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Simple Summary: Recurrent and/or metastatic head and neck squamous-cell carcinoma (R/M HNSCC) is a clinically challenging disease with a poor prognosis. Despite advances in survival through the use of immune-checkpoint blockade, only a minority of patients experience benefit from such treatments, and it is difficult to identify the patients most likely to benefit. Machine learning approaches integrating clinical and genomic data can predict response to immune-checkpoint blockade across all cancers; however, the performance of this model in HNSCC has not been examined. Here, we validate this previously described immune-checkpoint blockade response prediction model in R/M HNSCC patients. This model was able to predict response as well as overall survival following immune-checkpoint blockade in patients with R/M HNSCC. Further investigation will be needed to further delineate the importance of HNSCC-specific features. Head and neck squamous-cell carcinoma (HNSCC) is a disease with a generally poor prognosis; half of treated patients eventually develop recurrent and/or metastatic (R/M) disease. Patients with R/M HNSCC generally have incurable disease with a median survival of 10 to 15 months. Although immune-checkpoint blockade (ICB) has improved outcomes in patients with R/M HNSCC, identifying patients who are likely to benefit from ICB remains a challenge. Biomarkers in current clinical use include tumor mutational burden and immunohistochemistry for programmed death-ligand 1, both of which have only modest predictive power. Machine learning (ML) has the potential to aid in clinical decision-making as an approach to estimate a tumor's likelihood of response or a patient's likelihood of experiencing clinical benefit from therapies such as ICB. Previously, we described a random forest ML model that had value in predicting ICB response using 11 or 16 clinical, laboratory, and genomic features in a pan-cancer development cohort. However, its applicability to certain cancer types, such as HNSCC, has been unknown, due to a lack of cancer-type-specific validation. Here, we present the first validation of a random forest ML tool to predict the likelihood of ICB response in patients with R/M HNSCC. The tool had adequate predictive power for tumor response (area under the receiver operating characteristic curve = 0.65) and was able to stratify patients by overall (HR = 0.53 [95% CI 0.29–0.99], p = 0.045) and progression-free (HR = 0.49 [95% CI 0.27–0.87], p = 0.016) survival. The overall accuracy was 0.72. Our study validates an ML predictor in HNSCC, demonstrating promising performance in a novel cohort of patients. Further studies are needed to validate the generalizability of this algorithm in larger patient samples from additional multi-institutional contexts. [ABSTRACT FROM AUTHOR]

Purpose: Cavernous sinus dural arterio-venous malformations (dAVF) represent a pathologic connection between branches of the internal and/or external carotid artery and the cavernous sinus. Standard endovascular approaches for dAVF treatment are transvenous embolization through the inferior petrosal sinus or the facial vein and transarterial embolization. These approaches are not always successful or feasible, and alternative techniques are required. Here, we present a case series of a minimally invasive transorbital approach with surgical exposure and catheterization of the superior ophthalmic vein for transvenous fistula coiling. Methods: 14 patients with dAVFs (Barrow Type B to D) that were treated at a tertiary care medical center over a period of 13 years were included in the study. Patients with persisting dAVF associated symptoms were selected for this approach when conventional endovascular interventions were not successful or not feasible. The surgical procedure was performed under general anaesthesia. Results: A successful transorbital approach was performed in all 14 cases. In 12 of 14 patients a catheter assisted successful embolization of the fistula was performed using platinum coils with no relevant residual fistula flow. In two cases, a spontaneous thrombosis of the fistula during the surgical procedure required no further embolization. No postoperative therapy-associated complications were observed. Conclusion: The described approach is an effective method to embolize dAVFs in selected cases when catheter assisted transvenous and/or transarterial embolization is not successful or not feasible. In this case series we demonstrate an excellent success rate with no therapy-associated major complications. [ABSTRACT FROM AUTHOR]

