outcomes observed in non-randomized clinical trials. Patients and methods We reviewed all locoregionally advanced HNSCC patients treated with chemotherapy and radiation in prospective institutional trials at a single institution. Patients were divided into three groups (1, 2, 3) according to treatment time period (1993–1998, 1999–2003, 2004–2010, respectively). We reasoned that if a favorable trend was observed over time in OP but not non-OP patients, HPV status may be confounding treatment effects, whereas this would be unlikely if both subgroups improved over time. Results Four hundred and twenty-two patients were identified with OP (55.7%) and non-OP (44.3%) HNSCC. Five-year OP overall survival (OS) improved from 42.3% (group 1) to 72.5% (group 2), and 78.4% (group 3), adjusted P = 0.0084. Non-OP 5-year OS was 51.0% (group 1), 58.8% (group 2), and 66.3% (group 3), adjusted P = 0.51. Five-year recurrence-free survival (RFS) improved for OP groups from 42.3% to 68.4% to 75.8% (adjusted P = 0.017). Non-OP 5-year RFS was 42.9%, 53.6%, and 61.7% for sequential groups (adjusted P = 0.30). Five-year OP distant failure-free survival (DFFS) improved from 42.3% to 71.1% to 77.8% (adjusted P = 0.011). Five-year non-OP DFFS was 46.9%, 57.1%, and 66.0% for sequential groups (adjusted P = 0.38). Conclusions Over the past two decades, OP HNSCC outcomes improved significantly, while non-OP outcomes only trended toward improvement. Although our patients are not stratified by HPV status, improving OP outcomes are likely at least partly due to the increasing HPV incidence. These data further justify trial stratification by HPV status, investigations of novel approaches for carcinogen-related HNSCC, and current de-intensification for HPV-related HNSCC.

Sarcoidosis is chronic multisystem disease of unknown etiology. It is characterized by non caseating granulomas in the involved organs. Lung involvement is the most common organ involvement. Other common manifestations include skin, joint and ocular lesions. Otolaryngologic manifestations are seen in 10-15% of sarcoidosis patients. Sarcoidosis of the salivary glands present with a painless and persistent enlargement of the parotid glands. Xerostomia is often present. A second presentation is uveo parotid fever or Heerfordt's syndrome. The diagnosis of sarcoidosis is made when there is a histological evidence of non caseating granulomas in the absence of infection and malignancy. There are no FDA approved therapies for sarcoidosis. Corticosteroids remain the standard of care. Corticosteroid sparing agents may be used in patients with progressive disease. The use of tumor necrosis factor inhibitors may be effective in refractory cases.