Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state.

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq (n = 6) and exome sequencing (n = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted.

Promising New Diagnostic and Treatment Modalities for Allergic Rhinitis: What's Coming Next?

Novel diagnostic tests may help diagnose patients with local allergic rhinitis (AR) when systemic testing is negative or inconclusive. Surgical approaches including septoplasty, inferior turbinate reduction, nasal swell body reduction, and posterior nasal nerve ablation may improve symptoms in patients whose symptoms are refractory to medical therapy, though high-quality evidence is lacking in the AR population. Intralymphatic and epicutaneous immunotherapy have the potential to improve adherence to allergen immunotherapy, though comparisons with current gold standard treatments are lacking and studies reporting long-term outcomes are needed. Immunomodulatory agents in combination with subcutaneous immunotherapy (SCIT) may improve tolerance of SCIT but reports to date do not demonstrate a clear benefit in symptom alleviation. Future work in these areas may support these options as beneficial for testing and treatment of AR.

Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma.

Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.

Epithelial-Mesenchymal Plasticity in Tumor Immune Evasion.

Epithelial-mesenchymal transition (EMT) is a fundamental process that occurs during embryogenesis and tissue repair. However, EMT can be hijacked by malignant cells, where it may promote immune evasion and metastasis. Classically considered a dichotomous transition, EMT in cancer has recently been considered a plastic process whereby malignant cells display and interconvert among hybrid epithelial/mesenchymal (E/M) states. Epithelial-mesenchymal plasticity (EMP) and associated hybrid E/M states are divergent from classical EMT, with unique immunomodulatory effects. Here, we review recent insights into the EMP-immune cross-talk, highlighting possible mechanisms of immune evasion conferred by hybrid E/M states and roles of immune cells in EMP.

Anatomic variants of the subscapular-thoracodorsal arterial system: A radiologic analysis of 200 arterial systems.

BACKGROUND: Composite flaps based on the subscapular arterial system are excellent choices for complex defects, including those of the head and neck, though rates of anatomic variants are not well described. OBJECTIVE: Characterize subscapular-thoracodorsal arterial system in a large cohort of patients using CT chest angiography. METHODS: CTA chest studies from 100 adult patients were analyzed to characterize the bilateral subscapular-thoracodorsal arterial systems. RESULTS: Out of 200 arterial systems, 25 (12.5%) were lacking a subscapular artery, with the thoracodoral and circumflex scapular arteries arising independently off of the axillary (or other nearby vessels). Strikingly, the subscapular artery was absent bilaterally in 5 patients and absent unilaterally in 15 patients, meaning that one in five patients harbored abnormal anatomy on at least one side. There was no radiographic evidence of atherosclerosis in the studied vessels in any patient, including smokers and patients with atherosclerosis in other vessels. CONCLUSION: Variations in the subscapular-thoracodorsal arterial system appear more frequent than previously described. For select patients requiring complex reconstruction using the scapular system, CTA chest may aide surgical planning.

Partial EMT in head and neck cancer biology: a spectrum instead of a switch.

Our understanding of epithelial-to-mesenchymal transition (EMT) has slowly evolved from a simple two state, binary model to a multi-step, dynamic continuum of epithelial-to-mesenchymal plasticity, with metastable intermediate transition states that may drive cancer metastasis. Head and neck cancer is no exception, and in this review, we use head and neck as a case study for how partial-EMT (p-EMT) cell states may play an important role in cancer progression. In particular, we summarize recent in vitro and in vivo studies that uncover these intermediate transition states, which exhibit both epithelial and mesenchymal properties and appear to have distinct advantages in migration, survival in the bloodstream, and seeding and propagation within secondary metastatic sites. We then summarize the common and distinct regulators of p-EMT as well as methodologies for identifying this unique cellular subpopulation, with a specific emphasis on the role of cutting-edge technologies, such as single cell approaches. Finally, we propose strategies to target p-EMT cells, highlighting potential opportunities for therapeutic intervention to specifically target the process of metastasis. Thus, although significant challenges remain, including numerous gaps in current knowledge, a deeper understanding of EMT plasticity and a genuine identification of EMT as spectrum rather than a switch will be critical for improving patient diagnosis and treatment across oncology.

The role of age in treatment decisions for oral cavity squamous cell carcinoma: Analysis of the National Cancer Database.

BACKGROUND: The number of elderly patients with oral squamous cell carcinoma (OCSCC) is increasing as the elderly population increases. Unfortunately, evidence to guide the management of these patients is lacking. METHODS: Patients with OCSCC identified from the National Cancer Database (NCDB) were stratified into age-based cohorts. Demographics, comorbidities, and treatment patterns were analyzed. Patients were stratified into early stage (Stage I/II) and advanced stage (Stage III/IV) disease. The likelihood of receiving multimodality therapy by age was calculated using multinomial logistic regression for each stratum while controlling for potential confounders. Cox proportional hazard regression was used to calculate 5-year mortality risk while controlling for potential confounders. RESULTS: Surgery alone or palliative options were offered to older patients more frequently. After controlling for confounders, older patients were less likely to receive multimodality therapy for both early stage and advanced stage disease. Patients with advanced disease across all age cohorts had improved 5-year survival with surgery and adjuvant therapy. CONCLUSION: Our analyses suggest that elderly patients have unique demographic and pathologic features. They frequently receive less treatment than similarly staged younger patients, yet they benefit from multimodality therapy when feasible. These data suggest an urgent need to critically appraise the care of elderly OCSCC patients within the broader context of their individual comorbidity burden, functional status, and treatment goals.

