Aaron M. Wieland

Risk factors for unplanned readmission following head and neck microvascular reconstruction: Results from the National Surgical Quality Improvement Program, 2011-2014.

Unplanned readmissions are associated with decreased healthcare quality and increased costs. This nationwide study examines causes for unplanned readmission among head and neck cancer patients undergoing immediate microsurgical reconstruction.

Survival Outcomes for Patients With T3N0M0 Squamous Cell Carcinoma of the Glottic Larynx.

Importance Radiotherapy (RT)–based organ preservation approaches for patients with advanced laryngeal cancer have been established stepwise through prospective randomized clinical trials. However, broad adoption of these approaches has stimulated discussion about long-term results challenging their applicability in a heterogeneous patient population, most recently for patients with T3 disease. Objective To define outcomes in patients with clinical T3N0M0 glottic laryngeal cancer treated with definitive surgical and RT-based approaches. Design, Setting, and Participants This retrospective cohort study included patients treated from January 1, 2004, through December 31, 2013, with a median follow-up time of 58 months (range, 0-126.6 months) in the National Cancer Database. Of the 4003 patients with T3N0M0 disease, 2622 received definitive therapy defined by the study protocol. Data were obtained from the clinical oncology database sourced from hospital registry data that are collected from more than 1500 Commission on Cancer–accredited facilities. Data were analyzed from September 14, 2016, through April 24, 2017. Interventions Radiotherapy, chemoradiotherapy, surgery, surgery and RT, or surgery and chemoradiotherapy. Main Outcomes and Measures Five-year overall survival (OS). Results A total of 2622 patients (2251 men [85.9%] and 371 women [14.1%]; median age, 64 years [range, 19-90 years]) were included in the analytic cohort. In the overall patient cohort, the adjusted 5-year survival probability was 53%. No statistical differences were observed between the primary surgery (53%; 95% CI, 48%-57%) and primary RT (54%; 95% CI, 52%-57%) cohorts. In multivariate analysis, patient factors associated with decreased OS included age (hazard ratio [HR], 1.04; 95% CI, 1.03-1.04), insurance status (HR, 1.26; 95% CI, 1.06-1.50), and increasing comorbidity (HR, 1.20; 95% CI, 1.02-1.42). Conclusions and Relevance Current management of T3N0M0 glottic laryngeal cancer relies largely on RT-based organ preservation approaches. The present study substantiates randomized clinical trial data supporting the use of RT-based organ preservation approaches for patients with T3N0M0 glottic laryngeal cancer without compromising OS.

Patient and tumor characteristics predictive of primary parotid gland malignancy: A 20-year experience at the University of Wisconsin☆☆☆

PURPOSE To identify patient and tumor characteristics predictive of primary parotid malignancy. MATERIALS AND METHODS Records were reviewed for patients who underwent parotidectomy at the University of Wisconsin from 1994 to 2013. Patients with primary parotid neoplasms were separated into benign or malignant subgroups. A multivariate logistic regression model was employed to compare categorical (gender, lesion side, nature of presentation, recurrence) and numerical variables (age, tumor size) between the benign and malignant groups. Mean BMI was compared between the groups by univariate analysis. RESULTS 771 patients underwent parotidectomy from 1994 to 2013, and 474 had a primary parotid neoplasm. No relationship existed between malignancy and gender (p=0.610), lesion side (p=0.110), or BMI (p=0.196). Mean age (p=0.015) and tumor size (p=0.011) were significantly different between the benign and malignant groups. Patient presentation was classified into three categories: symptomatic (n=109), palpable and asymptomatic (n=303), and incidentally noted on imaging (n=57). From all patients with symptomatic, asymptomatic or incidentally noted masses, 41.3%, 10.6% and 5.3%, respectively, were diagnosed with malignant disease. There was a significant relationship between the patients initial presentation and malignancy (p<0.001), and patients with facial nerve dysfunction or skin involvement had the greatest likelihood of malignancy. Finally, there was a significant association between malignancy and recurrence (p=0.001). CONCLUSIONS In this study, age, tumor size, and nature of presentation were all associated with primary parotid malignancy. Understanding the impact of these features on the probability of malignancy is valuable in decision making and counseling of patients presenting with a newly diagnosed parotid neoplasm.