Background: Transoral robotic surgery (TORS) was approved by the Food and Drug Administration in 2009 for the treatment of oropharyngeal cancers (oropharyngeal squamous cell carcinoma [OPSCC]). This study investigated the adoption and safety of TORS. Methods: All patients who underwent TORS for OPSCC in the National Cancer Data Base from 2010 to 2016 were selected. Trends in the positive margin rate (PMR), 30‐day unplanned readmission, and early postoperative mortality were evaluated. Outcomes after TORS, nonrobotic surgery (NRS), and nonsurgical treatment were compared with matched‐pair survival analyses. Results: From 2010 to 2016, among 73,661 patients with OPSCC, 50,643 were treated nonsurgically, 18,024 were treated with NRS, and 4994 were treated with TORS. TORS utilization increased every year from 2010 (n = 363; 4.2%) to 2016 (n = 994; 8.3%). The TORS PMR for base of tongue malignancies decreased significantly over the study period (21.6% in 2010‐2011 vs 15.8% in 2015‐2016; P =.03). The TORS PMR at high‐volume centers (≥10 cases per year; 11.2%) was almost half that of low‐volume centers (<10 cases per year; 19.3%; P <.001). The rates of 30‐day unplanned readmission (4.1%) and 30‐day postoperative mortality (1.0%) after TORS were low and did not vary over time. High‐volume TORS centers had significantly lower rates of 30‐day postoperative mortality than low‐volume centers (0.5% vs 1.5%; P =.006). In matched‐pair analyses controlling for clinicopathologic cofactors, 30‐, 60‐, and 90‐day posttreatment mortality did not vary among patients with OPSCC treated with TORS, NRS, or nonsurgical treatment. Conclusions: TORS has become widely adopted and remains safe across the country with a very low risk of severe complications comparable to the risk with NRS. Although safety is excellent nationally, high‐volume TORS centers have superior outcomes with lower rates of positive margins and early postoperative mortality. Transoral robotic surgery (TORS) has become widely adopted and remains safe across the country with a very low risk of severe complications comparable to the risk with nonrobotic surgery. Although safety is excellent nationally, high‐volume TORS centers have superior outcomes with lower rates of positive margins and early postoperative mortality. [ABSTRACT FROM AUTHOR]

Objective: Assess the testing rates and prognostic significance of human papilloma virus (HPV) status in hypopharynx malignancies. Study Design: Historical cohort study. Setting: National Cancer Database. Methods: Review of the National Cancer Database was conducted between 2010 and 2017 for squamous cell carcinomas (SCCs) of the hypopharynx. We investigated how often the tumors were tested for HPV and whether it was associated with survival outcomes. Results: A total of 13,269 patients with hypopharynx malignancies were identified. Most cases were not tested for HPV status (n = 8702, 65.6%). Of those tested, 872 (19.1%) were positive for HPV and 3695 (80.9%) were negative. The proportion of nonoropharyngeal SCCs tested for HPV increased nearly every year during the study, with roughly one-third of cases (31.9%) being tested in 2017. In the facilities classified as high-testing centers of nonoropharyngeal SCCs of the head and neck, 18.7% of hypopharyngeal tumors were HPV positive. HPV-negative status was associated with worse survival on multivariable analysis. In propensity score–matched analysis controlling for all factors significant in multivariable regression, 2-year survival remained higher in the HPV-positive cohort (77.7% vs 63.1%, P <.001). Conclusions: HPV-positive tumors constitute a sizable minority of hypopharynx tumors and are associated with improved survival. Expansion of HPV testing to hypopharynx malignancies may be warranted. [ABSTRACT FROM AUTHOR]

The article focuses on Hürthle cell carcinomas (HCCs) display two exceptional genotypes: near-homoplasmic mutation of mitochondrial DNA (mtDNA) and genome-wide loss of heterozygosity (gLOH). It mentions mtDNA mutations and profound depletion of citrate pools are common in HCC and other thyroid malignancies, suggesting that thyroid cancers are broadly equipped to survive tricarboxylic acid cycle impairment.

