Augmentation of tumor expression of HLA-DR, CXCL9, and CXCL10 may improve olfactory neuroblastoma immunotherapeutic responses.

BACKGROUND: Olfactory neuroblastoma is a rare malignancy of the anterior skull base typically treated with surgery and adjuvant radiation. Although outcomes are fair for low-grade disease, patients with high-grade, recurrent, or metastatic disease oftentimes respond poorly to standard treatment methods. We hypothesized that an in-depth evaluation of the olfactory neuroblastoma tumor immune microenvironment would identify mechanisms of immune evasion in high-grade olfactory neuroblastoma as well as rational targetable mechanisms for future translational immunotherapeutic approaches. METHODS: Multispectral immunofluorescence and RNAScope evaluation of the tumor immune microenvironment was performed on forty-seven clinically annotated olfactory neuroblastoma samples. A retrospective chart review was performed and clinical correlations assessed. RESULTS: A significant T cell infiltration was noted in olfactory neuroblastoma samples with a stromal predilection, presence of myeloid-derived suppressor cells, and sparse natural killer cells. A striking decrease was observed in MHC-I expression in high-grade olfactory neuroblastoma compared to low-grade disease, representing a mechanism of immune evasion in high-grade disease. Mechanistically, the immune effector stromal predilection appears driven by low tumor cell MHC class II (HLA-DR), CXCL9, and CXCL10 expression as those tumors with increased tumor cell expression of each of these mediators correlated with significant increases in T cell infiltration. CONCLUSION: These data suggest that immunotherapeutic strategies that augment tumor cell expression of MHC class II, CXCL9, and CXCL10 may improve parenchymal trafficking of immune effector cells in olfactory neuroblastoma and augment immunotherapeutic responses.

Translocations and Gene Fusions in Sinonasal Malignancies.

PURPOSE OF REVIEW: During the past few years there has been an expansion in our understanding of gene fusions and translocations involved in cancer of the sinonasal tract. Here we review the downstream biologic effects, clinical characteristics, and pathologic features of these tumors. The molecular consequences and neo-antigens resulting from these chromosomal aberrations are considered and targets for current and future clinical trials discussed. RECENT FINDINGS: Several new, clinically relevant, chromosomal aberrations have been discovered and evaluated to varying degrees in sinonasal tumors including DEK::AFF2, BRD4::NUT, ADCK4::NUMBL, and ETV6::NTRK3. Sinonasal malignancies demonstrate a diverse genetic landscape and varying clinical courses. Recent studies illustrate that gene fusions and translocations may play a role in carcinogenesis in certain sinonasal tumor subtypes and may be used to develop new biomarker-driven and patient-centered treatments.

Elevated bone marrow sympathetic drive precedes systemic inflammation in angiotensin II hypertension.

Increased sympathetic nervous system activity is a hallmark of hypertension (HTN), and it is implicated in altered immune system responses in its pathophysiology. However, the precise mechanisms of neural-immune interaction in HTN remain elusive. We have previously shown an association between elevated sympathetic drive to the bone marrow (BM) and activated BM immune cells in rodent models of HTN. Moreover, microglial-dependent neuroinflammation is also seen in rodent models of HTN. However, the cause-effect relationship between central and systemic inflammatory responses and the sympathetic drive remains unknown. These observations led us to hypothesize that increase in the femoral BM sympathetic nerve activity (fSNA) initiates a cascade of events leading to increase in blood pressure (BP). Here, we investigated the temporal relationship between the BM sympathetic drive, activation of the central and peripheral immune system, and increase in BP in the events leading to established HTN. The present study demonstrates that central infusion of angiotensin II (ANG II) induces early microglial activation in the paraventricular nucleus of hypothalamus, which preceded increase in the fSNA. In turn, activation of fSNA correlated with the timing of increased production and release of CD4+.IL17+ T cells and other proinflammatory cells into circulation and elevation in BP, whereas infiltration of CD4+ cells to the paraventricular nucleus marked establishment of ANG II HTN. This study identifies cellular and molecular mechanisms involved in neural-immune interactions in early and established stages of rodent ANG II HTN. NEW & NOTEWORTHY Early microglia activation in paraventricular nucleus precedes sympathetic activation of the bone marrow. This leads to increased bone marrow immune cells and their release into circulation and an increase in blood pressure. Infiltration of CD4+ T cells into paraventricular nucleus paraventricular nucleus marks late hypertension.

Binocular microscopes versus exoscopes: Experiences and performance in simulated otologic surgery.