Chondroradionecrosis of the larynx: 24-year University of Wisconsin experience

Chondroradionecrosis (CRN) is an uncommon but significant complication of laryngeal radiotherapy that presents a diagnostic challenge to clinicians through its similarity in presentation to cancer recurrence.

Impact of HPV Status on the Prognostic Potential of the AJCC Staging System for Larynx Cancer

Objective We evaluated the ability of the American Joint Committee on Cancer (AJCC) seventh edition staging system to prognosticate the overall survival of patients with human papillomavirus (HPV)–positive laryngeal squamous cell carcinoma. Study Design Retrospective analysis. Setting National Cancer Database. Subjects and Methods Patients diagnosed with laryngeal squamous cell carcinoma who were treated with curative intent were identified in the National Cancer Database. Multivariate analysis was utilized to determine factors correlated with overall survival in the HPV-negative and HPV-positive cohorts. Unadjusted and propensity score–weighted Kaplan-Meier estimation was used to determine overall survival of HPV-negative and HPV-positive patients across AJCC stage groupings. Results We identified 3238 patients with laryngeal squamous cell carcinoma, of which 2812 were HPV negative and 426 were HPV positive. Overall survival adjusted for age, sex, and comorbidity status confirmed significant differences among all consecutive stage groupings (I vs II, P < .001; II vs III, P < .05; III vs IVA, P < .001; IVA vs IVB, P < .05) in the HPV-negative cohort, whereas only stages IVAs and IVB (P < .01) exhibited a significant difference in overall survival for HPV-positive patients. Conclusion The current AJCC staging system does not accurately distinguish risk of mortality for patients with HPV-positive disease. These data support the consideration of HPV status in estimating prognosis as well as clinical trial design and clinical decision making for patients with laryngeal squamous cell carcinoma.

Testing Personalized Medicine Using Patient-Derived Xenografts of Head and Neck Cancer

HPV status, or treatmentwithRTalone, concurrent chemotherapy, or upfront laryngectomy. We defined radiation-resistance as persistent or recurrent diseasewithin 3 years of receiving treatment. Early-stage LSCCwas defined as stage I or II tumors without lymph node involvement. Candidate genes associated with the radiation resistance included NFE2L2, KEAP1, CUL3, HRAS, NRAS, NOTCH2, NOTCH3, KRAS, RAF1, BCL-2, and BIRC5. Results: Twenty LSCC tumors were categorized as either radiation sensitive (RS, NZ9) or radiation resistant (RR, NZ11). Six were early-stage tumors (RR: NZ3 and RS: NZ3). Basic demographic factors were balanced between the 2 groups. Among all 20 samples, we found increased somatic mutations in the NOTCH pathway in RR patients (NOTCH 2: 44% vs. 0%, PZ .04; NOTCH 3 44% vs. 11%, PZ.19). In the 6 early-stage LSCC patients, we found all 3 RR tumors to have mutations in the KEAP1/ NFE2L2 pathway, while none of the RS tumors had mutations (PZ.014). Conclusion: In RR patients, there was a higher somatic mutational burden involving the NOTCH family. Interestingly, all early-stage LSCC patients with RR (NZ3) had mutations in the KEAP1/NRF2 oxidative stress pathway. In LSCC patients, downregulation of the KEAP1/NRF2 oxidative stress pathway may result in RT resistance. Further validation in a larger population is warranted. Alterations in both the NOTCH and KEAP1/ NRF2 oxidative stress pathway may serve as genomic determinants to predict radiation resistance in LSCC. Author Disclosure: D. Farquhar: None. S. Sheth: None. A. Mazul: None. P. Little: None. D.N. Hayes: None. J.P. Zevallos: None.

p16 Immunohistochemistry Is a Useful Diagnostic Adjunct in Cases of Metastatic Cervical Carcinoma of Unknown Origin