Objective: The outcomes of active surveillance (AS) for pleomorphic adenomas (PA) as an alternative to upfront parotidectomy have not been previously documented in the literature. This cohort study aims to assess the safety and feasibility of AS for parotid gland PA., Methods: All patients with of previously untreated PA managed between 1990 and 2015 were reviewed. Patients who underwent AS for a minimum of 1 year from the initial consultation were identified. Patient demographics, the reason for AS, tumor growth rate, indication for surgery in those patients eventually operated, final pathology, and surgical sequelae were analyzed., Results: During the study period, 610 patients with primary PA were treated in our institution. Of whom, 14 (2.3%) underwent AS for a period between 1 and 10 years with a median of 3.73 years (interquartile range [IQR] 1.3-4.9). Patient comorbidities were the most common reason for opting for AS (n = 6, 43%), followed by patients' preference to delay surgery (n = 4, 29%) and older age (n = 2, 14%). The median growth rate was 0.58 mm/year (IQR 0.04, 3.8, range -5.01 to 4.98 mm/year). In patients who eventually underwent parotidectomy (n = 10, 71.4%), the most common reason for intervention was tumor growth (8/10, 80%). Two patients had postsurgical mild transient facial nerve paresis with full recovery, and no carcinomas were discovered on final pathology., Conclusion: In this selected cohort of patients with PA, the tumor growth rate was lower than traditionally believed. Patients who eventually underwent surgery did not suffer from serious complications and there was no evidence of clinical or pathological malignancy., (© 2024 Wiley Periodicals LLC.)

Background: Head and neck squamous cell carcinomas (HNSCCs) are among the six most common cancers, with a constantly poor prognosis. Vitamin D has been found to have antineoplastic and immunomodulatory properties in various cancers. This study investigated the impact of Vitamin D on the initiation and progression as well as antitumor immune response in HNSCCs, both in vitro and in vivo., Methods: An immunocompetent, orthotopic oral carcinogenesis mouse model was used to examine the influence of Vitamin D 3 substitution on HNSCC initiation and progression in vivo. Tumor immune infiltration was analyzed by immunohistochemistry targeting CD3, CD8, NKR-P1C, FOXP3, and CD163. Two HPV- and two HPV+ HNSCC cell lines were treated with 1,25-dihydroxyvitamin D 3 to analyze effects on tumor cell proliferation, migration and transcriptomic changes using RNA-sequencing, differential gene expression and gene set enrichment analysis., Results: Vitamin D 3 treatment led to a significant suppression of HNSCC initiation and progression, while also stimulating tumor immune infiltration with CD3+, CD8+ and NKR-P1C+ cells and lowering levels of M2 macrophages and T reg cells in vivo. In vitro experiments showed an inhibition of HNSCC cell proliferation and migration in HPV+ and HPV- cell lines. RNA-sequencing showed significant regulations in IL6 JAK STAT3, hypoxia signaling and immunomodulatory pathways upon Vitamin D 3 treatment., Conclusion: The findings of our study highlight the promising potential of Vitamin D in the therapeutic repertoire for HNSCC patients given its immune modulating, anti-proliferative and anti-migratory properties. Clinical transferability of those in vitro and in vivo effects should be further validated in clinical trials., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Maximilian Linxweiler reports financial support was provided by Else Kroner-Fresenius Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multi-targeted, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC., Methods: Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The primary endpoints were best overall response (BOR) and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants., Results: Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR-TKIs. No objective responses were observed. Six-month PFS was 45%, and median PFS was 7.2 months (95%CI 5.2-11.9 months). Presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS (HR 2.6, 95%CI 1.1-6.1, p=0.03). Bulk RNA sequencing of pre-treatment tumors revealed that regorafenib clinical benefit (CB; PFS≥6 months; n=11) was associated with native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS<6 months; n=9) had greater expression of signatures related to cell cycle progression (E2F targets, G2/M checkpoint)., Conclusion: The trial failed to meet the pre-specified 6-month PFS and BOR targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, while programs promoting cell cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR-TKI should be considered.

