Faculty Bibliography

OBJECTIVES:Human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is a unique form of head and neck cancer with improved prognosis. We assessed survival for stage I patients with low- or intermediate-risk pathologic features with surgery alone compared with surgery with adjuvant radiation (RT) or chemoradiation (CRT). MATERIALS AND METHODS:We identified patients with stage I HPV+ OPSCC (after restaging with 8th edition staging system) treated with surgery alone, adjuvant RT or CRT in the National Cancer Data Base from 2010 to 2013. We compared survival for low-risk patients (≤1 metastatic lymph nodes with no adverse features) and intermediate-risk patients (2-4 metastatic lymph nodes, microscopic extranodal extension (ENE) or lymphovascular invasion). RESULTS:We examined 1677 patients with median follow-up of 43.9 months. In the intermediate-risk group, 4-year overall survival was 94.0% with surgery alone, 91.5% with adjuvant RT and 92.0% with adjuvant CRT (p = 0.72). There were similar rates of overall survival in the low-risk group. In multivariable models accounting for clinicopathologic differences the dose of adjuvant RT was not associated with mortality. On Cox proportional hazard modeling, adjuvant RT (HR 0.94; CI 0.43-2.08) or CRT (HR 0.96; CI 0.45-2.11) did not significantly improved survival compared with surgery alone in the intermediate-risk group (reference). Similar results were seen in the low-risk group. The composite number of pathologic risk features significantly improved risk stratification. CONCLUSION:We provide observational evidence that adjuvant RT or CRT does not provide a survival benefit for stage I HPV+ OPSCC with low- or intermediate-risk pathologic features.

BACKGROUND:Cetuximab combined with radiation therapy (RT) is an evidence-based treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, locoregional failure remains the primary cause of cancer-related death in this disease. Intratumoral injection of epidermal growth factor receptor (EGFR)-antisense plasmid DNA (EGFR-AS) is safe and has been associated with promising lesional responses in patients who have recurrent/metastatic HNSCC. For the current study, the authors investigated the antitumor effects of cetuximab and EGFR-AS in preclinical HNSCC models and reported their phase 1 experience adding intratumoral EGFR-AS to cetuximab RT. METHODS:Antitumor mechanisms were investigated in cell line and xenograft models. Phase 1 trial eligibility required stage IVA through IVC HNSCC and a measurable lesion accessible for repeat injections. Patients received standard cetuximab was for 9 weeks. EGFR-AS was injected weekly until they achieved a lesional complete response. RT was delivered by conventional fractionation for 7 weeks, starting at week 3. Research biopsies were obtained at baseline and week 2. RESULTS:When added to cetuximab, EGFR-AS decreased cell viability and xenograft growth compared with EGFR-sense control, partially mediated by reduced EGFR expression. Six patients were enrolled in the phase 1 cohort. No grade 2 or greater EGFR-AS-related adverse events occurred. The best lesional response was a complete response (4 patients), and 1 patient each had a partial response and disease progression. EGFR expression decreased in 4 patients who had available paired specimens. CONCLUSIONS:In preclinical models, dual EGFR inhibition with cetuximab and EGFR-AS enhanced antitumor effects. In a phase 1 cohort, intratumoral EGFR-AS injections, cetuximab, and RT were well tolerated. A phase 2 trial is needed to conduct an extended evaluation of safety and to establish efficacy.

OBJECTIVE:For the first time in 30 years, the eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual offers major changes in the staging of oral cavity cancer. We evaluated the predictive ability of the new staging system for oral cavity cancer to validate these changes and hypothesized that the new system would improve prognostic accuracy. METHODS:We conducted a retrospective cohort study of patients with oral cavity squamous cell carcinoma in the National Cancer Data Base from 2009 to 2013 and applied the seventh and eighth edition staging AJCC staging systems to all patients. Stage-specific overall survival was calculated using the Kaplan-Meier method and concordance indices to measure the system's prognostic accuracy. RESULTS:We identified 39,361 patients with a median follow-up of 27.1 months (range 0.1-80.4 months). In the seventh edition, there were 43.0%, 15.0%, 10.6%, and 25.7% of patients with pathologic stage I, II, III, and IV disease, respectively. After restaging based on eighth edition pathological guidelines, 10.0% of patients were upstaged (38.1%, 18.1%, 14.2%, and 25.2%, respectively, with stage I, II, III, and IV disease, respectively). The survival concordance index improved from the seventh to eighth edition for pathological staging (concordance index 0.699 and 0.704, respectively) and for clinical staging (concordance index 0.714 and 0.715, respectively). CONCLUSION:We provide validation of the new AJCC staging system for oral cavity cancer. Eighth edition AJCC staging guidelines upstage a substantial number of patients with greater depth of invasion or extranodal extension. This resulted in slightly improved prognostication. LEVEL OF EVIDENCE:2c. Laryngoscope, 128:2351-2360, 2018.

