Objectives  Pituitary carcinoma is a rare entity with fewer than 200 total cases reported in the English literature. Analysis of the population-level data from the National Cancer Database (NCDB) affords the opportunity to study this poorly understood tumor type. Methods  The NCDB was queried for site, histology, and metastasis codes corresponding to pituitary carcinoma. Statistical analyses were performed to determine factors associated with overall survival (OS). Results  A total of 92 patients with pituitary carcinoma met inclusion criteria. The 1 and 5 years of OS for all patients was 93.3% (95% confidence interval [CI]: 88.2-98.6%) and 80.0% (95% CI: 71.6-89.4%), respectively. Patients with invasive primary tumor behavior had 1 and 5 years of OS of 69.2% (95% CI: 48.2-99.5%) and 52.7% (95% CI: 31.2-89.2%), respectively. Multivariate analysis demonstrated that compared with benign primary behavior, invasive behavior had increased all-cause mortality (hazard ratio [HR], 1,296, 95% CI: 15.1- > 2,000). Surgery without adjuvant radiation or chemotherapy was the most common therapy (48.9%), followed by no treatment (40.2%). Compared with surgery alone, no treatment had worse OS (HR, 11.83, 95% CI: 1.41-99.56). Increasing age and female sex were both associated with increased mortality. Conclusions  The most common treatment for pituitary carcinoma is surgery alone followed by no surgery. Surgery alone has significantly better OS compared with no treatment. The efficacy of radiation, chemotherapy, and neurohormonal treatments needs to be examined with prospective studies.

BACKGROUND: Solitary chemosensory cells (SCCs) are rare epithelial cells enriched in nasal polyps and are the primary source of interleukin-25 (IL-25), an innate cytokine eliciting T-helper 2 (Th2) immune response. Although it is proposed that SCCs are stimulated by antigens released by upper airway pathogens, the exogenous triggers of human SCCs remain elusive. We studied patients with noninvasive fungal rhinosinusitis to determine whether extracts of Aspergillus fumigatus and Alternaria alternata stimulate SCC proliferation as an early event in type 2 inflammation. METHODS: Multicolor flow cytometry, immunofluorescence, and enzyme-linked immunoassay were used to interrogate mucosa from patients with mycetomas and allergic fungal rhinosinusitis (AFRS) for SCCs and IL-25. Primary sinonasal epithelial cells from AFRS patients and noninflamed inferior turbinates were stimulated with fungal extracts for 72 hours, and SCC population frequency as well as mitotic activity were quantified using flow cytometry. RESULTS: SCCs producing IL-25 are enriched in inflamed mucosa compared with intrapatient noninflamed control tissue (38.6% vs 6.5%, p = 0.029). In cultured sinonasal epithelial cells from AFRS nasal polyps, Aspergillus fumigatus and Alternaria alternata stimulated higher SCC frequency compared with controls (27.4% vs 10.6%, p = 0.002; 18.1% vs 10.6%, p = 0.046), which led to increased IL-25 secretion in culture media (75.5 vs 3.3 pg/mL, p < 0.001; 32.3 vs 3.3 pg/mL, p = 0.007). Ki-67 expression was higher in SCCs grown in fungal stimulation conditions compared with controls. CONCLUSION: Although fungal antigens are known to potentiate immune response through innate cytokines, including IL-25, the early expansion of SCCs in the presence of fungus has not been described. This early event in the pathogenesis of noninvasive fungal rhinosinusitis may represent a target for intervention.

Objectives  Pituitary carcinoma is a rare entity with fewer than 200 total cases reported in the English literature. Analysis of the population-level data from the National Cancer Database (NCDB) affords the opportunity to study this poorly understood tumor type. Methods  The NCDB was queried for site, histology, and metastasis codes corresponding to pituitary carcinoma. Statistical analyses were performed to determine factors associated with overall survival (OS). Results  A total of 92 patients with pituitary carcinoma met inclusion criteria. The 1 and 5 years of OS for all patients was 93.3% (95% confidence interval [CI]: 88.2-98.6%) and 80.0% (95% CI: 71.6-89.4%), respectively. Patients with invasive primary tumor behavior had 1 and 5 years of OS of 69.2% (95% CI: 48.2-99.5%) and 52.7% (95% CI: 31.2-89.2%), respectively. Multivariate analysis demonstrated that compared with benign primary behavior, invasive behavior had increased all-cause mortality (hazard ratio [HR], 1,296, 95% CI: 15.1- > 2,000). Surgery without adjuvant radiation or chemotherapy was the most common therapy (48.9%), followed by no treatment (40.2%). Compared with surgery alone, no treatment had worse OS (HR, 11.83, 95% CI: 1.41-99.56). Increasing age and female sex were both associated with increased mortality. Conclusions  The most common treatment for pituitary carcinoma is surgery alone followed by no surgery. Surgery alone has significantly better OS compared with no treatment. The efficacy of radiation, chemotherapy, and neurohormonal treatments needs to be examined with prospective studies.