Importance: The outcomes of patients with low-risk thyroid cancer who undergo surgery following a period of active surveillance (AS) are not well-defined., Objective: To evaluate surgical, pathologic, and oncologic outcomes among patients undergoing conversion surgery (CS) following AS for low-risk papillary thyroid carcinoma., Design, Setting, and Participants: In this cohort study, patients who underwent CS for disease progression were compared with patients who underwent CS without disease progression and with a propensity score-matched cohort of patients who underwent initial surgery (IS). The median (IQR) postsurgical follow-up time was 40.3 (18.0-59.0) months. Patients were treated at a quaternary cancer referral center in the United States., Exposures: Surgery., Main Outcomes and Measures: Surgical complications, pathologic characteristics, overall survival (OS), and recurrence-free survival (RFS)., Results: Of 550 patients who underwent AS, 55 (10.0%) had CS, of whom 39 (7.1%) had surgery due to suspected disease progression (median [IQR] age, 48 [39-56] years; 32 [82.1%] female). There were no clinically meaningful differences in rates of surgical sequalae between the progression CS group (12 of 39 [30.7%]) and the nonprogression CS group (7 of 16 [43.8%]) (Cramer V, 0.2; 95% CI, 0.01-0.5). The 5-year OS was 100% (95% CI, 100%-100%) in both the disease-progression CS cohort and the IS cohort. Although the cohort of patients undergoing CS after disease progression was by definition a subset with more aggressive tumor behavior, no clinically meaningful differences were observed in the rates of regional recurrence (2 of 39 [5.1%] vs 0 of 39 patients with IS), local recurrence (0 patients), distant metastasis (0 patients), or disease-specific mortality (0 patients) when compared with the matched IS group. Five-year RFS rates were similar: 100% in the IS group and 86% (95% CI, 70%-100%) in the CS group., Conclusions and Relevance: In this cohort study, CS for suspected disease progression was associated with surgical and oncologic outcomes similar to IS, supporting the feasibility and safety of AS for patients with low-risk papillary thyroid carcinoma.

Background: Genomic profiling is now available for risk stratification of cytologically indeterminate thyroid nodules (ITNs). Mutations in RAS genes ( HRAS , NRAS , KRAS ) are found in both benign and malignant thyroid nodules, although isolated RAS mutations are rarely associated with aggressive tumors. Because the long-term behavior of RAS -mutant ITNs is not well understood, most undergo immediate surgery. In this multicenter retrospective cohort study, we characterize tumor growth kinetics of RAS -mutant ITNs followed with active surveillance (AS) using serial ultrasound (US) scans and examine the histopathologic diagnoses of those surgically resected. Methods: US and histopathologic data were analyzed retrospectively from two cohorts: (1) RAS -mutant ITNs managed with AS at three institutions (2010-2023) and (2) RAS -mutant ITNs managed with immediate surgery at two institutions (2016-2020). AS cohort subjects had ≥3 months of follow-up and two or more US scans. Cumulative incidence of nodule growth was determined by the Kaplan-Meier method and growth by ≥72% change in tumor volume. Pathological diagnoses for the immediate surgery cohort were analyzed separately. Results: Sixty-two patients with 63 RAS -mutated ITNs under AS had a median diameter of 1.7 cm (interquartile range [IQR] 1.2-2.6) at time of diagnosis. During a median AS period of 23 months (IQR 9.5-53.5 months), growth was observed in 12 of 63 nodules (19.0%), with a cumulative incidence of 1.9% (1 year), 23.0% (3 years), and 28.0% (5 years). Most nodules (81.0%) demonstrated stability. Surgery was ultimately performed in 6 nodules, of which 1 (16.7%) was malignant. In the cohort of 209 RAS -mutant ITNs triaged to immediate surgery, 33% were malignant (23.9% American Thyroid Association [ATA] low-risk cancers, 7.2% ATA intermediate-risk, and 1.9% ATA high-risk. During a median follow-up of 6.9 (IQR 4.4-7.1) years, there were no disease-specific deaths in these patients. Conclusions: We describe the behavior of RAS -mutant ITNs under AS and find that most demonstrate stability over time. Of the resected RAS -mutant nodules, most were benign; of the cancers, most were ATA low-risk. Immediate surgical resection of all RAS -mutant ITNs appears to be a low-value practice. Further research is needed to help define cases most appropriate for AS or immediate surgery.