Objectives: Exoscopes represent a promising alternative to conventional binocular microscopes (OM) in otology offering potential advantages such as enhanced ergonomics and a more compact device design. While previous research has demonstrated the effectiveness of exoscopes in various surgical specialties, their objective assessment in the field of otology remains limited. Therefore, this investigation aims to assess task-based efficiency associated with exoscopes in the field of otology by use of simulated surgical models. Methods: A prospective cross-over study design was used to compare an OM to an exoscope in otolaryngology residents and medical students. Participants performed five tasks on 3D-printed ear models using both the exoscope and OM. Data collection included completion time, frequency of predefined errors, mental effort, and user experience. Subgroup analysis was performed based on level of experience. Results: Fourteen students and fifteen residents participated. Participants completed four of five tasks faster with the OM and there was no difference in number of errors committed. When separated by surgical experience, residents performed four of five tasks faster using the OM while students completed one of five tasks faster with the OM. Students committed more errors with the exoscope for one task with no difference in errors for residents. There was no difference in perceived difficulty performing tasks with either visualization system. Exit survey results showed more favorable opinions of the OM among residents and more favorable opinions of the exoscope among students. Conclusions: The exoscope permits successful performance in simulated otologic tasks. Task performance and user experience between operative microscopes and exoscopes differ based on level of surgical experience. Level of Evidence: 2.

Indications and outcomes for elective dissection of level V in primary parotid cancer.

BACKGROUND: The extent of cervical lymphadenectomy required for primary parotid cancer is not well-established. METHODS: In this retrospective case-control study, 84 patients who underwent primary parotidectomy and neck dissection for primary parotid cancer between 2010 and 2019 were identified and analyzed. RESULTS: Of the 84 patients, 37 underwent elective level V neck dissection. All six (16.0%) who had occult level V nodes had clinically evident, preoperative anterior cervical metastases, a statistically significant finding. No other clinical factors are correlated with posterior neck involvement. There was no significant difference in disease-free or overall survival for patients with occult level V disease relative to positive lymph nodes in other levels. CONCLUSIONS: Patients with clinically evident anterolateral cervical lymphatic metastases from parotid cancer preoperatively have high rates of occult level V nodes. Level V neck dissection can be avoided in cN0 patients and offered no survival advantage.

Impaired butyrate absorption in the proximal colon, low serum butyrate and diminished central effects of butyrate on blood pressure in spontaneously hypertensive rats.

AIM: Butyrate is a major gut microbiota-derived metabolite. Reduced butyrate-producing bacteria has been reported in the spontaneously hypertensive rat (SHR), a model of hypertension characterized by dysfunctional autonomic nervous system and gut dysbiosis. Here, we demonstrate a potential mechanism for butyrate in blood pressure regulation. METHODS: High-performance liquid chromatography and liquid chromatography-mass spectrometry were performed to measure butyrate levels in feces and serum. Ussing chamber determined butyrate transport in colon ex vivo. Real-time PCR and immunohistochemistry evaluated expression of butyrate transporter, Slc5a8, in the colon. Mean arterial blood pressure was measured in catheterized anesthetized rats before and after a single butyrate intracerebroventricular injection. Activity of cardioregulatory brain regions was determined by functional magnetic resonance imaging to derive neural effects of butyrate. RESULTS: In the SHR, we demonstrated elevated butyrate levels in cecal content, but diminished butyrate levels in circulation, possibly due to reduced expression of Slc5a8 transporter in the colon. In addition, we observed lower expression levels of butyrate-sensing receptors in the hypothalamus of SHR, likely leading to the reduced effects of centrally administered butyrate on blood pressure in the SHR. Functional magnetic resonance imaging revealed reduced activation of cardioregulatory brain regions following central administration of butyrate in the SHR compared to control. CONCLUSION: We demonstrated a reduced availability of serum butyrate in the SHR, possibly due to diminished colonic absorption. Reduced expression of butyrate-sensing receptors in the SHR hypothalamus may explain the reduced central responsiveness to butyrate, indicating microbial butyrate may play a role in blood pressure regulation.

Increased Abundance of Lactobacillales in the Colon of Beta-Adrenergic Receptor Knock Out Mouse Is Associated With Increased Gut Bacterial Production of Short Chain Fatty Acids and Reduced IL17 Expression in Circulating CD4+ Immune Cells.

Emerging evidence suggests an associative link between gut dysbiosis, the autonomic nervous system (ANS) and the immune system in pathophysiology of neurogenic hypertension (HTN). However, the close interplay between these three systems presents us with difficulties in deciphering the cause-effect relationship in disease. The present study utilized beta 1 and 2 adrenergic receptor knock out (AdrB1tm1BkkAdrB2tm1Bkk/J KO) mice to isolate the effects of reduced overall sympathetic drive on gut microbiota and systemic immune system. We observed the following: (i) Diminished beta adrenergic signaling mainly reflects in shifts in the Firmicutes phyla, with a significant increase in abundance of largely beneficial Bacilli Lactobacillales in the KO mice; (ii) This was associated with increased colonic production of beneficial short chain fatty acids (SCFAs) butyrate, acetate and propionate, confirming functional microbiota shifts in the KO mice; (iii) Dampened systemic immune responses in the KO mice reflected in reduction on circulating CD4+.IL17+ T cells and increase in young neutrophils, both previously associated with shifts in the gut microbiota. Taken together, these observations demonstrate that reduced expression of beta adrenergic receptors may lead to beneficial shifts in the gut microbiota and dampened systemic immune responses. Considering the role of both in hypertension, this suggests that dietary intervention may be a viable option for manipulation of blood pressure via correcting gut dysbiosis.