OBJECTIVES:Adjuvant radiation therapy (RT) is indicated for patients with salivary gland malignancies with risk factors for recurrence following resection. We analyzed patients treated with adjuvant RT with or without concurrent chemotherapy to determine the impact of prognostic and treatment factors. MATERIALS AND METHODS:Retrospective analysis was performed of 128 patients treated with surgical resection followed by intensity-modulated radiotherapy. In total, 31 (24.2%) patients were treated with concurrent chemoradiotherapy. The Kaplan-Meier method was used to estimate rates of progression-free survival (PFS), local-regional control, distant control, overall survival. Multivariable Cox regression was performed to evaluate factors significant on univariate analysis. RESULTS:The 5-year rates of PFS, local-regional control, freedom-from distant metastasis, and overall survival were 61.2%, 85.8%, 76.5%, and 73.7%, respectively. Predictors of decreased PFS on univariate analyses were age, tumor stage, nodal stage, positive surgical margins, histology, high grade, perineural invasion, lymphovascular space invasion, extranodal extension, and use of chemoradiotherapy. On multivariable analysis, elevated T-stage, positive surgical margins, and presence of extranodal extension were predictive of decreased PFS. The acute toxicity rates were 30.3% grade 1, 51.5% grade 2, 11.4% grade 3, and 0.8% grade 4. There was no difference in rates of grade 3 or higher acute toxicity with use of RT alone versus chemoradiotherapy (P=0.183). CONCLUSIONS:Use of chemoradiotherapy for adjuvant treatment of salivary gland malignancies was well-tolerated, but no improvement in survival was seen with the use of chemoradiotherapy in both the overall study population and a subset with high-risk features. Caution should be used when using this modality until randomized evidence becomes available.

IMPORTANCE/OBJECTIVE:The American Joint Committee on Cancer, 8th edition (AJCC-8) contains a new staging system for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). Our study aim was to evaluate the effectiveness of the AJCC-8 relative to the AJCC 7th edition (AJCC-7). MATERIALS AND METHODS/METHODS:A retrospective chart review was performed on a multi-institutional, prospectively collected dataset from two tertiary referral centers. All patients had HPV+ OPSCC treated primarily with surgery. The prognostic value of AJCC-7 and AJCC-8 were compared for 5-year overall survival (OS) and disease-specific survival (DFS). RESULTS:AJCC-8 pathological staging effectively risk stratified patients, creating a Cox model with a better fit (lower Akaike's Information Criterion, p < 0.0001) when compared to AJCC-7 pathological stages for both OS and DFS. The AJCC-8 pathologic staging did not produce a better fit than the AJCC-8 clinical staging (p = 0.15) for OS, however, AJCC-8 pathologic was more effective than AJCC-8 clinical for DFS (p < 0.0001). 76% of patients did not change their stage between clinical and pathologic AJCC-8 staging; 14% were upstaged by 1, <1% were upstaged by 2, 7% were downstaged by 1, and 3% downstaged by 2. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:The new AJCC-8 staging system represents a significant improvement over AJCC-7 for risk stratification into groups that predict overall survival and disease-specific survival of surgically treated HPV+ OPSCC patients. The AJCC- 8 pathologic staging system was not significantly better than the AJCC-8 clinical staging system for overall survival, however, the pathologic staging system was better than the clinical for disease free survival.

Although histology still plays a critical role in diagnosing diffuse gliomas, additional ancillary testing is an essential tool for VA pathology laboratories.

BACKGROUND:Oligometastasis is a good prognostic indicator when compared to widely metastatic disease in malignancies of other organ systems. We hypothesized that oligometastasis in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) would be associated with better overall survival. METHODS:This is a retrospective review of all HPV-positive oropharyngeal SCC treated at one center with at least 1-year of follow-up. Patients were stratified into 2 cohorts: oligometastasis (1-2 metastases, confined to 1 organ system) or polymetastasis (>2 metastases or multiple organ involvement) with cohorts compared for time to distant metastasis and overall survival after metastasis. RESULTS:Thirty-eight of 506 patients (7.5%) developed metachronous distant metastasis; 12 developed oligometastasis and 26 developed polymetastasis. Median overall survival after oligometastasis was significantly longer than polymetastasis at 45 months (95% confidence interval [CI] 19 months - not reached) and 10 months (95% CI 5-24 months; P = .00028). CONCLUSION:Oligometastasis in metastatic HPV-positive oropharyngeal SCC portends a better prognosis than polymetastasis.

