Moore, Eric J.

ImportanceThe De-escalated Adjuvant Radiation Therapy (DART) phase 3 randomized clinical trial (RCT) showed that in patients with human papillomavirus (HPV)−associated oropharyngeal squamous cell carcinoma, postoperative minimal residual disease (MRD), detected through circulating tumor HPV DNA (ctHPVDNA), was associated with a higher risk of disease progression. When considered along with pathologic factors, postoperative ctHPVDNA assessment may improve patient selection for adjuvant treatment de-escalation; however, more data are needed to demonstrate how it may be used in personalizing treatment intensity.ObjectiveTo determine the association of postoperative MRD status with progression-free survival (PFS) after surgery for HPV-associated oropharyngeal squamous cell carcinoma.Design, Setting, and ParticipantsThis was a secondary analysis of the DART RCT, which was conducted from October 2016 to August 2020 in multiple sites in the US. Participants from the de-escalated adjuvant radiation therapy group and the standard of care group with available blood specimen data were included. Reports from 3-month posttreatment surveillance visits were used to assess associations and outcomes. Data analyses were performed from March 2023 to March of 2025.InterventionsThe DART group received 30 to 36 Gy of radiation therapy in 1.5 to 1.8 Gy twice daily, plus docetaxel, 15 mg/m2, on days 1 and 8. The standard of care group received 60 Gy with or without weekly cisplatin, 40 mg/m2.Main Outcome and MeasurePFS.ResultsThe analysis included 140 patients (mean [SD] age, 59.1 [8.4] years; 12 [8.6%] females and 128 [91.4%] males; 97 [69.3%] with no smoking history); characteristics were similar to the overall DART RCT population. Of these, 17 patients (12.1%) had postoperative MRD (13 of 96 [13.5%] receiving DART and 4 of 44 [9.1%] receiving standard of care). For all patients, postoperative MRD positivity was strongly associated with worsened PFS at 24 months (MRD positivity, 69.5%; MRD negativity, 95.9%; hazard ratio [HR], 0.19; 95% CI, 0.06-0.59). MRD positivity was associated with PFS when evaluating only those patients in the DART group, where 24-month PFS was 68.4% compared to 92.6% for MRD-negative patients (HR, 0.28; 95% CI, 0.08-0.93). Three months after completion of all treatment, 8 of 117 patients (6.8%) had detectable ctHPVDNA, whereas 109 of 117 (93.2%) did not, and detection was highly associated with PFS (HR, 20.48; 95% CI, 6.91-60.67).Conclusions and RelevanceThis secondary analysis of the DART RCT found that patients with detectable ctHPVDNA after surgery had a higher risk of disease progression. When added to the pathologic factors considered, ctHPVDNA assessment may improve selection of patients for treatment de-escalation. In addition, the 3-month posttreatment time point, early in surveillance, may identify a sizable portion of patients with progression and may guide intervention and surveillance after surgery for HPV-associated oropharyngeal squamous cell carcinoma.Trial RegistrationClinicalTrials.gov Identifier: NCT02908477

AbstractObjectiveLow‐grade parotid malignancies have high overall survival rates; however, controversy remains about the appropriate extent of surgery. We aim to explore the trends in the extent of parotidectomy performed over time in low‐grade parotid malignancies in the United States, with a hypothesis that there has been a trend towards less aggressive surgery.Study DesignRetrospective cohort study of all low‐grade (grade I) acinic cell carcinoma (ACC) and mucoepidermoid carcinoma (MEC) in the Surveillance, Epidemiology, and End Results (SEER) from 2004 to 2020.SettingGeographic areas served by SEER.MethodsTrends were assessed using Cochran‐Armitage tests and logistic regression; Kaplan‐Meier survival curves were used to analyze overall and cancer‐specific survival, and chi‐square tests were used to analyze patient characteristics.ResultsIn total, 1288 patients were identified (916 MEC; 372 ACC). Most patients (n = 772, 60%) were non‐Hispanic white, with an average age of 50.6 years and had a slight female predominance (1.58:1). Most of the cohort presented with tumor stage T1 or T2 (84%), N0 (90.1%), and M0 (96.9%). Treatment with total parotidectomy decreased significantly (34.6 vs 17.7%, P = .02) whereas sacrificing the facial nerve (FN) slightly decreased (20 vs 15.7%, P = .1). A significant increase in N0 patients (71%‐94%, P < .0001) was observed, whereas T staging remained stable (61%‐64%, P = .3). Overall, both ACC and MEC had excellent cancer‐specific survival.ConclusionOver the last 17 years, there has been a significant de‐escalation in the extent of parotidectomy for low‐grade parotid malignancy in the United States.

