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Objective Primary repair of posteriorly located anterior skull base (ASB) dural defects following cranial trauma is made difficult by narrow operative corridors and adherent dura mater. Inadequate closure may result in continued cerebrospinal fluid (CSF) leak and infectious sequelae. Here, we report surgical outcomes following the use of nonpenetrating titanium microclips as an adjunctive repair technique in traumatic anterior skull base dural defects extending from the olfactory groove to the tuberculum sellae. Methods All trauma patients who underwent a bifrontal craniotomy from January 2013 to October 2019 were retrospectively reviewed. Patients with ASB defects located at posterior to the olfactory groove were analyzed. Patients with isolated frontal sinus fractures were excluded. All patients presented with CSF leak or radiographic signs of dural compromise. Patients were divided according to posterior extent of injury. Patient characteristics, imaging, surgical technique, and outcomes are reported. Results A total of 19 patients who underwent a bifrontal craniotomy for repair of posteriorly located ASB dural defects using nonpenetrating titanium microclips were included. Defects were divided by location: olfactory groove (10/19), planum sphenoidale (6/19), and tuberculum sellae (3/19). No patients demonstrated a postoperative CSF leak. No complications related to the microclip technique was observed. Clip artifact did not compromise postoperative imaging interpretation. Conclusion Primary repair of posteriorly located ASB dural defects is challenging due to narrow working angles and thin dura mater. Use of nonpenetrating titanium microclips for primary repair of posteriorly located dural defects is a reasonable adjunctive repair technique and was associated with no postoperative CSF leaks in this cohort.

Background Orbital cavernous hemangiomas (OCH) are the most common adult orbital tumor and represent an ideal index lesion for endonasal orbital tumor surgery. In order to standardize outcomes reporting, an anatomic-based staging system was developed. Methods An international, multidisciplinary panel of 23 experts in orbital tumor surgery was formed. A modified Delphi method was used to develop the cavernous hemangioma exclusively endonasal resection (CHEER) staging system with a total of 2 rounds being completed. Results Tumors medial to a plane along the long axis of the optic nerve may be considered amenable for an exclusively endonasal resection. In select cases, tumors may extend inferolaterally if the tumor remains below a plane from the contralateral naris through the long axis of the optic nerve (ie, plane of resectability [POR]). This definition reached consensus with 91.3% of panelists in agreement. Five stages were designed based on increasing technical resection difficulty and potential for morbidity. Stages were based on the relationship of the tumor to the extraocular muscles, the inferomedial muscular trunk of the ophthalmic artery (IMT), and orbital foramina. Staging by anatomic location also reached consensus with 87.0% of panelists in agreement. Size was not included in the staging system due to the lack of agreement on the contribution of size to resection difficulty. Conclusion Endoscopic orbital tumor surgery is a nascent field with a growing, yet heterogeneous, body of literature. The CHEER staging system is designed to facilitate international, high-quality, standardized studies establishing the safety, efficacy, and outcomes of endonasal resection of OCH.

Background: Basilar invagination (BI) is a complex condition characterized by prolapse of the odontoid into the brain stem/upper cervical cord. This lesion is often associated with Chiari malformations, and rheumatoid arthritis (RA). Treatment options for BI typically include cervical traction, an isolated anterior transoral odontoidectomy, anterior endonasal odontoidectomy, an isolated posterior fusion, or combined anterior/ posterior surgical approach. Case Description: A 45-year-old female with a Chiari I malformation and RA underwent a combined posterior C0-C5 posterior decompression/fusion, followed by an anterior odontoidectomy (i.e. endoscopic/endonasal under neuronavigation). Postoperatively, the patient’s symptoms and neurological signs resolved. Conclusion: BI in was successfully managed with a combined posterior C0-C5 decompression/fusion followed by an anterior endoscopic/endonasal odontoidectomy performed under neuronavigation.

