Sex-Specific Survival and Treatment Delay in Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVE: As the majority of oropharyngeal squamous cell carcinoma (OPSCC) is diagnosed in males, outcomes among females are not well-characterized. We identify sex-specific factors in OPSCC to refine female prognostication. STUDY DESIGN: Retrospective cohort. SETTING: National Cancer Database (NCDB). METHODS: OPSCC cases from the 2004 to 2019 NCDB were identified. Sociodemographic, clinical, and treatment characteristics (including timing between diagnosis and treatment administration) were compared between sexes. Multivariable Cox proportional hazard regression models were constructed to characterize survival in overall and female-only cohorts. Similar multivariable binomial logistic regression and survival models were constructed to assess odds of treatment delays and their effects on survival, respectively. RESULTS: A total of 192,973 OPSCC patients were identified; 36,695 (19%) were female. Females had more human papillomavirus (HPV) negative, lower clinical T and N stage, and higher comorbidity disease. Females experienced lower survival in HPV negative (hazard ratio, HR = 1.11, P < .001) but not HPV-positive disease. Females were more likely to have any treatment initiated over the median of 28 days (odds ratio, OR = 1.04, P = .014) or delays in adjuvant radiotherapy initiation over 6 weeks (OR = 1.11, P = .032). Treatment delay over 60 days (HR = 1.17, P = .016) and delay in adjuvant therapy initiation (HR = 1.24, P = .02) were associated with worse survival among females. CONCLUSION: In one of the largest analyses of OPSCC, females had poorer survival than males, specifically in HPV-negative disease, despite presentation with less advanced disease. Notably, delays in any treatment initiation and adjuvant radiotherapy initiation were more likely in HPV-negative women and associated with worse survival, highlighting potential systemic weaknesses contributing to poor prognosis among females.

Clinical and genomic characterization of chemoradiation-resistant HPV-positive oropharyngeal squamous cell carcinoma.

Introduction: Most patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) have an excellent response to chemoradiation, and trials are now investigating de-escalated treatment. However, up to 25% of patients with HPV-positive OPSCC will experience recurrence, and up to 5% will even progress through primary treatment. Currently, there are no molecular markers to identify patients with poor prognosis who would be harmed by de-escalation. Herein we report the clinical and genomic characteristics of persistent HPV-positive OPSCC after definitive platinum-based chemoradiation therapy. Methods: Patients with HPV-positive OPSCC treated with curative intent platinum-based chemoradiation between 2007 and 2017 at two institutions and with a persistent locoregional disease were included. We evaluated clinical characteristics, including smoking status, age, stage, treatment, and overall survival. A subset of five patients had tissue available for targeted exome DNA sequencing and RNA sequencing. Genomic analysis was compared to a previously published cohort of 47 treatment-responsive HPV+ OPSCC tumors after batch correction. Mutational landscape, pathway activation, and OncoGPS tumor states were employed to characterize these tumors. Results: Ten patients met the inclusion criteria. The tumor and nodal stages ranged from T1 to T4 and N1 to N2 by AJCC 8th edition staging. All patients were p16-positive by immunohistochemistry, and eight with available in situ hybridization were confirmed to be HPV-positive. The 1-year overall survival from the time of diagnosis was 57%, and the 2-year overall survival was 17%. TP53 mutations were present in three of five (60%) persistent tumors compared to 2% (one of 47) of treatment-responsive HPV-positive tumors (p = 0.008). Other genes with recurrent mutations in persistent HPV-positive OPSCC tumors were NF1, KMT2D, PIK3C2B, and TFGBR2. Compared to treatment-responsive HPV-positive tumors, persistent tumors demonstrated activation of DNA Repair and p53, EMT, MYC, SRC, and TGF-beta signaling pathways, with post-treatment samples demonstrating significant activation of the PI3K-EMT-Stem pathways compared to pretreatment samples. Conclusion: Chemoradiation-resistant HPV-positive OPSCC occurs infrequently but portends a poor prognosis. These tumors demonstrate higher rates of p53 mutation and activation of MYC, SRC, and TGF-beta pathways. A comparison of tumors before and after treatment demonstrates PI3K-EMT-Stem pathways post-treatment in HPV-positive tumors with persistent disease after platinum-based chemoradiation.