Objective  Surgical resection is widely accepted as a critical component for definitive treatment of sinonasal mucosal melanoma. Systemic immunotherapy, including multiple newer agents, has been used to treat metastatic or unresectable disease. In this study, we examine its efficacy in locoregional control when used in conjunction with surgical resection for primary mucosal lesions. Design  Present study is a retrospective review of all patients at a tertiary academic medical center with primary sinonasal mucosal melanoma and distant metastatic disease. Results  A total of four patients were identified. In all cases, patients were treated with a combination of surgical resection of the primary tumor and systemic immunotherapy. Three patients were initially treated with surgery at the primary site followed by immunotherapy for distant metastases. Response to immunotherapy at the sites of primary and metastatic disease was seen in two patients. All four patients developed progression or recurrence at the primary site following initiation of immunotherapy for which they underwent surgical resection. One patient remains in follow-up without evidence of disease 20 months after initial treatment; three succumbed to the disease at 135, 37, and 16 months after initial treatment. Conclusion  Surgical resection for local control plays a critically important role in the treatment of sinonasal mucosal melanoma regardless of the presence of metastases and whether immunotherapy will be given. This case series suggests that, though immunotherapy may demonstrate efficacy in managing distant disease, surgery should remain the first-line treatment for the primary site.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is commonly characterized by type-2 inflammation. It is established that group-2 innate lymphoid cells (ILC2s) are a subset of immune cells important in orchestrating mucosal type-2 response. IL-25 is an epithelial-derived cytokine that is a critical activator of ILC2s. Recent evidence demonstrates that specialized taster epithelial cells, such as solitary chemosensory cells (SCCs), may be producers of IL-25. To elucidate the relationship between SCCs and ILC2s in CRSwNP, we sought to quantify ILC2s and SCCs to determine if these cell types are enriched in nasal polyps compared to healthy sinonasal mucosa. METHODS: We quantified SCCs and ILC2s using multicolor flow cytometry in nasal polyps and non-inflamed turbinate mucosa from seven patients and investigated the role of IL-13 and dexamethasone on SCC frequency using tissue explants of nasal polyps and turbinate mucosa. RESULTS: SCCs were found to be the primary source of IL-25. Nasal polyps demonstrated higher populations of SCCs (33.0% vs 5.6%, p < 0.001) and ILC2s (2.40% vs 0.19%, p = 0.008) compared to patient-matched nonpolypoid turbinates. In cultured polyp explants, exogenous IL-13 increased the proportion of epithelial SCCs (40.2% IL-13 condition vs 28.9% untreated, p = 0.012), and this effect was reversed by addition of dexamethasone (40.2% vs 8.9%, p < 0.0005). CONCLUSION: These data support SCC and ILC2 expansion as well as increased IL-25 production in nasal polyps and may represent early events in the pathogenesis of CRSwNP. IL-13 stimulates proliferation of SCC in a feed-forward loop, a process that is steroid-sensitive.

Background  Sinonasal adenocarcinoma (SNAC) is a rare malignancy arising from mucus-secreting glandular tissue. Limited large-scale studies are available due to its rarity. We evaluated SNAC in the National Cancer Database (NCDB), a source that affords multi-institutional, population studies of rare cancers and their outcomes. Methods  The NCDB was queried for adenocarcinoma in the sinonasal tract. Multivariate analyses were performed to evaluate for factors contributing to overall survival (OS). Results  A total of 553 patients were identified. The cohort was composed of 59.3% males. The nasal cavity was the most common primary site, representing 44.1% of cases. About 5.7% of patients presented with nodal disease, while 3.3% had distant metastases. About 40.6% of cases presented with stage IV disease. About 73.5% of patients underwent surgery, 54.2% received radiation therapy, and 27.7% had chemotherapy. Median OS was 71.7 months, while OS at 1, 2, and 5 years was 82, 73.0, and 52%, respectively. On multivariate analysis, advanced age (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 1.02-1.05), Charlson-Deyo score of 1 (HR: 1.99; 95% CI: 1.20-3.30), advanced tumor grade (HR: 2.73; 95% CI: 1.39-5.34), and advanced tumor stage (HR: 2.71; 95% CI: 1.33-5.50) were associated with worse OS, whereas surgery (HR: 0.34; 95% CI: 0.20-0.60) and radiation therapy (HR: 0.55; 95% CI: 0.33-0.91), but not chemotherapy (HR: 1.16; 95% CI: 0.66-2.05), predicted improved OS. Conclusions  SNAC is a rare malignancy with 5-year survival approximating 50%. Surgery and radiation therapy, but not chemotherapy, are associated with improved survival, and likely play a critical role in the interdisciplinary management of SNAC.