Objective: Adenoid cystic carcinoma (ACC) is a head and neck cancer with a poor long-term prognosis that shows frequent local recurrences and distant metastases. The tumors are characterized by MYB oncogene activation and are notoriously unresponsive to systemic therapies. The biological underpinnings behind therapy resistance of disseminated ACC are largely unknown. Here, we have studied the molecular and clinical significance of MYB alternative promoter (TSS2) usage in ACC metastases., Materials and Methods: MYB TSS2 activity was investigated in primary tumors and metastases from 26 ACC patients using RNA-sequencing and quantitative real-time PCR analysis. Differences in global gene expression between MYB TSS2 high and low cases were studied, and pathway analyses were performed., Results: MYB TSS2 activity was significantly higher in ACC metastases than in primary tumors (median activity 15.1 vs 3.0, P = 0.0003). MYB TSS2 high ACC metastases showed a specific gene expression signature, including increased expression of multi-drug resistance genes and canonical MYB target genes, and suppression of the p53 and NOTCH pathways., Conclusions: Collectively, our findings indicate that elevated MYB TSS2 activity is associated with metastases, potential drug resistance, and augmented MYB-driven gene expression in ACC. Our study advocates the need for new therapies that specifically target MYB and drug resistance mechanisms in disseminated ACC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy., Methods: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18 F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin., Results: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia., Conclusion: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Objectives/hypothesis: Cancer cells evade recognition by the immune system to survive. Head and neck squamous cell carcinoma (HNSCC) is characterized by high levels of immune infiltration and mutation-associated neoantigens; therefore, immune evasion is likely to be an important mechanism in HNSCC tumorigenesis and progression. A commonly employed mechanism of immune evasion is downregulation of human leukocyte antigen (HLA) or loss of heterozygosity (LOH) in tumor cells. The objective of this study was to integrate multi-dimensional genomic and transcriptomic data from HNSCC tumors to better understand the clinical and immunologic implications of HLA LOH., Study Type/design: Cross-sectional integrated clinical and genomic analysis., Methods: Whole-exome sequencing and RNA-sequencing data from 522 tumors profiled in The Cancer Genome Atlas HNSCC cohort were analyzed and integrated with secondary analyses including immune cell deconvolution data. Associations were analyzed with categorical hypothesis testing and multivariable logistic and Cox regression., Results: HLA LOH was a prevalent event that was identified in 53% of HNSCC tumors; in many cases, more than one class I HLA gene was targeted for LOH. HLA LOH was more common in advanced-stage tumors. Tumors with somatic HLA LOH had tumor microenvironments defined by decreased lymphocyte and T cell infiltration., Conclusions: HLA LOH is one of the most prevalent genetic alterations in HNSCC, and is associated with a cold immune microenvironment, suggesting that HLA LOH is a means of immune evasion. It may have value as a predictive biomarker or potential as a cancer cell-specific therapeutic target., Level of Evidence: 3 Laryngoscope, 134:160-165, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Head and neck squamous-cell carcinoma (HNSCC) is a disease with a generally poor prognosis; half of treated patients eventually develop recurrent and/or metastatic (R/M) disease. Patients with R/M HNSCC generally have incurable disease with a median survival of 10 to 15 months. Although immune-checkpoint blockade (ICB) has improved outcomes in patients with R/M HNSCC, identifying patients who are likely to benefit from ICB remains a challenge. Biomarkers in current clinical use include tumor mutational burden and immunohistochemistry for programmed death-ligand 1, both of which have only modest predictive power. Machine learning (ML) has the potential to aid in clinical decision-making as an approach to estimate a tumor's likelihood of response or a patient's likelihood of experiencing clinical benefit from therapies such as ICB. Previously, we described a random forest ML model that had value in predicting ICB response using 11 or 16 clinical, laboratory, and genomic features in a pan-cancer development cohort. However, its applicability to certain cancer types, such as HNSCC, has been unknown, due to a lack of cancer-type-specific validation. Here, we present the first validation of a random forest ML tool to predict the likelihood of ICB response in patients with R/M HNSCC. The tool had adequate predictive power for tumor response (area under the receiver operating characteristic curve = 0.65) and was able to stratify patients by overall (HR = 0.53 [95% CI 0.29-0.99], p = 0.045) and progression-free (HR = 0.49 [95% CI 0.27-0.87], p = 0.016) survival. The overall accuracy was 0.72. Our study validates an ML predictor in HNSCC, demonstrating promising performance in a novel cohort of patients. Further studies are needed to validate the generalizability of this algorithm in larger patient samples from additional multi-institutional contexts.

