Advanced Human Papillomavirus-Negative Head and Neck Squamous Cell Carcinoma: Unmet Need and Emerging Therapies.

Despite notable progress in the treatment of advanced head and neck squamous cell carcinoma (HNSCC), survival remains poor in patients with recurrent and/or metastatic (R/M) human papillomavirus (HPV)-negative HNSCC. Worse outcomes in the HPV-negative patients may be partly related to loss of cell-cycle regulators and tumor suppressors as well as a noninflamed and hypoxic tumor microenvironment, both of which contribute to treatment resistance and disease progression. Anti-programmed cell death protein 1-based regimens as current standard-of-care treatment for R/M HNSCC are associated with durable responses in a limited number of patients. The anti-epidermal growth factor receptor (EGFR) monoclonal antibody, cetuximab, has antitumor activity in this treatment setting, but responses are short-lived and inevitably curtailed due to treatment resistance. Crosstalk between the EGFR and hepatocyte growth factor (HGF)-dependent mesenchymal-epithelial transition (c-MET) receptor tyrosine kinase pathway is a known mechanism of resistance to cetuximab. Dual targeting of EGFR and c-MET pathways may overcome resistance to cetuximab in patients with HPV-negative HNSCC. Here, we review clinical data of treatments evaluated in patients with R/M HPV-negative HNSCC and highlight the potential role of combining HGF/c-MET and EGFR pathway inhibitors to overcome cetuximab resistance in this population.

Emergency Department Slit Lamp Interdisciplinary Training Via Longitudinal Assessment in Medical Practice.

Introduction: Eye emergencies make up nearly 3% of US emergency department (ED) visits. While emergency physicians (EP) should diagnose and treat these ophthalmologic emergencies, many trainees report limited ocular exposure and insufficient training throughout their residency to confidently conduct a thorough slit-lamp exam. Methods: We created an interdisciplinary, simulation-based mastery learning (SBML) curriculum to teach emergency attending physicians how to operate the slit lamp with multimodal learning methodology at a tertiary academic center. The EPs first demonstrate their initial slit-lamp competency with a 20-item checklist, and they then review the necessary curricular content to pass their independent readiness test before completing their in-person teaching and demonstration session with an ophthalmology attending to demonstrate procedural mastery (minimal passing score >90%). Results: Fifteen EPs were enrolled; all completed the final exam of the curriculum. The pre- and post-curriculum checklist scores increased by an average of seven points (P = .002); 86.7% of EPs felt confident in completing a slit-lamp exam after the curriculum, compared to 20% at the beginning. Five of 15 reported teaching learners within the two-month post-curricular period, ranging from 5-30 students. The hands-on teaching was the most positively reviewed element of the curriculum. Conclusion: The SBML program successfully trained EPs on performing a comprehensive slit-lamp exam with promising results of downstream education to junior learners. We encourage other institutions to leverage SBML as a teaching modality for procedural-based training and advocate cross-discipline education initiatives.

Principles of clinical genetics for rheumatologists: clinical indications and interpretation of broad-based genetic testing.

Advances in DNA sequencing technologies, especially next-generation sequencing (NGS), which is the basis for whole-exome sequencing (WES) and whole-genome sequencing (WGS), have profoundly transformed immune-mediated rheumatic disease diagnosis. Recently, substantial cost reductions have facilitated access to these diagnostic tools, expanded the capacity of molecular diagnostics and enabled the pursuit of precision medicine in rheumatology. Understanding the fundamental principles of genetics and diversity in genetic variant classification is a crucial milestone in rheumatology. However, despite the growing availability of DNA sequencing platforms, a significant number of autoinflammatory diseases (AIDs), neuromuscular disorders, hereditary collagen diseases, and monogenic bone diseases remain unsolved, and variants of uncertain significance (VUS) pose a formidable challenge to addressing these unmet needs in the coming decades. This article aims to provide an overview of the clinical indications and interpretation of comprehensive genetic testing in the medical field, addressing the related complexities and implications.

Significant age-related differences between lower leg muscles of older and younger female subjects detected by ultrashort echo time magnetization transfer modeling.

