Phase 2 trial of regorafenib in recurrent or metastatic adenoid cystic carcinoma.

BACKGROUND: There is a significant need for effective therapies to treat recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). This study evaluated the multi-targeted, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) regorafenib in patients with R/M ACC. METHODS: Patients with progressive R/M ACC were treated with regorafenib until disease progression, consent withdrawal, or excessive toxicity. The primary endpoints were best overall response (BOR) and 6-month progression-free survival (PFS). Genomic and transcriptomic biomarker analyses were performed in tumors from trial participants. RESULTS: Thirty-eight patients were enrolled, including 7 (18%) patients with prior VEGFR-TKIs. No objective responses were observed. Six-month PFS was 45%, and median PFS was 7.2 months (95%CI 5.2-11.9 months). Presence of either activating NOTCH1 (22%) or KDM6A alterations (24%) was associated with decreased PFS (HR 2.6, 95%CI 1.1-6.1, p=0.03). Bulk RNA sequencing of pre-treatment tumors revealed that regorafenib clinical benefit (CB; PFS≥6 months; n=11) was associated with native enrichment of immune-related signatures. Immune deconvolution revealed a greater degree of macrophage and T-cell infiltration in CB tumors. Tumors from patients with no clinical benefit (NCB; PFS<6 months; n=9) had greater expression of signatures related to cell cycle progression (E2F targets, G2/M checkpoint). CONCLUSION: The trial failed to meet the pre-specified 6-month PFS and BOR targets. We hypothesize that TKI efficacy may be reliant upon an interplay between kinase inhibition and the ACC immune microenvironment, while programs promoting cell cycle progression may contribute to TKI resistance. These observations suggest that trials evaluating CDK4/6 inhibition plus a VEGFR-TKI should be considered.

Transoral laser microsurgery for supraglottic carcinomas: results of a prospective multicenter trial (SUPRATOL).

Background: A limited number of single institutions have published retrospective cohort studies on transoral laser microsurgery for supraglottic laryngectomy (TLM-SGL). These studies have shown that the oncologic outcomes of TLM-SGL are comparable to those of open SGL. However, there is limited information available regarding swallowing rehabilitation and quality of life (QoL). Patients and methods: SUPRATOL is a prospective, multicenter trial assessing the functional outcomes of TLM-SGL +/- adjuvant radio-(chemo)-therapy. The primary endpoint was aspiration-free swallowing at 12 months, as established using fibreoptic endoscopic evaluation of swallowing (FEES) and defined as a grade < 6 on the penetration-aspiration scale. Secondary endpoints were swallowing- and voice-related QoL, the prevalence of temporary and permanent tracheostomy and percutaneous gastrostomy, local control, laryngectomy-free survival, overall survival, and disease-free survival, as well as the influence of treatment centers on outcomes. Results: From April 2015 to February 2018, 102 patients were recruited from 26 German Otorhinolaryngology (ORL) hospitals. All patients had TLM-SGL and 96.1% underwent uni- or bilateral, mostly selective neck dissection. To 47.0% of patients, adjuvant radio-(chemo)-therapy (R(C)T) was administered. The median follow-up period was 24.1 months. At 12-month follow-up, completed by 84.3% of patients, 98.2%, 95.5%, and 98.8% were free of aspiration when tested with saliva, liquid, or pulp. Adjuvant R(C)T, pT category, and type of resection had no significant influence on swallowing rehabilitation. A total of 40.2% of patients had been tracheotomized, and in 46.1% of patients, a PEG tube was inserted. At the 24-month follow-up, 5.3% of patients still required a tracheostomy, and 8.0% continued to use a percutaneous endoscopic gastrostomy (PEG) tube. Deterioration of swallowing- and voice-related QoL was observed immediately after treatment, but patients recovered, and baseline values were reached again. The Kaplan-Meier 2-year rates for local control, laryngectomy-free survival, overall survival, and disease-free survival were 88%, 92%, 93%, and 82%, respectively. Conclusions: Our prospective multicenter trial shows that, at 12 months post-TLM-SGL +/- R(C)T, 95.5%-98.8% of patients achieved aspiration-free swallowing. Morbidity was higher than previously reported. The rates of permanent tracheostomy and gastrostomy tube placement correspond to previous cohort studies. The 2-year oncologic outcomes are within the reported range. Clinical trial registration: https://drks.de/search/en/trial/DRKS00004641, identifier (DRKS00004641).