Transoral Surgery in HPV-Positive Oropharyngeal Carcinoma: Oncologic Outcomes in the Veterans Affairs System.

OBJECTIVES: Most transoral robotic surgery (TORS) literature for HPV-positive oropharyngeal squamous cell carcinoma (HPV-OPC) derives from high-volume tertiary-care centers. This study aims to describe long-term recurrence and survival outcomes among Veterans Health Administration patients. MATERIALS AND METHODS: Using the US Veterans Affairs database, we identified patients with HPV-OPC treated with TORS between January 2010 and December 2016. Patients were stratified in risk categories: low (0-1 metastatic nodes, negative margins), intermediate (close margins, 2-4 metastatic nodes, lymphovascular or perineural invasion, pT3-pT4 tumor), or high (positive margins, extranodal extension (ENE), and/or ≥5 metastatic nodes). Primary outcomes included overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS). RESULTS: The cohort included 161 patients of which 29 (18%) were low-risk, 45 (28%) intermediate-risk, and 87 (54%) high-risk. ENE was present in 41% of node-positive cases and 24% had positive margins. Median follow-up was 5.6 years (95% CI, 3.0-9.3). The 5-year DSS for low, intermediate, and high-risk groups were: 100%, 90.0% (95% CI, 75.4-96.1%), and 88.7% (95% CI, 78.3-94.2%). Pathologic features associated with poor DSS on univariable analysis included pT3-T4 tumors (HR 3.81, 95% CI, 1.31-11; p = 0.01), ≥5 metastatic nodes (HR 3.41, 95% CI, 1.20-11; p = 0.02), and ENE (HR 3.53, 95% CI, 1.06-12; p = 0.04). Higher 5-year cumulative incidences of recurrence were observed in more advanced tumors (pT3-T4, 33% [95% CI, 14-54%] versus pT1-T2, 13% [95% CI, 8-19%]; p = 0.01). CONCLUSIONS: In this nationwide study, patients with HPV-OPC treated with TORS followed by adjuvant therapy at Veterans Affairs Medical Centers demonstrated favorable survival outcomes comparable to those reported in high-volume academic centers and clinical trials. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:207-214, 2024.

Early Improved Functional Outcomes in Head and Neck Cancer Patients with Primary Tumor Detection.

OBJECTIVES: We characterize functional outcomes in head and neck cancer of unknown primary (CUP) based on primary site identification. METHODS: In this retrospective study, CUP cases were categorized as known primaries (KP) if a tumor was localized after diagnostic workup or persisting unknown primaries (UP). Age, sex, HPV status, diagnostic methods, and treatments regimens were collected. Pretreatment and short-term posttreatment (3-6 months after completion of treatment) weights, PHQ-9, Eating Assessment Tool (EAT-10), and Voice Handicap Index (VHI-10) scores were compared between UP and KP. RESULTS: Among 67 CUP patients, 35 (52.2%) had identified primaries (91.4% oropharyngeal and 8.6% nasopharyngeal). KP patients were younger (58 vs. 64, p = 0.04) and more likely to be HPV-positive (88.6% vs. 50%, p = 0.002). Overall detection rates were 16.7% for PET/CT, 34.7% for direct laryngoscopy, and 46.6% for transoral robotic oropharyngectomy. Diagnostic workup was not significantly different between groups. Patients with KP received smaller intermediate radiation dose volumes (436.5 vs. 278.9 cc, p = 0.03) and lower doses to the cricopharyngeal muscle (41.6 vs. 24.6 Gy, p = 0.03).Pretreatment weights, PHQ-9, EAT-10, and VHI-10 scores did not differ between groups. However, posttreatment, UP had greater relative weight loss (-14.1% vs. -7.6%, p = 0.032), higher EAT-10 scores (12.5 vs. 3, p = 0.004), and higher PHQ-9 scores (6 vs. 1.4, p = 0.017). Specifically, UP reported more stressful swallowing, difficulty swallowing solids and pills, and swallowing affecting public eating. CONCLUSION: KP patients experienced less weight loss, depression, and reduced swallowing dysfunction, highlighting an early functional benefit of primary tumor identification likely driven by reduced radiation treatment volumes. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:701-707, 2024.