BACKGROUND:Human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinomas (OPSCCs) have an excellent response rate to platinum-based chemoradiotherapy. Genomic differences between primary HPV-related OPSCCs that do or do not recur are unknown. Furthermore, it is unclear if HPV-related OPSCCs that recur share a genomic landscape with HPV-negative head and neck cancers (HNCs). METHODS:We utilized whole exome sequencing to analyze somatic nucleotide (SNVs) and copy number variants (CNVs) among a unique set of 51 primary HPV-related OPSCCs, including 35 that did not recur and 16 that recurred. We evaluated 12 metachronous recurrent OPSCCs (7 with paired primary OPSCCs) and 33 primary HPV-unrelated oral cavity and OPSCCs. RESULTS:KMT2D was the most frequently mutated gene among primary HPV-related OPSCCs (n = 51; 14%) and among metachronous recurrent OPSCCs (n = 12; 42%). Primary HPV-related OPSCCs that recurred shared a genomic landscape with primary HPV-related OPSCCs that did not recur. However, TSC2, BRIP1, NBN, and NFE2L2 mutations occurred in primary OPSCCs that recurred but not in those that did not recur. Moreover, primary HPV-related OPSCCs that recur harbor features of HPV-unrelated HNCs, notably including MAPK, JAK/STAT, and differentiation signaling pathway aberrations. Metachronous recurrent OPSCCs shared a genomic landscape with HPV-unrelated HNCs, including a high frequency of TP53, CASP8, FAT1, HLA-A, AJUBA, and NSD1 genomic alterations. CONCLUSION:Overall, primary HPV-related OPSCCs that recur share a genomic landscape with nonrecurrent OPSCCs. Metachronous recurrent OPSCCs share genomic features with HPV-negative HNCs. These data aim to guide future deescalation endeavors and functional experiments. FUNDING:This study is supported by the American Cancer Society (RSG TBG-123653), funding support for RAH (T32DC00018, Research Training in Otolaryngology, University of Washington), funds to EM from Seattle Translational Tumor Research (Fred Hutchinson Cancer Research Center), and center funds from the Fred Hutchinson Cancer Research Center to EM. UD is supported by the Department of Veterans Affairs, Biomedical Laboratory Research and Development (BLR&D), grant IO1-oo23456, and funds from the Pittsburgh Foundation and PNC Foundation.

OBJECTIVE:Previously, we have reported the feasibility of retroauricular (RA) robotic thyroidectomy. Despite its promising surgical outcomes, there were certain intrinsic mechanical limitations inherent to the da Vinci Si System (Intuitive Surgical, Sunnyvale, California, U.S.A.). Since the advent of an upgraded model, the Xi System (Intuitive Surgical), we have actively incorporated the new model into performing RA thyroidectomy. Here, we intend to verify the feasibility of RA robotic thyroidectomy using the new da Vinci Xi System (Intuitive Surgical) with comparison of the former Si-applied surgery (Intuitive Surgical). STUDY DESIGN:Comparative analysis. METHODS:There were total 165 consecutive patients who received RA robotic thyroidectomy from January 2013 to February 2016. The patients were divided into two groups: Si group (n = 125) and Xi group (n = 40). Perioperative and treatment outcomes were compared and analyzed. RESULTS:Compared with the previous system, new da Vinci Xi system (Intuitive Surgical) enabled insertion of an extra third robotic instrumental arm. Unlike the previous robotic surgical technique, the robotic dissection could be initiated immediately after the establishment of working space and the resulting total operation time could be significantly decreased. There was no difference in the surgical completeness, as confirmed by postoperative thyroglobulin levels. Additionally, flexed EndoWrist (Intuitive Surgical) instruments equipped with the Erbe (Erbe USA Inc., Marietta, Georgia, U.S.A.) system could be mounted, which further facilitated the operation. There were no significant differences in postoperative complications between the two groups. CONCLUSION:The RA robotic thyroidectomy with the new Xi System (Intuitive Surgical) can greatly facilitate the robotic surgery with comparable or improved surgical outcomes. Its application is expected to open up a new era of robotic neck surgery. LEVEL OF EVIDENCE:4. Laryngoscope, 128:1730-1737, 2018.