Cutting the Gordian Knot: Rare Presentation of Nodular Fasciitis as Supraclavicular Swelling with Muscular Involvement in 68Ga-FAPI-PET/CT.

Background: Nodular fasciitis is a benign, singularly occurring nodular fibroblastic/myofibroblastic neoplasia. Due to the rapid growth and cellular atypia, this rare differential diagnosis in the head and neck region can be mistaken for malignant sarcomas. Methods: We present a 40-year-old female patient with an unclear, rough, and poorly displaceable supraclavicular swelling on the right as part of a medical check-up. Sonographically, the lump was poorly circumscribed with little vascularization. A consecutive core needle biopsy of the lesion yielded inconclusive results showing spindle-shaped tumor cells. 68Ga-FAPI-PET/CT showed an intensive uptake of the right supraclavicular lesion in addition to postoperative changes in the right tonsil. Subsequent operative partial excision of the lesion confirmed the histopathological diagnosis of nodular fasciitis. Results: Nodular fasciitis is the most prevalent pseudosarcoma found in soft tissues. This case is the first description of 68Ga-FAPI-PET/CT in nodular fasciitis. Surgical removal is advised; nevertheless, the tumor frequently diminishes on its own, and recurrence is rare. Extensive surgical therapy is not necessary. Conlcusions: The recognition of nodular fasciitis and its benign characteristics is crucial to prevent diagnostic errors and the subsequent unnecessary operative treatment of the patient.

Effects of Vitamin D on tumor cell proliferation and migration, tumor initiation and anti-tumor immune response in head and neck squamous cell carcinomas.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are among the six most common cancers, with a constantly poor prognosis. Vitamin D has been found to have antineoplastic and immunomodulatory properties in various cancers. This study investigated the impact of Vitamin D on the initiation and progression as well as antitumor immune response in HNSCCs, both in vitro and in vivo. METHODS: An immunocompetent, orthotopic oral carcinogenesis mouse model was used to examine the influence of Vitamin D3 substitution on HNSCC initiation and progression in vivo. Tumor immune infiltration was analyzed by immunohistochemistry targeting CD3, CD8, NKR-P1C, FOXP3, and CD163. Two HPV- and two HPV+ HNSCC cell lines were treated with 1,25-dihydroxyvitamin D3 to analyze effects on tumor cell proliferation, migration and transcriptomic changes using RNA-sequencing, differential gene expression and gene set enrichment analysis. RESULTS: Vitamin D3 treatment led to a significant suppression of HNSCC initiation and progression, while also stimulating tumor immune infiltration with CD3+, CD8+ and NKR-P1C+ cells and lowering levels of M2 macrophages and Treg cells in vivo. In vitro experiments showed an inhibition of HNSCC cell proliferation and migration in HPV+ and HPV- cell lines. RNA-sequencing showed significant regulations in IL6 JAK STAT3, hypoxia signaling and immunomodulatory pathways upon Vitamin D3 treatment. CONCLUSION: The findings of our study highlight the promising potential of Vitamin D in the therapeutic repertoire for HNSCC patients given its immune modulating, anti-proliferative and anti-migratory properties. Clinical transferability of those in vitro and in vivo effects should be further validated in clinical trials.

The tumor cell killing capacity of head and neck cancer patient-derived neutrophils depends on tumor stage, gender and the antibody isotype.