Severe anterior septal deviation and resultant nasal obstruction represent a difficult surgical task to correct. The goal of surgery is to straighten the anterior dorsal and caudal struts, while maintaining nasal tip and midvault support. This study presents a novel extracorporeal septoplasty technique to straighten the crooked anterior septum.To describe the novel anterior septal transplant technique, which consists of complete resection of the caudal septum and reconstruction with extended spreader grafts and a columellar strut, without a separate caudal septal replacement graft.This study was a retrospective case series at a tertiary academic referral center. Participants were sequential adult patients undergoing anterior septal transplant from January 1, 2008, to December 31, 2015.Patient-reported nasal obstruction using Nasal Obstruction Symptom Evaluation (NOSE) scores and objective photographic analysis. Nasal tip deviation, projection, and rotation were measured. Preoperative and postoperative outcomes were compared. Complications are reported.Seventy-one patients (mean age, 46 years [age range, 16-72 years]; 48 [67.6%] female and 23 [32.4%] male) were included in the case series. Postoperative NOSE scores (mean [SD], 24.00 [24.58]) were significantly better than preoperative NOSE scores (mean [SD], 72.25 [14.55]) (P .001). A separate cohort of 32 patients (mean age, 42 years [age range, 13-72 years]; 23 [71.9%] female and 9 [28.1%] male) had photographs available for analysis. In the frontal view, nasal deviation improved from a mean (SD) of 2.9 (2.0) degrees before surgery to a mean (SD) of 1.4 (1.7) degrees after surgery (P = .004). In the base view, the deviation was corrected from a mean (SD) of 4.9 (2.8) degrees to a mean (SD) of 1.7 (1.2) degrees (P .001). Tip rotation and projection were unchanged after surgery. Four patients had mild dorsal irregularities after surgery.Anterior septal transplant by the described technique is a safe and effective treatment option for severe anterior septal deviation.4.

Background & Aims Intestinal epithelial homeostasis is maintained by active-cycling and slow-cycling stem cells confined within an instructive crypt-based niche. Exquisite regulating of these stem cell populations along the proliferation-to-differentiation axis maintains a homeostatic balance to prevent hyperproliferation and cancer. Although recent studies focus on how secreted ligands from mesenchymal and epithelial populations regulate intestinal stem cells (ISCs), it remains unclear what role cell adhesion plays in shaping the regulatory niche. Previously we have shown that the cell adhesion molecule and cancer stem cell marker, CD166/ALCAM (activated leukocyte cell adhesion molecule), is highly expressed by both active-cycling Lgr5+ ISCs and adjacent Paneth cells within the crypt base, supporting the hypothesis that CD166 functions to mediate ISC maintenance and signal coordination. Methods Here we tested this hypothesis by analyzing a CD166–/– mouse combined with immunohistochemical, flow cytometry, gene expression, and enteroid culture. Results We found that animals lacking CD166 expression harbored fewer active-cycling Lgr5+ ISCs. Homeostasis was maintained by expansion of the transit-amplifying compartment and not by slow-cycling Bmi1+ ISC stimulation. Loss of active-cycling ISCs was coupled with deregulated Paneth cell homeostasis, manifested as increased numbers of immature Paneth progenitors due to decreased terminal differentiation, linked to defective Wnt signaling. CD166–/– Paneth cells expressed reduced Wnt3 ligand expression and depleted nuclear β-catenin. Conclusions These data support a function for CD166 as an important cell adhesion molecule that shapes the signaling microenvironment by mediating ISC–niche cell interactions. Furthermore, loss of CD166 expression results in decreased ISC and Paneth cell homeostasis and an altered Wnt microenvironment., Graphical abstract

Here we describe a multiplexed immunohistochemical platform, with computational image processing workflows including image cytometry, enabling simultaneous evaluation of 12 biomarkers in one formalin-fixed paraffin-embedded tissue section. To validate this platform, we used tissue microarrays containing 38 archival head and neck squamous cell carcinomas, and revealed differential immune profiles based on lymphoid and myeloid cell densities, correlating with human papilloma virus status and prognosis. Based on these results, we investigated 24 pancreatic ductal adenocarcinomas from patients who received neoadjuvant GVAX vaccination, and revealed that response to therapy correlated with degree of mono-myelocytic cell density, and percentages of CD8+ T cells expressing T cell exhaustion markers. These data highlight the utility of in situ immune monitoring for patient stratification, and provide digital image processing pipelines (https://github.com/multiplexIHC/cppipe) to the community for examining immune complexity in precious tissue sections, where phenotype and tissue architecture are preserved to thus improve biomarker discovery and assessment.