Aim: Recovery of damaged mucosal surfaces following inflammatory insult requires diverse regenerative mechanisms that remain poorly defined. Previously, we demonstrated that the reparative actions of Trefoil Factor 3 (TFF3) depend upon the enigmatic receptor, leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2 (LINGO2). This study examined the related orphan receptor LINGO3 in the context of intestinal tissue damage to determine whether LINGO family members are generally important for mucosal wound healing and maintenance of the intestinal stem cell (ISC) compartment needed for turnover of mucosal epithelium.Methods and Results: We find that LINGO3 is broadly expressed on human enterocytes and sparsely on discrete cells within the crypt niche, that contains ISCs. Loss of function studies indicate that LINGO3 is involved in recovery of normal intestinal architecture following dextran sodium sulfate (DSS)-induced colitis, and that LINGO3 is needed for therapeutic action of the long acting TFF2 fusion protein (TFF2-Fc), including a number of signaling pathways critical for cell proliferation and wound repair. LINGO3-TFF2 protein-protein interactions were relatively weak however and LINGO3 was only partially responsible for TFF2 induced MAPK signaling suggesting additional un-identified components of a receptor complex. However, deficiency in either TFF2 or LINGO3 abrogated budding/growth of intestinal organoids and reduced expression of the intestinal ISC gene leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), indicating homologous roles for these proteins in tissue regeneration, possibly via regulation of ISCs in the crypt niche.Conclusion: We propose that LINGO3 serves a previously unappreciated role in promoting mucosal wound healing.

Background

Solitary chemosensory cells (SCCs) are rare epithelial cells enriched in nasal polyps and are the primary source of interleukin-25 (IL-25), an innate cytokine eliciting T-helper 2 (Th2) immune response. Although it is proposed that SCCs are stimulated by antigens released by upper airway pathogens, the exogenous triggers of human SCCs remain elusive. We studied patients with noninvasive fungal rhinosinusitis to determine whether extracts of Aspergillus fumigatus and Alternaria alternata stimulate SCC proliferation as an early event in type 2 inflammation.

Methods

Multicolor flow cytometry, immunofluorescence, and enzyme-linked immunoassay were used to interrogate mucosa from patients with mycetomas and allergic fungal rhinosinusitis (AFRS) for SCCs and IL-25. Primary sinonasal epithelial cells from AFRS patients and noninflamed inferior turbinates were stimulated with fungal extracts for 72 hours, and SCC population frequency as well as mitotic activity were quantified using flow cytometry.

Results

SCCs producing IL-25 are enriched in inflamed mucosa compared with intrapatient noninflamed control tissue (38.6% vs 6.5%, p = 0.029). In cultured sinonasal epithelial cells from AFRS nasal polyps, Aspergillus fumigatus and Alternaria alternata stimulated higher SCC frequency compared with controls (27.4% vs 10.6%, p = 0.002; 18.1% vs 10.6%, p = 0.046), which led to increased IL-25 secretion in culture media (75.5 vs 3.3 pg/mL, p < 0.001; 32.3 vs 3.3 pg/mL, p = 0.007). Ki-67 expression was higher in SCCs grown in fungal stimulation conditions compared with controls.

Conclusion

Although fungal antigens are known to potentiate immune response through innate cytokines, including IL-25, the early expansion of SCCs in the presence of fungus has not been described. This early event in the pathogenesis of noninvasive fungal rhinosinusitis may represent a target for intervention.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is commonly characterized by type-2 inflammation. It is established that group-2 innate lymphoid cells (ILC2s) are a subset of immune cells important in orchestrating mucosal type-2 response. IL-25 is an epithelial-derived cytokine that is a critical activator of ILC2s. Recent evidence demonstrates that specialized taster epithelial cells, such as solitary chemosensory cells (SCCs), may be producers of IL-25. To elucidate the relationship between SCCs and ILC2s in CRSwNP, we sought to quantify ILC2s and SCCs to determine if these cell types are enriched in nasal polyps compared to healthy sinonasal mucosa. We quantified SCCs and ILC2s using multicolor flow cytometry in nasal polyps and non-inflamed turbinate mucosa from seven patients and investigated the role of IL-13 and dexamethasone on SCC frequency using tissue explants of nasal polyps and turbinate mucosa. SCCs were found to be the primary source of IL-25. Nasal polyps demonstrated higher populations of SCCs (33.0% vs 5.6%, p < 0.001) and ILC2s (2.40% vs 0.19%, p = 0.008) compared to patient-matched nonpolypoid turbinates. In cultured polyp explants, exogenous IL-13 increased the proportion of epithelial SCCs (40.2% IL-13 condition vs 28.9% untreated, p = 0.012), and this effect was reversed by addition of dexamethasone (40.2% vs 8.9%, p < 0.0005). These data support SCC and ILC2 expansion as well as increased IL-25 production in nasal polyps and may represent early events in the pathogenesis of CRSwNP. IL-13 stimulates proliferation of SCC in a feed-forward loop, a process that is steroid-sensitive.