Background: Malignant mesenchymal tumors involving the parotid gland are uncommon, characteristically aggressive, and little is known with few reports documented. Study Design: Retrospective case series. Setting: Single institution tertiary care center, 2010 to 2022. Method: Patients were identified from an institutional parotid tumor database. Patient history, demographics, pathologic diagnosis, treatment, and follow up were documented. Results: Eight patients were identified, 3 were males. The average age was 61 years old, and the most common tumors identified were pleomorphic sarcomas (3 patients). Presenting symptoms included: preauricular/cheek mass in 7 patients, facial pain (4), otalgia (4), aural fullness (3), and numbness (1). All patients received a parotidectomy, and 4 patients received adjuvant therapy of either radiation or chemoradiation. Post-operatively, there were 3 cases of distant recurrence, 2 cases of regional recurrence, and 1 case of local recurrence. There were 2 reports of death. Conclusion: Malignant mesenchymal tumors of the parotid are rare, represent varied histologies. Due to their aggressive nature, surgical resection with radiation and close follow-up may be an appropriate treatment regimen in controlling the disease.

Importance Circulating tumor human papillomavirus DNA (ctHPVDNA) is an important biomarker for the presence of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), but little is known about early postoperative kinetics of ctHPVDNA clearance. Objective To investigate early postoperative kinetics of ctHPVDNA in patients with HPV-associated OPSCC. Design, Setting, and Participants This prospective cohort study was conducted at a single tertiary care center from January 4, 2020, to January 26, 2023. Patients with newly diagnosed HPV-associated OPSCC undergoing surgical management were enrolled. HPV status was defined as positive if findings of p16 immunohistochemistry and/or HPV DNA in situ hybridization and/or E6/E7 RNA in situ hybridization were positive. Exclusion criteria included history of prior head and neck cancer and metastatic disease at presentation. Data were analyzed from September 1, 2024, to April 25, 2025. Exposures Transoral robotic surgery with concurrent neck dissection. Main Outcomes and Measures Blood was drawn prior to surgery (pretreatment), 1 to 2 days after surgery (postoperative days 1 to 2), and approximately 2 weeks after surgery (postoperative week 2; range, 8 to 20 days). ctHPVDNA was quantified by a tumor tissue–modified viral (TTMV) HPV DNA test. Correlations were tested between the pretreatment and postoperative day 1 to 2 TTMV HPV DNA levels using Gaussian regression. Concordance between detectability at postoperative day 1 to 2 and postoperative week 2 was explored using negative predictive value and positive predictive value. Results Of 57 included patients with detectable pretreatment TTMV HPV DNA, 51 (89%) were male, and the median (IQR) age was 59 (54-66) years. A total of 35 patients (61%) had blood draws at all 3 time points; 16 (28%) had detectable TTMV HPV DNA on postoperative day 1 to 2. Pretreatment and postoperative day 1 to 2 TTMV HPV DNA levels had a medium positive linear correlation ( r = 0.31; 95% CI, 0.04-0.54). Undetectable TTMV HPV DNA on postoperative day 1 to 2 blood draw had a negative predictive value of 0.95 (95% CI, 0.74-1.00) for an undetectable level on postoperative week 2 blood draw, but a detectable level on postoperative day 1 to 2 blood draw only had a positive predictive value of 0.19 (95% CI, 0.04-0.46). Of the 16 patients with detectable TTMV HPV DNA pretreatment and at postoperative day 1 to 2, only 3 (19%) continued to have detectable TTMV HPV DNA at postoperative week 2. One patient had undetectable levels at postoperative day 1 to 2 and detectable levels at postoperative week 2. Conclusions and Relevance In this study, ctHPVDNA detectability early after surgery did not predict detectability at 2 weeks after surgery. ctHPVDNA clearance early after surgery could predict a negative test at 2 weeks. A negative blood draw finding on postoperative day 1 may be used to omit a postoperative blood draw at 2 weeks for minimal residual disease detection in future clinical trials.