Magnetization transfer (MT) magnetic resonance imaging (MRI) can be used to estimate the fraction of water and macromolecular proton pools in tissues. MT modeling paired with ultrashort echo time acquisition (UTE-MT modeling) has been proposed to improve the evaluation of the myotendinous junction and fibrosis in muscle tissues, which the latter increases with aging. This study aimed to determine if the UTE-MT modeling technique is sensitive to age-related changes in the skeletal muscles of the lower leg. Institutional review board approval was obtained, and all recruited subjects provided written informed consent. The legs of 31 healthy younger (28.1 ± 6.1 years old, BMI = 22.3 ± 3.5) and 20 older (74.7 ± 5.5 years old, BMI = 26.7 ± 5.9) female subjects were imaged using UTE sequences on a 3 T MRI scanner. MT ratio (MTR), macromolecular fraction (MMF), macromolecular T2 (T2-MM), and water T2 (T2-W) were calculated using UTE-MT modeling for the anterior tibialis (ATM), posterior tibialis (PTM), soleus (SM), and combined lateral muscles. Results were compared between groups using the Wilcoxon rank sum test. Three independent observers selected regions of interest (ROIs) and processed UTE-MRI images separately, and the intraclass correlation coefficient (ICC) was calculated for a reproducibility study. Significantly lower mean MTR and MMF values were present in the older compared with the younger group in all studied lower leg muscles. T2-MM showed significantly lower values in the older group only for PTM and SM muscles. In contrast, T2-W showed significantly higher values in the older group. The age-related differences were more pronounced for MMF (-17 to -19%) and T2-W (+20 to 47%) measurements in all muscle groups compared with other investigated MR measures. ICCs were higher than 0.93, indicating excellent consistency between the ROI selection and MRI measurements of independent readers. As demonstrated by significant differences between younger and older groups, this research emphasizes the potential of UTE-MT MRI techniques in evaluating age-related skeletal muscle changes.

Qualitative and Quantitative MR Imaging of the Cartilaginous Endplate: A Review.

The cartilaginous endplate (CEP) plays a pivotal role in facilitating the supply of nutrients and, transport of metabolic waste, as well as providing mechanical support for the intervertebral disc (IVD). Recent technological advances have led to a surge in MR imaging studies focused on the CEP. This article describes the anatomy and functions of the CEP as well as MRI techniques for both qualitative and quantitative assessment of the CEP. Effective CEP MR imaging sequences require two key features: high spatial resolution and relatively short echo time. High spatial resolution spoiled gradient echo (SPGR) and ultrashort echo time (UTE) sequences, fulfilling these requirements, are the basis for most of the sequences employed in CEP imaging. This article reviews existing sequences for qualitative CEP imaging, such as the fat-suppressed SPGR and UTE, dual-echo subtraction UTE, inversion recovery prepared and fat-suppressed UTE, and dual inversion recovery prepared UTE sequences. These sequences are employed together with other techniques for quantitative CEP imaging, including measurements of T2*, T2, T1, T1ρ, magnetization transfer, perfusion, and diffusion tensor parameters. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Teaming up to overcome challenges toward translation of new therapeutics for osteoarthritis.

As a leading global cause of musculoskeletal-related disability, osteoarthritis (OA) represents a public health urgency. Understanding of disease pathogenesis has advanced substantially in the past decade, yet no disease-modifying therapeutics have advanced to the clinic. To address this challenge, the CARE-AP (Cartilage Repair strategies to alleviate Arthritis Pain) collaborative research team was convened to bring together relevant multidisciplinary expertise and perspectives from across the VA research community nationwide. The first CARE-AP Annual Research Symposium took place (virtually) in February 2022 with roughly 90 participants. A number of innovative and therapeutic strategies were discussed, including siRNA approaches coupled with novel nanoparticle-based delivery systems, cellular engineering approaches to develop reparative cells that can probe the joint environment and respond to disease-specific cues, and novel biofabrication techniques to improve tissue engineering and effect "biological joint replacement." In addition, challenges and advances in rehabilitation approaches, imaging outcomes, and clinical studies were presented, which were integrated into a framework of recommendations for running "preclinical trials" to improve successful clinical translation.

Pembrolizumab and cabozantinib in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC): long-term survival update with a biomarker analysis.

