IL-8 correlates with nonresponse to neoadjuvant nivolumab in HPV positive HNSCC via a potential extracellular vesicle miR-146a mediated mechanism.

Therapy using anti-PD-1 immune checkpoint inhibitors (ICI) has revolutionized the treatment of many cancers including head and neck squamous cell carcinomas (HNSCC), but only a fraction of patients respond. To better understand the molecular mechanisms driving resistance, we performed extensive analysis of plasma and tumor tissues before and after a 4-week neoadjuvant trial in which HNSCC patients were treated with the anti-PD-1 inhibitor, nivolumab. Luminex cytokine analysis of patient plasma demonstrated that HPVpos nonresponders displayed high levels of the proinflammatory chemokine, interleukin-8 (IL-8), which decreased after ICI treatment, but remained higher than responders. miRNAseq analysis of tetraspanin-enriched small extracellular vesicles (sEV) purified from plasma of HPVpos nonresponders demonstrated significantly lower levels of seven miRNAs that target IL-8 including miR-146a. Levels of the pro-survival oncoprotein Dsg2, which has been to down-regulate miR-146a, are elevated with HPVpos tumors displaying higher levels than HPVneg tumors. Dsg2 levels decrease significantly following ICI in responders but not in nonresponders. In cultured HPVpos cells, restoration of miR-146a by forced expression or treatment with miR-146a-loaded sEV, reduced IL-8 level, blocked cell cycle progression, and promoted cell death. These findings identify Dsg2, miR-146a, and IL-8 as potential biomarkers for ICI response and suggest that the Dsg2/miR-146a/IL-8 signaling axis negatively impacts ICI treatment outcomes and could be targeted to improve ICI responsiveness in HPVpos HNSCC patients.

Metastatic skull base chordoma: A systematic review.

Objective/Hypothesis: To investigate the clinical features, management strategies and outcomes for patients with metastatic primary skull base chordomas. Study Design: Systematic review. Methods: A systematic search through Pubmed/Medline, Web of Science, and EBSCOhost (CINAHL) was conducted without restriction on dates. After study screening and full-text assessment, two authors independently extracted all data using a pre-established abstraction form. Results: Forty cases were included from 38 studies. The average age (standard deviation [SD]) of the sample at presentation was 28.5 (23.3) and was equally distributed across genders. The average time (SD) between initial diagnosis to local recurrence was 40.1 (60.3) months. The average time (SD) from primary tumor detection to the diagnosis of metastatic disease was 55.2 (49.0) months. The most common subsite for metastatic spread were the lungs (32.5%). Of the 33 patients with data on outcomes, 48.5% were found to have expired by the time of publication. The median overall survival was estimated to be 84 months (95% confidence interval [CI] 62.3-105.7). Conclusions: The most common subsites for metastatic spread of skull base chordoma were the lungs and bone. Overall survival for patients in the current cohort was a median of 84 months, with no significant differences noted when stratifying by the extent of surgery or the site of metastases. Level of Evidence: 3a.

Intraoperative In Vivo Imaging Modalities in Head and Neck Cancer Surgical Margin Delineation: A Systematic Review.

Surgical margin status is one of the strongest prognosticators in predicting patient outcomes in head and neck cancer, yet head and neck surgeons continue to face challenges in the accurate detection of these margins with the current standard of care. Novel intraoperative imaging modalities have demonstrated great promise for potentially increasing the accuracy and efficiency in surgical margin delineation. In this current study, we collated and analyzed various intraoperative imaging modalities utilized in head and neck cancer to evaluate their use in discriminating malignant from healthy tissues. The authors conducted a systematic database search through PubMed/Medline, Web of Science, and EBSCOhost (CINAHL). Study screening and data extraction were performed and verified by the authors, and more studies were added through handsearching. Here, intraoperative imaging modalities are described, including optical coherence tomography, narrow band imaging, autofluorescence, and fluorescent-tagged probe techniques. Available sensitivities and specificities in delineating cancerous from healthy tissues ranged from 83.0% to 100.0% and 79.2% to 100.0%, respectively, across the different imaging modalities. Many of these initial studies are in small sample sizes, with methodological differences that preclude more extensive quantitative comparison. Thus, there is impetus for future larger studies examining and comparing the efficacy of these intraoperative imaging technologies.

Testicular abnormalities in mice with Y chromosome deficiencies.

We recently investigated mice with Y chromosome gene contribution limited to two, one, or no Y chromosome genes in respect to their ability to produce haploid round spermatids and live offspring following round spermatid injection. Here we explored the normalcy of germ cells and Sertoli cells within seminiferous tubules, and the interstitial tissue of the testis in these mice. We performed quantitative analysis of spermatogenesis and interstitial tissue on Periodic acid-Schiff and hematoxylin-stained mouse testis sections. The seminiferous epithelium of mice with limited Y gene contribution contained various cellular abnormalities, the total number of which was higher than in the males with an intact Y chromosome. The distribution of specific abnormality types varied among tested genotypes. The males with limited Y genes also had an increased population of testicular macrophages and internal vasculature structures. The data indicate that Y chromosome gene deficiencies in mice are associated with cellular abnormalities of the seminiferous epithelium and some changes within the testicular interstitium.