Insurance Status is Associated With Recurrence in Cutaneous Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: To identify socioeconomic factors influencing the presentation and outcomes of cutaneous head and neck squamous cell carcinoma (cHNSCC). STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center with comprehensive cancer center. METHODS: Patients treated for cHNSCC at a single institution between 2008 and 2022 were included. Demographic, socioeconomic data and disease characteristics were obtained from medical record abstraction. Outcome measures included tumor stage, number of distinct primaries, recurrence, and disease-related death. χ2 and Mann-Whitney tests were implemented to evaluate clinicopathologic distributions across disease stages. Survival analyses were performed using Cox regression and Kaplan-Meier analysis. RESULTS: A total of 346 patients met the inclusion criteria. The median age at presentation and length of follow-up was 70.8 and 3.1 years, respectively. The majority of the cohort was white, male, and English-speaking. 13.3% of patients were underinsured and 27.5% were immunosuppressed. Patients who presented with advanced disease were more likely to be underinsured (21.7% vs 9.6%, P = .006) and have a history of homelessness (8.5% vs 2.1%, P = .014). Immunosuppressed patients were more likely to be underinsured (P = .009). Insurance status (1.97 [1.06-3.66], P = .032) and immune status (2.35 [1.30-4.26], P = .005) were independently associated with worse recurrence-free survival. CONCLUSION: Socioeconomic factors that influence access to care, such as insurance status, are associated with cHNSCC disease stage and disease recurrence. These factors may impose barriers that delay diagnosis and treatment. This may result in worse disease-related outcomes and greater treatment-associated morbidity for certain patients.

Fluorescent Guided Sentinel Lymph Mapping of the Oral Cavity with Fluorescent-Labeled Tilmanocept.

OBJECTIVE: With the shift toward utilization of sentinel lymph node biopsy (SLNB) in oral cavity cancer, improved techniques for intraoperative sentinel node identification are needed. This study investigates the feasibility of fluorescently labeled tilmanoscept in SLNB in an oral cancer rabbit model. METHODS: An animal study was designed using 21 healthy male New Zealand rabbits. Gallium-68-labeled tilmanocept labeled with IRDye800CW was injected submucosally into the buccal mucosa (n = 6) or lateral tongue (n = 7) followed by PET imaging. One hour after injection, SLNB was performed using fluorescence imaging followed by a bilateral neck dissection and sampling of non-nodal surrounding tissue. All tissues were measured for radioactivity and fluorescence. In addition, eight rabbits were injected with delayed SLNB performed 48 h after injection. RESULTS: Buccal injections all had ipsilateral SLN drainage and tongue injections exhibited 18.2% contralateral drainage. An average of 1.9 ± 1.0 SLN (range 1-5) were identified. In addition, an average of 16.9 ± 3.3 non-sentinel lymph nodes were removed per animal. SLNs had an average of 0.69 ± 0.60 percent-of-injected dose (%ID) compared with non-sentinel nodes with 0.012 ± 0.025 %ID and surrounding tissue with 0.0067 ± 0.015 %ID. There was 98.0% agreement between sentinel lymph nodes identified using fluorescence compared to radioactivity with Cohen's kappa coefficient of 0.879. In 48-h delayed SLNB, results were consistent with 97.8% agreement with radioactivity and Cohen's Kappa coefficient of 0.884. Fluorescence identified additional lymph nodes that were not identified by radioactivity, and with one false negative. CONCLUSION: Fluorescent-labeled Tc-99 m-tilmanocept represents a highly accurate adjunct to enhance SLNB for oral cavity cancer. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:1299-1307, 2024.

Factors associated with unknown primary status in head and neck squamous cell carcinoma.