Low-risk human papilloma virus positive oropharyngeal cancer with one positive lymph node: Equivalent outcomes in patients treated with surgery and radiation therapy versus surgery alone.

BACKGROUND: For human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), management recommendations for patients with a single metastatic lymph node <6 cm in diameter remain nebulous, leading to treatment heterogeneity in this common subgroup of patients. METHODS: We utilized the National Cancer Database to perform survival and multivariable analyses of patients with HPV+ OPSCC with one positive lymph node <6 cm and negative surgical margins. RESULTS: We found that 5-year survival is comparable between patients who receive surgery and adjuvant radiation versus surgery alone. In multivariable analyses, we found no significant difference in the hazard ratio of overall survival after adjusting for various potential confounders. CONCLUSIONS: These data suggest that patients with margin-negative HPV+ OPSCC with a single positive lymph node <6 cm have comparable survival with or without adjuvant radiation. Future studies exploring outcomes for this specific group in randomized-controlled trials will be critical for further evaluating these initial observations.

Duration of radiation therapy is associated with worse survival in head and neck cancer.

INTRODUCTION: Delays in radiation are multifactorial, frequent, and associated with poor outcomes. This study investigates the effect of both primary and adjuvant radiation therapy duration and their interaction with other measures of treatment delay on survival in head and neck squamous cell carcinoma (HNSCC). METHODS: We built a retrospective cohort using the National Cancer Database, consisting of primary oral cavity, hypopharynx, larynx and oropharynx squamous cell carcinoma without distant metastasis and with at least six weeks of radiation. The primary exposure was the duration of radiation therapy (DRT), and the primary outcome was death. We estimated the association between DRT and 5-year overall survival (OS) using Kaplan-Meier curves and hazard ratios (HRs) with Cox proportional hazard regression. RESULTS: In both primary (definitive) and adjuvant (post-surgical) radiation settings, increased DRT results in decreased survival. In the primary radiation cohort, 5-year OS was 59.7% [59.1%-60.3%] among those with 47-53 days DRT, which decreased significantly with each subsequent week to completion (81+ days: 38.4% [36.2%-40.7%]). In the surgical cohort, survival decreased 16.5% when DRT extended beyond 75 days (40-46 days: 68.2% [67.3%-69.1%] vs. 75+ days: 53.3% [50.1%-56.7%]). Multivariate analyses showed increased hazard of death with increased DRT (primary radiation: 81+ days HR: 1.69 [1.58-1.81]); surgical: 75+ days HR: 1.61 [1.37-1.88]), with effects intensifying when restricting to those receiving full-dose radiation. CONCLUSION: A prolonged DRT was associated with worse OS in head and neck cancer. Radiation treatment delays of even a week lead to a significant survival disadvantage. DRT had a stronger association with survival than time to initiation of postoperative adjuvant radiotherapy.

Brain metastasis from squamous cell carcinoma of the head and neck: a review of the literature in the genomic era.

Squamous cell carcinoma of the head and neck (HNSCC) affects nearly 500,000 individuals globally each year. With the rise of human papillomavirus (HPV) in the general population, clinicians are seeing a concomitant rise in HPV-related HNSCC. Notably, a hallmark of HPV-related HNSCC is a predilection for unique biological and clinical features, which portend a tendency for hematogenous metastasis to distant locations, such as the brain. Despite the classic belief that HNSCC is restricted to local spread via passive lymphatic drainage, brain metastases (BMs) are a rare complication that occurs in less than 1% of all HNSCC cases. Time between initial diagnosis of HNSCC and BM development can vary considerably. Some patients experience more than a decade of disease-free survival, whereas others present with definitive neurological symptoms that precede primary tumor detection. The authors systematically review the current literature on HNSCC BMs and discuss the current understanding of the effect of HPV status on the risk of developing BMs in the modern genomic era.

Technical Note: Preemptive Surgical Revision of Impending Deep Brain Stimulation Hardware Erosion.

BACKGROUND: While deep brain stimulation (DBS) is a relatively safe procedure, skin erosion is a commonly reported hardware complication that can threaten the DBS system. Patients with Parkinson disease are especially at risk for this complication due to their autonomic dysregulation and impaired nutrition. Early detection of impending skin erosion allows for intervention that may prevent hardware destruction. Here we report a novel technique to address this complication preemptively. We describe the use of an acellular dermal matrix to prevent skin erosion in 20 patients with Parkinson disease who were treated with DBS and showed signs of impending skin erosion. METHODS: Twenty patients with signs of impending hardware erosion were identified. An acellular dermal matrix was surgically placed under the at-risk skin overlying the DBS lead. RESULTS: None of the 20 patients treated with this technique went on to require further revision surgery or removal of hardware. CONCLUSIONS: Surgical placement of acellular dermal matrix in patients identified as having impending hardware erosions is a safe and cost-effective way to prevent hardware complications.