PURPOSE: Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) have immunomodulatory properties and improve clinical outcomes in combination with anti-PD-1 therapy. We report the long-term efficacy and safety of pembrolizumab and cabozantinib and include a correlative biomarker analysis. PATIENTS AND METHODS: This open-label, single-arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. Primary endpoint was overall response rate (ORR), safety, and tolerability. Secondary endpoints included progression free survival (PFS), overall survival (OS), and correlative studies of tissue and blood. We report the long-term PFS, OS, safety, and describe correlative biomarkers. RESULTS: With median follow-up of 22.4 months, median PFS was 12.8 months 2-year PFS of 32.6% (95%CI 18.8-56.3%) and median OS of 27.7 months,2-year OS of 54.7% (95%CI 38.9-76.8%). Median duration of response was 12.6 months, with 2-year rate of 38.5% (95%CI 30.8-81.8%). Long-term TRAEs included manageable hypothyroidism (5.5%) and grade 1 elevated AST and ALT (2.8%). Baseline tumor p-MET expression correlated with ORR (p=0.0055). Higher density of CD8+, CD103+, and CSF1-R+ cells at baseline correlated with improved OS (hazard ratio [HR]=5.27, p=0.030; HR =8.79, p=0.017; HR =6.87, p=0.040, respectively). CONCLUSION: Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic significance of increased CD8+, CD103+ and CSF1-R+ cell density in TIME deserve further evaluation in similar clinical settings.

Effective Use of Interpreter Services for Diverse Patients in a Safety-Net Hospital: Provider Perceptions of Barriers and Solutions.

INTRODUCTION: Culturally and linguistically diverse (CALD) patients should but do not routinely receive professional interpretation. The authors examined provider perceptions of barriers and solutions to interpreter services (IS) in a safety-net hospital to inform quality improvement (QI). METHODS: A 13-item survey was distributed to 750 clinicians representing 10 services across professional roles, including social workers. Closed- and open-ended questions addressed accessing IS, IS value, and care for CALD patients. Respondents ranked eight barriers to routine IS use and provided ideas for improvement. Descriptive statistics characterized survey results in aggregate and by professional role and care team. Quantitative and qualitative results were triangulated for agreement between survey domains and coded free-text response themes. RESULTS: A total of 221 responses were analyzed (29.5% response rate). Cost was the lowest-ranked barrier across roles. Leading barriers were efficiency pressures and cumbersome access. Free-text responses agreed with these findings. CALD patients were perceived to have higher complication risk by 87.5% of social workers but by 56.8% of other roles. Recommendations to increase IS varied by team: streamlined access process (46.2% emergency, 37.8% inpatient respondents), expanded in-person interpretation (55.6% inpatient, 45.8% perioperative respondents), and better equipment (44.4% outpatient, 35.9% emergency, 25.0% perioperative respondents). CONCLUSION: Provider experiences vary by care team and interpretation modality. Interpretation services are cumbersome to access and compete with efficiency pressures, leading to shortcuts that fail to provide adequate language access. Three initial QI efforts resulted: increased video interpretation equipment, a new language access committee, and a new language access leadership role.

Preexisting Skin-Resident CD8 and γδ T-cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ∼50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA sequencing (RNA-seq) with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In nonresponders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL1. Responders have increased type I/II interferons and preexisting tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public T-cell receptors. Spatial transcriptomics demonstrated colocalization of T cells with B and dendritic cells, which supply chemokines and costimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and Vδ1 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC. Significance: MCC serves as a model of ICB response. We utilized the largest-to-date, multimodal MCC dataset (n = 116 patients) to uncover unique tumor-intrinsic properties and immune circuits that predict response. We identified CD8 Trm and Vδ1 T cells as clinically actionable mediators of ICB response in major histocompatibility complex-high and -low MCCs, respectively.

Molecular characterization of the salivary adenoid cystic carcinoma immune landscape by anatomic subsites.

Adenoid cystic carcinoma (AdCC) is a slow-growing salivary gland malignancy that relapses frequently. AdCCs of the submandibular gland exhibit unique differences in prognosis and treatment response to adjuvant radiotherapy compared to other sites, yet the role of tumor anatomic subsite on gene expression and tumor immune microenvironment (TIME) composition remains unclear. We used 87 samples, including 48 samples (27 AdCC and 21 normal salivary gland tissue samples) from 4 publicly available AdCC RNA sequencing datasets, a validation set of 33 minor gland AdCCs, and 39 samples from an in-house cohort (30 AdCC and 9 normal salivary gland samples). RNA sequencing data were used for single sample gene set enrichment analysis and TIME deconvolution. Quantitative PCR and multiplex immunofluorescence were performed on the in-house cohort. Wilcoxon rank-sum, nonparametric equality-of-medians tests and linear regression models were used to evaluate tumor subsite differences. AdCCs of different anatomic subsites including parotid, submandibular, sublingual, and minor salivary glands differed with respect to expression of several key tumorigenic pathways. Among the three major salivary glands, the reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway signature was significantly underexpressed in AdCC of submandibular compared to parotid and sublingual glands while this association was not observed among normal glands. Additionally, the NRF2 pathway, whose expression was associated with favorable overall survival, was overexpressed in AdCCs of parotid gland compared to minor and submandibular glands. The TIME deconvolution identified differences in CD4+ T cell populations between AdCC of major and minor glands and natural killer (NK) cells among AdCC of minor, submandibular, and parotid glands while plasma cells were enriched in normal submandibular glands compared to other normal gland controls. Our data reveal key molecular differences in AdCC of different anatomic subsites. The ROS and NRF2 pathways are underexpressed in submandibular and minor AdCCs compared to parotid gland AdCCs, and NRF2 pathway expression is associated with favorable overall survival. The CD4+ T, NK, and plasma cell populations also vary by tumor subsites, suggesting that the observed submandibular AdCC tumor-intrinsic pathway differences may be responsible for influencing the TIME composition and survival differences.