PURPOSE Metastatic cervical carcinoma of unknown primary (MCCUP) is increasing in frequency owing in part to rising human papillomavirus (HPV)-driven oropharyngeal carcinoma. Identifying the primary site is valuable, because it is associated with increased survival and decreased morbidity. HPV-positive cervical nodal disease focuses attention on the oropharynx for directed biopsy examinations, including tonsillectomy. When the primary is small, carcinoma might not be apparent by traditional hematoxylin and eosin (H&E) staining alone. MATERIALS AND METHODS This report describes 2 cases of p16-positive MCCUP in which a small primary carcinoma was not readily identified in surgical specimens using H&E staining. RESULTS Additional evaluation of the specimens with p16 immunohistochemistry (IHC) showed carcinoma in these 2 cases. CONCLUSIONS When H&E staining does not show carcinoma in cases of MCCUP, p16 IHC should be considered given the high prevalence of HPV-positive MCCUP and the potential for identification of a small primary tumor that might otherwise be missed with H&E staining.

Clinical outcomes for patients presenting with N3 head and neck squamous cell carcinoma: Analysis of the National Cancer Database

There is a paucity of data regarding head and neck squamous cell carcinomas (HNSCCs) and N3 nodal disease.

Radiosensitization of adenoid cystic carcinoma with MDM2 inhibition

Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition. Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient-derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy. Results: AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment. Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy. Clin Cancer Res; 23(20); 6044–53. ©2017 AACR.

Abstract 3044: Patient-derived adenoid cystic carcinoma xenografts to study molecular target modulation of tumor radiosensitivity

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Background: Adenoid cystic carcinoma (ACC) is a relatively rare cancer that typically arises in salivary tissues of the head and neck region. Hallmark characteristics include slow growth rate, peri-neural tumor spread, and a high propensity for late distant metastasis. Surgery and radiation are the mainstays of treatment with no effective systemic agents to date. Due to infrequency, studies of novel therapeutics are not routinely feasible. In addition, whether these tumors can be sensitized to radiation by concurrent chemotherapy is not known. We report here the establishment and examination of ACC patient derived xenografts (PDX) to investigate the efficacy of novel chemotherapies and combinations of chemotherapy and radiation. Methods: PDXs have been established and maintained in NOD-SCID gamma (NSG) mice from both research biopsies and surgical specimens. Common cancer-associated mutations in both the primary patient tumor and PDX were identified using the Illumina TruSeq Amplicon Cancer panel. Well described immunohistochemical markers of ACC were used to compare histological characteristics between the primary tumor and PDX. The ACC PDX was engrafted into the flanks of nude mice and treated with focal radiotherapy (5 Gy x 8 fractions delivered twice weekly), a panel of chemotherapeutic agents, or combination radiochemotherapy. Tumor size was measured over time and comparisons between treatment groups made by the extra-sum-of-squares f test. Results: PDXs established from ACC maintain the histologic and physical characteristics of the primary tumor. Targeted mutational analysis of ACC identified expected alterations based on previously reported large scale sequencing of other human tumors including mutations in the receptor tyrosine kinases(RTKs) cKit and KDR/VEGFR2. Based on identified tumor mutations, several targeted therapies were selected including dovitinib, a multi-RTK inhibitor, BEZ235, a PI3K/mTORC inhibitor, and cetuximab, an EGFR mAB. Treatment with each of these compounds showed varying degrees of growth inhibition without evidence of frank tumor regression. However, combining these drugs with radiation demonstrated significantly improved tumor control in comparison to drug alone. Conclusions: Studies using our PDX model suggest that several molecular targeting agents can significantly augment the impact of radiation on ACC tumor growth. These preliminary data identify the rationale to investigate selected molecular drug/radiation combinations for ACC, particularly when driven by tumor specific genetic biomarkers. Expansion of these ACC studies may be valuable to advance the design of new investigational treatment strategies for this challenging tumor. Citation Format: Prashanth Prabakaran, Kwangok P. Nickel, David T. Yang, Lauryn R. Werner, Justine Y. Bruce, Aaron M. Wieland, Timothy M. McCulloch, Gregory K. Hartig, Paul M. Harari, Adam D. Swick, Randall J. Kimple. Patient-derived adenoid cystic carcinoma xenografts to study molecular target modulation of tumor radiosensitivity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3044.