First Application of 7-T Magnetic Resonance Imaging in Endoscopic Endonasal Surgery of Skull Base Tumors.

BACKGROUND: Successful endoscopic endonasal surgery for the resection of skull base tumors is reliant on preoperative imaging to delineate pathology from the surrounding anatomy. The increased signal-to-noise ratio afforded by 7-T MRI can be used to increase spatial and contrast resolution, which may lend itself to improved imaging of the skull base. In this study, we apply a 7-T imaging protocol to patients with skull base tumors and compare the images with clinical standard of care. METHODS: Images were acquired at 7 T on 11 patients with skull base lesions. Two neuroradiologists evaluated clinical 1.5-, 3-, and 7-T scans for detection of intracavernous cranial nerves and internal carotid artery (ICA) branches. Detection rates were compared. Images were used for surgical planning and uploaded to a neuronavigation platform and used to guide surgery. RESULTS: Image analysis yielded improved detection rates of cranial nerves and ICA branches at 7 T. The 7-T images were successfully incorporated into preoperative planning and intraoperative neuronavigation. CONCLUSIONS: Our study represents the first application of 7-T MRI to the full neurosurgical workflow for endoscopic endonasal surgery. We detected higher rates of cranial nerves and ICA branches at 7-T MRI compared with 3- and 1.5-T MRI, and found that integration of 7 T into surgical planning and guidance was feasible. These results suggest a potential for 7-T MRI to reduce surgical complications. Future studies comparing standardized 7-, 3-, and 1.5-T MRI protocols in a larger number of patients are warranted to determine the relative benefit of 7-T MRI for endonasal endoscopic surgical efficacy.

Application of Ultrahigh Field Magnetic Resonance Imaging in the Treatment of Brain Tumors: A Meta-Analysis.

BACKGROUND: Magnetic resonance imaging (MRI) is the imaging modality of choice for the clinical management of brain tumors, and the majority of scanners operate with static magnetic field strengths of 1.5 or 3.0 Tesla (T). During the past decade, ultrahigh field (UHF) MRI has been investigated for its clinical applicability. This meta-analysis evaluates studies pertaining to the application of UHF MRI to patients with brain tumors. METHODS: The authors performed a systematic review of the literature. Articles relating to application of UHF MRI to brain anatomy and brain tumors with living subjects were included. Studies were grouped into 1 of 3 categories based on area of focus: "Anatomical Structures Involved with Brain Tumors," "Tumor characterization," and "Treatment Monitoring." Comparison studies with extractable outcomes measure data were analyzed for performance of UHF MRI versus clinical field strengths (1.5 T and 3 T). RESULTS: Twenty-four studies (361 subjects) met inclusion criteria. The field of study was heterogeneous and rigorous statistical analysis was not possible. Overall, 279 patients with brain tumors scanned at UHF MRI have been reported. Of these, glioma and glioblastoma multiforme are the most commonly studied lesions (38.9% and 24.4%, respectively). In comparison studies between UHF MRI and clinical field strengths, 24 of 51 patients had outcome measures that were better with UHF MRI, 17 of 24 were equivalent at both field strengths, and 9 were worse at UHF MRI. The most common causes of a worse performance were susceptibility artifacts and magnetic field inhomogeneities (3 of 9). Imaging of the pituitary gland, pineal gland veins, cranial nerves, and tumor microvasculature were all shown to be feasible. CONCLUSIONS: UHF MRI shows promise to improve detection and characterization of brain tumors, preoperative planning for neurosurgical resection, and longitudinal monitoring of the effects of radiation and antibody-based therapies. Technical innovations are needed to overcome field inhomogeneity and susceptibility artifacts in certain regions of the skull. Finally, larger studies comparing 1.5 T, 3.0 T, and 7.0 T or greater will determine whether UHF MRI gains acceptance as a clinical standard.

Manic defenses against loneliness in adolescence.

This essay focuses on the challenges adolescents face as they progress in the process of object removal. The loosening of primary libidinal object ties triggers object loss and a unique form of loneliness specific to adolescence, which may be misdiagnosed as depression. Rather than stemming from a fear of loss of love from the primary object, the loneliness results from the adolescent's need to transfer love from primary objects to new adult relationships not yet available to him. The resultant emptiness may be defended against by overuse of the Internet, alcohol, cigarettes, drugs, and food. These defenses are manic in quality in that they suggest an orally based regressive attempt to "take in" and "expel out, "preserving the felt "lost" object and converting the loneliness into elation. Clinical vignettes illustrate work with adolescents wherein the ability to tolerate lonely feelings is recognized as a developmental accomplishment leading to personality growth and maturity.