High-Field MRI Advantages and Applications in Rheumatology.

Imaging of rheumatologic diseases has historically been performed using conventional radiography. MRI offers an opportunity for detection of altered marrow signal in early disease that is not visible on other imaging modalities such as radiography, computed tomography, or sonography. This review describes the advantages of current MRI techniques in the diagnosis and treatment monitoring of rheumatologic diseases. In addition, this review discusses novel MRI techniques at high-field magnetic strength which may be deployed in the future to allow for improved imaging resolution and quantitative assessment of both axial and peripheral joints.

Neurovascular crossing patterns between leash of Henry and deep branch of radial nerve: implications for neurointervention and diagnostic imaging.

OBJECTIVE: To detail the neurovascular crossing patterns between the leash of Henry (LoH) and the deep branch of the radial nerve (DBRN) in supination and pronation of the forearm, using imaging methods with anatomic correlation. MATERIALS AND METHODS: This cross-sectional study was performed ex vivo with HRUS and MRI with anatomic correlation on 6 samples and in vivo with HRUS with Doppler on 55 participants scanned bilaterally. The in vivo participants were enrolled over a 6-month period. The crossing patterns between the LoH and DBRN were assessed ex vivo and in vivo. Additional morphological features of the DBRN, LoH, and fat plane were assessed in vivo only. Biometric features of the participants were recorded. Statistical analyses were performed using Shapiro-Wilk, parametric and non-parametric tests. RESULTS: The most common neurovascular crossing pattern was the ascending branch of the radial recurrent artery (RRAab) crossing below (ex vivo: 83.3%, in vivo: 85.3%) and the muscular branch crossing above (ex vivo: 100%, in vivo: 63.2% %) the DBRN. Both the deep and superficial surfaces of the DBRN exhibited an intimate relationship with the vessels of the LoH. A positive correlation between vessel diameter and anthropometric factors was observed. In addition, the muscular branch exhibited a significantly smaller diameter than the RRAab. CONCLUSION: Our study detailed the relationship between the LoH and the DBRN and highlighted the high incidence of vessel crossing above the DBRN at the level of the muscular branch. Knowledge of neurovascular crossings is crucial for understanding neurovascular entrapment syndromes and planning interventional procedures to reduce vascular complications.

Evaluation of spine disorders using high contrast imaging of the cartilaginous endplate.

Introduction: Many spine disorders are caused by disc degeneration or endplate defects. Because nutrients entering the avascular disc are channeled through the cartilaginous endplate (CEP), structural and compositional changes in the CEP may block this solute channel, thereby hindering disc cell function. Therefore, imaging the CEP region is important to improve the diagnostic accuracy of spine disorders. Methods: A clinically available T1-weighted and fat-suppressed spoiled gradient recalled-echo (FS-SPGR) sequence was optimized for high-contrast CEP imaging, which utilizes the short T1 property of the CEP. The FS-SPGR scans with and without breath-hold were performed for comparison on healthy subjects. Then, the FS-SPGR sequence which produced optimal image quality was employed for patient scans. In this study, seven asymptomatic volunteers and eight patients with lower back pain were recruited and scanned on a 3T whole-body MRI scanner. Clinical T2-weighted fast spin-echo (T2w-FSE) and T1-weighted FSE (T1w-FSE) sequences were also scanned for comparison. Results: For the asymptomatic volunteers, the FS-SPGR scans under free breathing conditions with NEX = 4 showed much higher contrast-to-noise ratio values between the CEP and bone marrow fat (BMF) (CNRCEP-BMF) (i.e., 7.8 ± 1.6) and between the CEP and nucleus pulposus (NP) (CNRCEP-NP) (i.e., 6.1 ± 1.2) compared to free breathing with NEX = 1 (CNRCEP-BMF: 4.0 ± 1.1 and CNRCEP-NP: 2.5 ± 0.9) and breath-hold condition with NEX = 1 (CNRCEP-BMF: 4.2 ± 1.3 and CNRCEP-NP: 2.8 ± 1.3). The CEP regions showed bright linear signals with high contrast in the T1-weighted FS-SPGR images in the controls, while irregularities of the CEP were found in the patients. Discussion: We have developed a T1-weighted 3D FS-SPGR sequence to image the CEP that is readily translatable to clinical settings. The proposed sequence can be used to highlight the CEP region and shows promise for the detection of intervertebral disc abnormalities.