Abstract Objective To (1) track the incidence of pleomorphic adenomas (PAs) and (2) compare demographic and treatment trends in PAs over the last five decades in a single county. Study Design Retrospective cohort of all patients with a pathologic diagnosis of nonrecurrent PA from January 1976 to December 2022. Setting Olmsted County, Minnesota. Methods Incidence was calculated per 100,000 persons/year and age and sex‐adjusted to the US 2020 census data. Incidence trends were identified using Poisson rate regression models. Changes in clinical features of diagnosis were evaluated using Spearman rank correlation coefficient tests, Wilcoxon rank sum tests, and Kruskal‐Wallis tests. Results In total, 251 patients with PA were identified. The median age at diagnosis was 50.0 years with a slight female predominance (1.24:1). The adjusted incidence during this period is 4.79/100,000 person‐years, increasing from 2.50 in 1976 to 1979 to 5.73/100,000 persons/year in 2020 to 2022. Less extensive surgery, including partial and superficial parotidectomies, increased significantly from 1976 to 2022, whereas total parotidectomies decreased ( P < .0001). The number of patients who presented with an incidental imaging finding increased during this time period ( P < .001), as did the age at diagnosis (45‐51 years, P = .05) Conclusion The average annual incidence of PAs in Olmsted County from 1976 to 2022 is higher than reported US estimates and has increased over the last five decades. The percentage of patients who presented with incidental imaging findings increased over this period, as did the age at diagnosis. These findings highlight modern imaging techniques and an aging population more willing to seek workup and treatment of a benign parotid mass.

Objective: To assess the impact of extent of parotidectomy on surgical and oncologic outcomes in low grade mucoepidermoid carcinoma (LGMEC). Methods: A retrospective chart review of all patients undergoing primary surgical treatment for LGMEC from 2000 to 2022 was conducted. Clinical features collected included demographics, facial nerve function, operative techniques, postoperative complications/facial nerve function, and recurrence. Results: 58 patients were included; 10 patients underwent partial parotidectomy (PP), 38 underwent superficial parotidectomy (SP), and 10 underwent near-total/total parotidectomy. PP and SP patients had smaller tumors and more superficial tumors compared to near-total/total parotidectomy group ( P = .03). PP and SP were more likely to have negative margins and less locoregional disease compared to near-total/total parotidectomy patients ( P < .01). Near-total/total parotidectomy were more likely to undergo facial nerve resection (20% vs 0% for PP & SP respectively) ( P = .05). Immediate postoperative facial nerve function was significantly better among PP patients (73% HB I) compared to SP (44% HB I) and near-total/total parotidectomy patients (0% HB I) ( P < .01). Most patients regained their facial nerve function although only 40% of the near-total/total parotidectomy patients had a HB I at the time of last follow up ( P < .01). Patients were followed for a median of 6.2 years, during which only 1 patient (total parotidectomy) had a recurrence. Conclusions: PP offers a safe and effective approach for small LGMEC tumors, ensuring better facial nerve function postoperatively with minimal complications compared to more extensive surgery.