OBJECTIVES: Head and neck cancer of unknown primary (CUP) poses significant therapeutic challenges. We compare CUP and oropharyngeal primary (OP) cases to identify factors associated with tumor detection. METHODS: The 2004-2019 National Cancer Database was queried to identify CUP and OP cases based on clinical and pathologic TNM staging. Clinical and demographic characteristics were compared by primary detection and HPV status with descriptive statistics. Multivariable logistic regression models to characterize OP detection were constructed. Among HPV-positive and negative patients, respectively, OP and CUP patients were matched by clinical nodal disease. Cox proportional-hazards models were constructed using matched cohorts to characterize survival. RESULTS: 81,053 CUP and OP cases were identified; 64.3 % were HPV-positive. OP detection increased over time in HPV-positive and negative disease. HPV-positive status had higher odds of OP detection (odds ratio (OR) = 1.77, p < 0.001), while females (OR = 0.95, p = 0.008), and black (OR = 0.82, p < 0.001) and Asian (OR = 0.7, p < 0.001) patients had lower odds compared to males and whites, respectively. In HPV-positive and negative disease, OP patients had higher 2 and 5-year survival rates than CUP (p < 0.001). Primary detection status conferred lower death risk in HPV-positive (hazard ratio (HR) = 0.85, p < 0.001) and negative disease (HR = 0.87, p < 0.001) when controlling for age, sex, race, comorbidities, insurance, treatment facility, and income. CONCLUSION: In the largest cohort of CUP to date, we report a survival benefit in primary tumor detection regardless of HPV status. Groups with higher persistent CUP rates, including non-white, female, HPV-negative, and low income patients, may benefit from increased diagnostic workup to improve detection and treatment.

Defining the relationship of salivary gland malignancies to novel cell subpopulations in human salivary glands using single nucleus RNA-sequencing.

Salivary glands have essential roles in maintaining oral health, mastication, taste and speech, by secreting saliva. Salivary glands are composed of several types of cells, and each cell type is predicted to be involved in the carcinogenesis of different types of cancers including adenoid cystic carcinoma (ACC), acinic cell carcinoma (AciCC), salivary duct carcinoma (SDC), myoepithelial carcinoma (MECA) and other histology. In our study, we performed single nucleus RNA-seq on three human salivary gland samples to clarify the gene expression profile of each complex cellular component of the salivary glands and related these expression patterns to expression found in salivary gland cancers (SGC) to infer cell of origin. By single nucleus RNA-seq, salivary gland cells were stratified into four clusters: acinar cells, ductal cells 1, ductal cells 2 and myoepithelial cells/stromal cells. The localization of each cell group was verified by IHC of each cluster marker gene, and one group of ductal cells was found to represent intercalated ductal cells labeled with HES1. Furthermore, in comparison with SGC RNA-seq data, acinar cell markers were upregulated in AciCC, but downregulated in ACC and ductal cell markers were upregulated in SDC but downregulated in MECA, suggesting that markers of origin are highly expressed in some SGC. Cell type expressions in specific SGC histology are similar to those found in normal salivary gland populations, indicating a potential etiologic relationship.

Antibody dependent cell-mediated cytotoxicity selection pressure induces diverse mechanisms of resistance.

Targeted monoclonal antibody therapy has emerged as a powerful therapeutic strategy for cancer. However, only a minority of patients have durable responses and the development of resistance remains a major clinical obstacle. Antibody-dependent cell-mediated cytotoxicity (ADCC) represents a crucial therapeutic mechanism of action; however, few studies have explored ADCC resistance. Using multiple in vitro models of ADCC selection pressure, we have uncovered both shared and distinct resistance mechanisms. Persistent ADCC selection pressure yielded ADCC-resistant cells that are characterized by a loss of NK cell conjugation and this shared resistance phenotype is associated with cell-line dependent modulation of cell surface proteins that contribute to immune synapse formation and NK cell function. We employed single-cell RNA sequencing and proteomic screens to interrogate molecular mechanisms of resistance. We demonstrate that ADCC resistance involves upregulation of interferon/STAT1 and DNA damage response signaling as well as activation of the immunoproteasome. Here, we identify pathways that modulate ADCC sensitivity and report strategies to enhance ADCC-mediated elimination of cancer cells. ADCC resistance could not be reversed with combinatorial treatment approaches. Hence, our findings indicate that tumor cells utilize multiple strategies to inhibit NK cell mediated-ADCC. Future research and development of NK cell-based immunotherapies must incorporate plans to address or potentially prevent the induction of resistance.