Spatial interactions modulate tumor growth and immune infiltration.

Lenia, a cellular automata framework used in artificial life, provides a natural setting to implement mathematical models of cancer incorporating features such as morphogenesis, homeostasis, motility, reproduction, growth, stimuli response, evolvability, and adaptation. Historically, agent-based models of cancer progression have been constructed with rules that govern birth, death and migration, with attempts to map local rules to emergent global growth dynamics. In contrast, Lenia provides a flexible framework for considering a spectrum of local (cell-scale) to global (tumor-scale) dynamics by defining an interaction kernel governing density-dependent growth dynamics. Lenia can recapitulate a range of cancer model classifications including local or global, deterministic or stochastic, non-spatial or spatial, single or multi-population, and off or on-lattice. Lenia is subsequently used to develop data-informed models of 1) single-population growth dynamics, 2) multi-population cell-cell competition models, and 3) cell migration or chemotaxis. Mathematical modeling provides important mechanistic insights. First, short-range interaction kernels provide a mechanism for tumor cell survival under conditions with strong Allee effects. Next, we find that asymmetric interaction tumor-immune kernels lead to poor immune response. Finally, modeling recapitulates immune-ECM interactions where patterns of collagen formation provide immune protection, indicated by an emergent inverse relationship between disease stage and immune coverage.

Imaging of Rheumatic Diseases Affecting the Lower Limb.

Imaging methods capable of detecting inflammation, such as MR imaging and ultrasound, are of paramount importance in rheumatic disease management, not only for diagnostic purposes but also for monitoring disease activity and treatment response. However, more advanced stages of arthritis, characterized by findings of cumulative structural damage, have traditionally been accomplished by radiographs and computed tomography. The purpose of this review is to provide an overview of imaging of some of the most prevalent inflammatory rheumatic diseases affecting the lower limb (osteoarthritis, rheumatoid arthritis, and gout) and up-to-date recommendations regarding imaging diagnostic workup.

Phase Ib trial of IRX-2 plus durvalumab in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

OBJECTIVES: IRX-2 is a multi-cytokine immune-activating agent with anti-tumor activity in non-metastatic head and neck squamous cell carcinoma (HNSCC). Here, we evaluated combined IRX-2 and durvalumab in patients with recurrent and/or metastatic HNSCC. MATERIALS AND METHODS: This was a phase Ib trial consisting of dose escalation and expansion. Primary endpoints were safety and biomarkers to assess the immune response in the tumor microenvironment including significant increases in PD-L1 expression and CD8 + tumor infiltrating lymphocytes (TIL) comparing pre- and on-treatment tumor biopsies. Secondary endpoints were objective response rates (ORR) and survival outcomes. RESULTS: Sixteen patients were evaluable for response, and nine patients were evaluable for biomarkers. Thirteen patients (68 %) had exposure to prior anti-PD-1 therapy. No dose-limiting or grade ≥ 3 treatment-related adverse events were observed. On-treatment biopsies showed significantly increased PD-L1 (p = 0.005), CD3+ (p = 0.020), CD4+ (p = 0.022), and CD8 + T cells (p = 0.017) compared to pre-treatment. Median overall survival and progression-free survival (PFS) were 6.18 months (95 % CI, 2.66-8.61) and 2.53 months (95 % CI, 1.81-4.04), respectively. One patient had an objective response (ORR, 5.3 %) with an ongoing PFS of > 25 months. Disease control rate was 42 %. The responder harbored an ARID1A variant of unknown significance (VUS) that was predicted to bind her HLA-I alleles with a higher affinity than the reference peptide. CONCLUSIONS: IRX-2 and durvalumab were safe and elicited the evidence of immune activation in the tumor microenvironment determined by increased PD-L1 expression and CD8+ TILs. CLINICAL TRIAL REGISTRATION NUMBER: NCT03381183.