Background Lymphomas of the sinonasal tract are a rare and heterogeneous subset of solid sinonasal neoplasms. Objective To characterize, in this case series, presenting symptoms, treatment modalities, and outcomes for patients with sinonasal lymphoma within a single institution. Methods Retrospective patient data were collected from an academic, oncologic center and entered into a repository designed to capture outcomes for sinonasal malignancies. Patient demographics, presenting symptoms, imaging findings, treatment modalities, and health status were retrospectively extrapolated and evaluated by using Kaplan-Meier estimations for survival probability. Results Patients with sinonasal lymphoma with a mean follow-up of 50 months were identified (n = 18). Histologic diagnosis included the following: diffuse large B-cell lymphoma (n = 9), natural killer/T-cell lymphoma (n = 5), follicular lymphoma (n = 1), T-cell lymphoma (n = 1), and lymphoma-not otherwise specified (n = 2). The most frequent presenting symptoms were nasal obstruction (78%), facial pain (72%), facial swelling (50%), and nasal discharge (44%). Treatment before lymphoma diagnosis included antibiotics (83%), oral steroids (22%), decongestants (22%), and topical steroids (11%). Treatment regimens after diagnosis included both chemotherapy (94%) and chemoradiotherapy (56%). Survival rates by lymphoma subtype were 56% for B-cell lymphoma and 40% for natural killer/T-cell lymphoma. Overall, 2- and 5-year survival rates were 67% and 50%, respectively. The combination of chemotherapy and radiation resulted in significantly higher survival rates (p ≤ 0.001) than chemotherapy alone. Conclusion Sinonasal lymphomas are characterized by meager survival rates, which differ by histopathologic subtype. The diagnosis of sinonasal lymphoma is challenging because symptoms frequently parallel those of chronic rhinosinusitis. Increased awareness of these rare malignancies may improve detection and more timely treatment. Clinical trial registration NCT01332136.

As cell-cell interactions among tumor and immune cells are known to contribute to tumor progression, in depth evaluation of tumor-immune heterogeneity will enable biomarker-guided patient stratification and improvement of treatment response. Here we examined head and neck squamous cell carcinomas (HNSCC) to reveal the prognostic significance of leukocytes in tumors with regards to their complexity, effector status and spatial characteristics via multiplex immunohistochemistry and image cytometry. To accomplish this, we examined oropharyngeal HNSCC (N = 38), where lymphoid, myeloid, and hypo-inflamed leukocyte complexity correlated with HPV-status (Tsujikawa et al. Cell Reports, 2017). In the present study, quantitative analysis of cell density and distribution of 14-distinct immune cell lineages (e.g., CD8+ T cells, regulatory T cells, Th1, Th2, Th17, Th0 lymphocytes, B cells, NK cells, CD163+ and CD163- macrophages, mature and immature dendritic cells, mast cells, granulocytes) was analyzed via immune cell density mapping and tissue segmentation algorithms. We revealed tropism of polarized Th1-type cells within tumor nests versus stroma in HPV-associated HNSCC. In addition, Cox regression analysis of cell density and distribution of the 14 immune populations revealed that CD66b+ granulocyte infiltration within tumor nests reflected a negative prognostic indicator for HNSCC outcome. Furthermore, cell-cell proximity analysis in HPV-associated HNSCC further revealed a correlation between PD-L1 positive immune cells, and micro-regionally polarized immune characteristics biased towards Th1, coincident with high density of CD8+ T cells. These results reveal intra-tumor immune heterogeneity is associated with micro-regional immune complexity profiles, and provide insight into in situ immune characteristics that may aid patient stratification for immune therapy going forward. Acknowledgement: This project was supported by the Japan Society for the Promotion of Science Grant-in-Aid for Young Scientists (Start-up, 17H07016), Oregon Clinical and Translational Research Institute (OCTRI), grant number (UL1TR000128) from the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH), and P30 CA069533-17 OHSU Knight Cancer Institute. LMC acknowledges support from the NIH/NCI, DOD BCRP Era of Hope Scholar Expansion Award, Susan G. Komen Foundation, Stand Up To Cancer - Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant, Breast Cancer Research Foundation, and the Brenden-Colson Center for Pancreatic Health. Citation Format: Takahiro Tsujikawa, Guillaume Thibault, Young Hwan Chang, Edward El Rassi, Daniel R. Clayburgh, David Sauer, Akihito Arai, Molly F. Kulesz-Martin, Motomi Mori, Shigeru Hirano, Paul W. Flint, Lisa M. Coussens. Intra-tumor immune heterogeneity is associated with prognosis of oropharyngeal head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 220.