A Network Landscape of HPVOPC Reveals Methylation Alterations as Significant Drivers of Gene Expression via an Immune-Mediated GPCR Signal.

HPV-associated oropharynx carcinoma (HPVOPC) tumors have a relatively low mutational burden. Elucidating the relative contributions of other tumor alterations, such as DNA methylation alterations, alternative splicing events (ASE), and copy number variation (CNV), could provide a deeper understanding of carcinogenesis drivers in this disease. We applied network propagation analysis to multiple classes of tumor alterations in a discovery cohort of 46 primary HPVOPC tumors and 25 cancer-unaffected controls and validated our findings with TCGA data. We identified significant overlap between differential gene expression networks and all alteration classes, and this association was highest for methylation and lowest for CNV. Significant overlap was seen for gene clusters of G protein-coupled receptor (GPCR) pathways. HPV16-human protein interaction analysis identified an enriched cluster defined by an immune-mediated GPCR signal, including CXCR3 cytokines CXCL9, CXCL10, and CXCL11. CXCR3 was found to be expressed in primary HPVOPC, and scRNA-seq analysis demonstrated CXCR3 ligands to be highly expressed in M2 macrophages. In vivo models demonstrated decreased tumor growth with antagonism of the CXCR3 receptor in immunodeficient but not immunocompetent mice, suggesting that the CXCR3 axis can drive tumor proliferation in an autocrine fashion, but the effect is tempered by an intact immune system. In conclusion, methylation, ASE, and SNV alterations are highly associated with network gene expression changes in HPVOPC, suggesting that ASE and methylation alterations have an important role in driving the oncogenic phenotype. Network analysis identifies GPCR networks, specifically the CXCR3 chemokine axis, as modulators of tumor-immune interactions that may have proliferative effects on primary tumors as well as a role for immunosurveillance; however, CXCR3 inhibition should be used with caution, as these agents may both inhibit and stimulate tumor growth considering the competing effects of this cytokine axis. Further investigation is needed to explore opportunities for targeted therapy in this setting.

Patterns of Lymph Node Metastasis in Parotid Cancer and Implications for Extent of Neck Dissection.

OBJECTIVE: The role and extent of neck dissection in primary parotid cancer are controversial. Herein, we characterize patterns of lymph node metastasis in parotid cancer. STUDY DESIGN: Retrospective analysis. SETTING: National Cancer Database. METHODS: Patients with the 6 most common histologic subtypes of parotid cancer were selected. Primary outcomes were the distribution of positive lymph nodes by level and overall survival assessed by Cox analysis. Secondary outcomes included predictors of extended lymph node involvement (≥3 lymph nodes or Level IV/V involvement), via logistic regression. RESULTS: Six thousand nine hundred seventy-seven patients with acinic cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, carcinoma ex pleomorphic adenoma (CExPA), mucoepidermoid carcinoma, and salivary duct carcinoma (SDC) were included. Among cN0 patients, 8.2% of low-grade tumor patients had occult nodal metastasis versus 30.9% in high-grade tumor patients. Elective neck dissection was not associated with an overall survival benefit (adjusted hazard ratio: 1.10; 0.94-1.30, p = .238). Among cN+ tumors, CExPA (odds ratio [OR]: 1.88, 1.05-3.39, p = .034) and high-grade pathology (OR: 3.03, 1.87-4.93, p < .001) were predictive of having ≥3 pathologic nodes. CExPA (OR: 2.13, 1.22-3.72, p = .008), adenocarcinoma (OR: 1.60, 1.11-2.31, p = .013), SDC (OR: 1.92, 1.17-3.14, p < .01), and high-grade pathology (OR: 3.61, 2.19-5.97, p < .001) were predictive of Level IV/V neck involvement. CONCLUSIONS: In parotid malignancy, nodal metastasis distribution is dependent on histology and grade. High-grade tumors and certain histologies (SDC and adenocarcinoma) had a higher incidence of occult nodes. Comprehensive neck dissection should also be considered for node-positive high-grade tumors, SDC, and adenocarcinoma.