ImportanceThere is a lack of reliable, patient-reported quality-of-life (QOL) instruments to address the multidimensional nature of patient-centered outcomes for patients undergoing parotidectomy. The Parotidectomy Quality of Life Index is a new 35-item validated patient-reported outcome instrument specific to recovery after parotidectomy.ObjectiveTo establish and validate a comprehensive English-language patient-reported QOL instrument specific to parotidectomy.Design, Setting, and ParticipantsThis survey study was conducted in 2 phases: first, in a single-institution cohort (October 12, 2021, to March 7, 2022), and second, as an anonymous web-based survey enrolled via printed promotional brochures and social media platforms (March 13 to July 31, 2023). Inclusion criteria were age at least 18 years and parotidectomy within the last year. For test-retest reliability, a subset of phase II participants volunteered to answer the survey a second time within 2 weeks. Data were analyzed from March 8, 2022, to November 3, 2023.Main Outcomes and MeasuresItem rankings from phase I participants were used to narrow the original 61-item survey down to 45 items in the phase II survey. To assess construct validity, an exploratory factor analysis was performed. Cronbach α and pairwise Pearson correlation coefficients were used to measure internal consistency, reliability, and redundancy. Test-retest reliability was evaluated using intraclass correlation coefficients.ResultsPhase I enrolled 38 individuals, of whom 30 completed the survey (15 women [60%]; 21 participants [84%] aged &amp;gt;40 years). Phase II enrolled 342 participants, of whom 317 completed the survey (305 women [89%]; 284 participants [83%] aged &amp;gt;40 years). A total of 42 items across 7 domains were selected based on exploratory factor analysis. After Cronbach α and pairwise correlation analysis, 33 items across 6 multi-item domains and 2 standalone items were incorporated into the final QOL instrument. Cronbach αs for each of the final 6 domains were at least 0.77, suggesting excellent internal validity. Pairwise correlations did not show strong correlations (ie, none ≥0.80), suggesting minimal redundancy between domains. Younger age was significantly associated with a lower global score. Participants with malignant tumors scored lower on 4 of the 6 multi-item domains. Test-retest reliability coefficients for the domains ranged from 0.82 to 0.93, indicating very good reproducibility over a 2-week interval.Conclusions and RelevanceThese findings suggest the Parotidectomy Quality of Life Index demonstrated excellent internal validity and test-retest reliability. With further external validation, this instrument may provide opportunity for quality improvement in clinical practice and has potential as a key patient-reported outcome in future parotidectomy clinical trials.

Abstract Purpose: Tumor-infiltrating lymphocytes are associated with a decreased risk of recurrence in human papillomavirus–associated oropharyngeal squamous cell carcinoma. The composition and spatial distribution of tumor-infiltrating lymphocytes and tumor-infiltrating immune cells are not well characterized. Experimental Design: Formalin-fixed, paraffin-embedded primary and lymph node (LN) tumor tissues from 10 progressors (cases) and 10 matched nonprogressors (controls) were interrogated by imaging mass cytometry. Immune, stromal, and tumor cells were quantified from selected regions of interest using machine learning. Nearest neighbors, cell–cell interactions, and niche analyses were performed. Results: In primary regions of interest, immune cell, lymphocyte, T cell, CD8+ T cell, and innate cell prevalence was significantly greater in controls. High prevalence of immune cells, lymphocytes, innate cells, and CD4+ T cells in primary tissues was significantly associated with increased time to event (TTE). Although primary and LN prevalence of T cells, CD4+ T cells, CD8+ T cells, macrophages, and tumor cells were significantly correlated, differences in LNs were neither significant nor associated with TTE. Average distances between T cells and the nearest B cells and between lymphocytes and the nearest tumor cells were decreased in control primary tissues. Interactions between B and T cells were less organized in primary tissues from cases. A niche predominantly comprising lymphocytes was associated with longer TTE. Conclusions: In human papillomavirus–associated oropharyngeal squamous cell carcinoma, immune cell subset prevalence in primary tumors differs with outcome and is associated with TTE. Interactions between B cells and both T-cell subsets are associated with longer TTE, underscoring the importance of active intratumoral immune responses in outcomes.