Immunoglobulin G4-related disease (IgG4-RD) is an emerging clinicopathologic entity characterized by both IgG4+ plasma cell infiltration and fibrosis in one or more organs, prototypically pancreas or salivary/lacrimal glands. IgG4-RD in the thyroid (IgG4-RTD) is an area of active study, and the relationship between IgG4-RTD and Hashimoto thyroiditis is not fully delineated due to their overlapping histologic features. Retrospective review was performed of all thyroidectomy cases demonstrating lymphocytic inflammation at a single institution over a 4-year period. Approximately half (23/38) of patients had a clinical diagnosis of Hashimoto thyroiditis (HT). Nine of the 38 patients had increased absolute and relative numbers of IgG4+ plasma cells. Patients with a clinical diagnosis of HT had increased lymphoplasmacytic inflammation, but the relative proportion of IgG4+ plasma cells was not increased compared to patients without HT. There was no correlation between IgG4 levels and the amount of fibrosis in patients with or without HT. Patients identified as having the fibrosing variant of HT were not more likely to have increased levels of IgG4+ plasma cells than those without. There is significant morphologic and immunohistochemical overlap between HT and IgG4-RTD. Future studies to identify specific characteristics of IgG4-RTD involving the thyroid are necessary to accurately define this entity.

Introduction. Head and neck squamous cell carcinomas (HNSCCs) account for nearly 600,000 deaths worldwide annually and have limited treatment options. Approximately 20% of HNSCCs harbor amplifications of fibroblast growth factor receptor 1 (FGFR1) on chromosome 8p, however FGFR1 amplification by itself does not predict clinical response to FGFR inhibitors. We hypothesized that FGF2, or basic FGF, ligand expression is a better marker of FGFR activation and predictor of response to FGFR inhibitors. Results. A tissue micro array (TMA) of HNSCC patient biopsies was stained and quantitated for FGF2 expression by Aperio ImageScope software. FGF2 was significantly increased in recurrent tissue samples (p = 0.04). We examined a number of immortalized HNSCC cell lines and found that overexpression of both FGF2 and FGFR1 predicted response to the selective FGFR inhibitor PD173074. FGFR inhibition did not cause apoptosis, but rather induced a G0/G1 arrest and growth inhibition. FGFR inhibition also induced a change in cell morphology, with a significant increase in cell size and adherence. The expression of epithelial-to-mesenchymal transition (EMT) proteins was examined and FGF2-FGFR1 activation was associated with a more mesenchymal phenotype. Accordingly, FGFR inhibition reversed invasiveness as measured using the Incucyte WoundMaker scratch assay, suggesting that HNSCCs with FGF2-FGFR1 activation have more metastatic potential. Invasiveness of these cells in vivo was confirmed using orthotopic injection into the buccal pad of NSG mice. Once primary tumors reached 0.8 cm in size, mice were sacrificed and buccal mucosa, lung, liver, and neck tissue were examined post-mortem. All of the injected animals developed local invasion, and distant metastases in the lungs. 5/7 mice also had metastases in the liver and this model is being used to test the ability of FGFR inhibition to prevent metastasis. The mechanism of autocrine FGF2-FGFR1 activation was further explored and FGF2 was found to be secreted in association with extracellular vesicles (ECVs). Interestingly, inhibition of FGFR reduced secretion of ECVs and FGF2, providing a novel approach to target autocrine and paracrine FGFR1 activation within the tumor. We further tested a number of small molecule inhibitors in combination with PD173074 to look for synergistic combinations of kinase inhibitors and found significant synergy between EGFR and FGFR inhibitors suggesting this combination may be most effective in patients with HNSCC. Conclusions. Increased FGF2 in HNSCC patient samples is correlated with recurrent disease. FGF2-FGFR1 activation increases invasiveness through activation of EMT genes both in vitro, and in an orthotopic model. Inhibition of FGF2-FGFR1 reversed the invasive phenotype in vitro and may be an effective therapeutic strategy to reduce metastases in HNSCC patients. Citation Format: Isabel A. English, Jacqueline Martinez, Edward El Rassi, Mark Schmidt, Ellen Langer, Sophia Bornstein, John Gleysteen, Melissa Wong, Brian Druker, Elie Traer. FGF2 activation of FGFR1 in head and neck squamous cell carcinoma is associated with more invasive disease and can be attenuated by FGFR inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1631.