A Young Man Presenting With Tongue Lesions.

A 19-year-old man presented with tongue pain of 3 months' duration and a raised tongue lesion with slightly hairy appearance. What is your diagnosis?

Role of sentinel lymph node biopsy for oral squamous cell carcinoma: Current evidence and future challenges.

Sentinel lymph node biopsy (SLNB) has been used across oncological specialties for prognostication, staging, and identification of occult nodal metastasis. Recent studies demonstrated the potential clinical utility of SLNB in oral cavity squamous cell carcinoma (OCSCC). Elective neck dissection is the current standard of care in early management of OCSCC with depth of invasion greater than 2-4 mm; however, majority of patients ultimately do not have nodal disease on final pathology. SLNB is an alternative procedure widely adopted in early cancer management in many oncological subspecialities. Several considerations such as depth of invasion, nodal mapping, histopathology methods, operator variability, postoperative complications, and advancement in preoperative and intraoperative imaging technology can guide the appropriate application to SLNB in OCSCC. The aim of this review is to discuss the current evidence for SLNB in the treatment of early stage OCSCC, imaging technologies that support SLNB procedures, and studies that are currently underway.

Cutaneous Squamous Cell Carcinoma With Orbital Extension.

A 72-year-old homeless man was referred for management of a recurrent cutaneous squamous cell carcinoma of the right temple and brow. He was seen again 5 months later with an enlarged crusting and ulcerating lesion of the right temple/brow. What would you do next?

Updates in the management of unknown primary of the head and neck.

Squamous cell carcinoma (SCC) from an unknown primary tumor (SCCUP) accounts for 2.0%-5.0% of all head and neck cancers. SCCUP presents as enlarged cervical lymph nodes without evidence of a primary tumor upon physical examination. Primary site detection is important to target treatment and avoid treatment-related morbidity. In this review, we discuss updates in SCCUP management. Diagnostic workup should focus on localization of the primary tumor in SCCUP. Initial workup centers on neck biopsy to confirm the presence of SCC. Given the increasing incidence of HPV-related SCC in the oropharynx, HPV testing is crucial. An HPV-positive status can localize the tumor to the oropharynx, a common site for occult tumors. Imaging includes neck CT and/or MRI, and PET/CT. After imaging, panendoscopy, palatine tonsillectomy or diagnostic transoral robotic surgery can facilitate high rates of primary tumor localization. Primary tumor localization influences treatments administered. SCCUP has traditionally been treated aggressively with large treatment fields to all potential disease sites, which can induce weight loss and swallowing dysfunction. As a result, primary localization can reduce radiation fields and provide possible de-escalation to primary surgical management. Advances in intensity-modulated radiation therapy and dose management also have the potential to improve functional outcomes in SCCUP patients. Given the improved prognosis associated with HPV-positive SCCs, HPV tumor status may also inform future treatment de-intensification to reduce treatment-related toxicity.

Current perspectives on recurrent HPV-mediated oropharyngeal cancer.

In the recent years, the prevalence of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) has increased significantly. Currently, nearly 80-90% of all oropharynx tumors are HPV-positive. In addition, it is now recognized that HPV-positive tumor status is associated with good prognosis and improved response to chemoradiation. However, within this setting, there are still patients with HPV-positive OPSCC who will experience recurrence. With the increasing incidence of HPV-mediated OPSCC, recurrent HPV disease is also becoming more prevalent and there is an increasing need to understand the unique presentation and treatment of recurrent HPV-mediated disease. In this review, we will discuss epidemiology of recurrent HPV-positive OPSCC, role of surgical salvage, re-irradiation, and the role of upcoming novel treatments and immunotherapy. Historically, recurrent oropharyngeal disease has been associated with poor prognosis and high morbidity. However, recent advances have transformed the landscape for salvage treatment of HPV-mediated OPSCC. Liquid biomarkers offer potential for early detection of recurrence, robotic techniques may reduce morbidity of surgical salvage, improvements in re-irradiation approaches reduce toxicities, and novel immune based therapies on the horizon are offering promising results. These advances combined with the improved prognosis of HPV-positive disease offer to transform our approach to recurrent disease of the oropharynx.