Importance: Surgery is the mainstay of treatment for pleomorphic adenomas (PAs) of the parotid to prevent further growth and potential future malignant transformation. While historical case series have reported transformation rates as high as 10%, there is a lack of contemporary methodologically sound data., Objective: To examine the rate of carcinoma ex pleomorphic adenoma (CXPA) detection in untreated PAs and investigate factors associated with malignant neoplasm., Design, Setting, and Participants: This cohort study reviewed all cases of primary PAs managed at a quaternary referral center between December 1990 and January 2015. Patients whose clinical presentation was compatible with a primary benign PA and whose history indicated tumor duration of over 1 year were included. Data were analyzed from January to April 2023., Exposure: Untreated PA., Main Outcomes and Measures: Rate of CXPA detection among untreated PAs and association of tumor duration with rates of CXPA detection. Pathology slides of patients who underwent surgery were reviewed by a single expert pathologist for the presence of CXPA. Univariable logistic regression was performed to evaluate possible factors associated with CXPA., Results: A total of 260 patients (median age, 47 years [IQR, 38-60 years]; 174 [66.9%] female) had a median tumor duration of 3.2 years (range, 1-30 years; mean [SD], 5.7 [5.5] years). Patients were divided into 4 groups by tumor duration: 1 to 4 years (158 [60.7%]), 5 to 9 years (47 [18.1%]), 10 to 14 years (27 [10.4%]), and 15 to 30 years (28 [10.8%]). In 156 of 170 patients who underwent preoperative fine-needle aspiration (91.8%), a benign tumor was diagnosed; 5 of these patients (3.2%; 95% CI, 1.4%-7.3%) were later diagnosed with CXPA on pathology after eventual excision, and the rate of high grade CXPA was 1.3%. None of the patients had permanent facial nerve paralysis. Tumor size at presentation (odds ratio [OR], 1.66; 95% CI, 1.22-2.24) and incremental (per year) increase in age (OR, 1.04; 95% CI, 1.01-1.08) were found to be associated with CXPA, whereas tumor duration was not (OR, 1.00; 95% CI, 1.00-1.01)., Conclusions and Relevance: In this study, the rate of malignant neoplasm detection among initially untreated PA was 3.2%. The results suggest that tumor size and older age are associated with the development of CXPA, while tumor duration is not. Observation of PA for longer periods was not associated with serious permanent complications.

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8 + T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8 + tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX + ) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX + ZNF683 + CD8 + TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103 + PD-1 + T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of + T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683 + CTX + TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683 + CTX + TILs is a major mechanism of response in the immediate postneoadjuvant setting.

Hürthle cell carcinoma (HCC) is a rare type of thyroid cancer with high rates of distant metastasis and recurrence. Along with the scarcity of effective systemic therapies for HCC, these factors contribute to poor clinical outcomes. The immunologic features of HCC are poorly defined and response rates with immune checkpoint blockade have not been reported. A more comprehensive understanding of the immune landscape and factors that predict response to checkpoint inhibitors is needed. We performed RNA sequencing on 40 tumors to characterize the neoantigen landscape and immune microenvironment of HCC. We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T-cell activation/dysfunction and correlated these to genetic features such as tumor mutation burden, neoantigen burden, mitochondrial mutations, and LOH from chromosomal uniparental disomy. Finally, immune profiles of patients with recurrence were compared with those of patients without recurrence. HCC tumors exhibited low levels of immune infiltration, with the more aggressive widely invasive phenotype associated with more immune depletion. There was a negative correlation between tumor mutation burden, neoantigen burden, programmed cell death ligand 1 (PD-L1) expression, and the immune infiltration score. HCC tumors that exhibited a global LOH from chromosomal uniparental disomy or haploidization had the lowest level of immune infiltration. HCC tumors that recurred displayed an immune-depleted microenvironment associated with global LOH and aerobic glycolysis. These findings offer new insights into the functional immune landscapes and immune microenvironment of HCC. Our data identify potential immunologic vulnerabilities for these understudied and often fatal cancers., Significance: The immune landscape of HCC is poorly defined and response rates to immunotherapy have not been reported. The authors found the immune microenvironment in HCC to be depleted. This immunosuppression is associated with a global LOH from haploidization and uniparental disomy, resulting in whole chromosome losses across the genome., (© 2023 The Authors; Published by the American Association for Cancer Research.)