Thyroid Carcinoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Differentiated thyroid carcinomas is associated with an excellent prognosis. The treatment of choice for differentiated thyroid carcinoma is surgery, followed by radioactive iodine ablation (iodine-131) in select patients and thyroxine therapy in most patients. Surgery is also the main treatment for medullary thyroid carcinoma, and kinase inhibitors may be appropriate for select patients with recurrent or persistent disease that is not resectable. Anaplastic thyroid carcinoma is almost uniformly lethal, and iodine-131 imaging and radioactive iodine cannot be used. When systemic therapy is indicated, targeted therapy options are preferred. This article describes NCCN recommendations regarding management of medullary thyroid carcinoma and anaplastic thyroid carcinoma, and surgical management of differentiated thyroid carcinoma (papillary, follicular, Hürthle cell carcinoma).

Necrotizing Tracheitis Complicated by Tracheal Wall Perforation.

Necrotizing tracheitis is a rare condition, mainly seen in immunocompromised patients, that may lead to pseudomembrane formation, airway obstruction and in severe cases, tracheal perforation. We present a case of a 32-year-old male with poorly controlled diabetes who presented with productive cough, dysphagia, and respiratory distress. Bronchoscopy revealed extensive tracheal necrosis along a 4-5 cm segment of cartilaginous trachea and was complicated by tracheal perforation with false passage into the anterior mediastinum. Once the airway was re-established, a multidisciplinary team discussed options for definitive airway management, including tracheal reconstruction, pulmonary stent, or tracheostomy. Ultimately, a distal XLT tracheostomy was placed. Microbiology specimens of the tracheal tissue were positive for Actinomyces. The patient was started on long-term antibiotics and diabetes management. At three-month follow-up, the trachea was patent with near complete mucosalization of the previously necrotic segment. An area of proximal tracheal stenosis was successfully managed with a customized tracheal T-tube. In conclusion, this is a case of necrotizing tracheitis complicated by tracheal perforation. Successful treatment required a multidisciplinary team for airway management as well as medical treatment of immunocompromising risk factors and antimicrobial therapy. This enabled timely healing of the trachea and a durable airway.

Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription.

PURPOSE: Human papillomavirus (HPV) plays a major role in oncogenesis and circular extrachromosomal DNA (ecDNA) is found in many cancers. However, the relationship between HPV and circular ecDNA in human cancer is not understood. EXPERIMENTAL DESIGN: Forty-four primary tumor tissue samples were obtained from a cohort of patients with HPV-positive oropharynx squamous cell carcinoma (OPSCC). Twenty-eight additional HPV oropharyngeal cancer (HPVOPC) tumors from The Cancer Genome Atlas (TCGA) project were analyzed as a separate validation cohort. Genomic, transcriptomic, proteomic, computational, and functional analyses of HPVOPC were applied to these datasets. RESULTS: Our analysis revealed circular, oncogenic DNA in nearly all HPVOPC, with circular human and human-viral hybrid ecDNA present in over a third of HPVOPC and viral circular DNA in remaining tumors. Hybrid ecDNA highly express fusion transcripts from HPV promoters and HPV oncogenes linked to downstream human transcripts that drive oncogenic transformation and immune evasion, and splice multiple, diverse human acceptors to a canonical SA880 viral donor site. HPVOPC have high E6*I expression with specific viral oncogene expression pattern related to viral or hybrid ecDNA composition. CONCLUSIONS: Nonchromosomal circular oncogenic DNA is a dominant feature of HPVOPC, revealing an unanticipated link between HPV and ecDNA that leverages the power of extrachromosomal inheritance to drive HPV and somatic oncogene expression.