Neutrophils play a crucial role in the tumor microenvironment (TME) of head and neck squamous cell carcinomas (HNSCC) and significantly influence treatment outcomes. Phenotypic and functional properties of neutrophils adapt to the TME with distinct subsets modulating disease progression and therapeutic interventions. Here, we evaluated phenotypic and functional differences of neutrophils derived from HNSCC patients and healthy donors. We observed significant phenotypic differences between neutrophils from healthy donors and HNSCC patient-derived neutrophils. Gender and tumor stage influenced neutrophil phenotypes and their ability to lyse tumor cells through antibody-dependent cell-mediated cytotoxicity (ADCC). Patients with advanced HNSCC and males may benefit less from neutrophil-centered immunotherapy. An engineered IgA2 antibody specific for the epidermal growth factor receptor (EGFR) demonstrated superior efficacy in activating neutrophils for ADCC compared to Panitumumab using healthy and patient-derived neutrophils, underscoring the potential of the IgA isotype as a therapeutic alternative. The distinct behavior and antibody-isotype dependent ADCC competence of CD177+/- neutrophils of healthy but not HNSCC donors warrants further exploration. Our study emphasizes the importance of personalized immunotherapy treatments that consider the characteristics of neutrophils, patient demographics, and the type of antibody to improve ADCC and ultimately enhance treatment outcomes for HNSCC.

Immunohistochemical expression of the cation channel TRPC6 in the submandibular and lacrimal gland and in salivary gland tumors.

BACKGROUND: Canonical transient receptor potential channels play a crucial role in cancer cell proliferation. While TRPC6 subtype detection in submandibular glands and the relevance of some TRPC channels in this gland have been shown in animal models, its histological detection in human lacrimal and submandibular glands, as well as related tumors, lacks systematic study. Studying TRPC6 in humans could lead to new therapeutic options. This research aimed to immunohistochemically detect TRPC6 in human samples of physiological lacrimal and submandibular glands and of adenoid cystic carcinoma and mucoepidermoid carcinoma. METHODS: Seven fixed body donors and samples of six cancer patients were examined. The ten tissue samples collected from the submandibular and lacrimal glands were then processed into histological slides and stained with hematoxylin-eosin. Tumor samples were provided as sections. TRPC6 presence was determined by immunohistochemistry, which was performed by indirect detection with a primary TRPC6 antibody, a secondary HRP-conjugated antibody and the chromogen diaminobenzidine. RESULTS: Results confirm TRPC6 expression in all ten physiological gland samples: all samples showed a immunohistochemical signal with varying intensity. No significant gender-specific differences could be observed. TRPC6 was detected in four of six submandibular adenoid cystic carcinoma and the mucoepidermoid carcinoma samples, especially in tumor cells' cytoplasma and nuclei. Excretory ducts consistently showed TRPC6. Mucous tubules, their nuclei and the nuclei of adipocytes generally showed no signal while serous acini and their nuclei showed a weak TRPC6 signal. CONCLUSION: The discovery of TRPC6 in glandular tissue indicates a role in salivary gland function and calcium homeostasis is a basis for further research into its significance for tumor development in adenoid cystic carcinoma and mucoepidermoid carcinoma of salivary glands. TRPC6 could be used as a target for treatment of these tumors. However, the correlation between TRPC6 and submandibular and lacrimal gland diseases requires further exploration.

Widespread Distribution of Luteinizing Hormone/Choriogonadotropin Receptor in Human Juvenile Angiofibroma: Implications for a Sex-Specific Nasal Tumor.

Juvenile angiofibroma (JA) is a rare, sex-specific, and highly vascularized nasal tumor that almost exclusively affects male adolescents, but its etiology has been controversial. The G protein-coupled hormone receptor LHCGR [luteinizing hormone (LH)/choriogonadotropin (hCG) receptor] represents a promising new candidate for elucidating the underlying mechanisms of sex specificity, pubertal manifestation, and JA progression. We used highly sensitive RNAscope technology, together with immunohistochemistry, to investigate the cellular expression, localization, and distribution of LHCGR in tissue samples from JA patients. Our results provide evidence for LHCGR expression in subsets of cells throughout JA tissue sections, with the majority of LHCGR+ cells located in close vicinity to blood vessels, rendering them susceptible to endocrine LH/hCG signaling, but LHCGR+ cells were also detected in fibrocollagenous stroma. A majority of LHCGR+ cells located near the vascular lumen co-expressed the neural crest stem cell marker CD271. These results are intriguing as both LH and hCG are produced in a time- and sex-dependent manner, and are known to be capable of inducing cell proliferation and angiogenesis. Our results give rise to a new model that suggests endocrine mechanisms involving LHCGR and its ligands, together with autocrine and paracrine signaling, in JA vascularization and cell proliferation.

Engineering Dimeric EGFR-directed IgA Antibodies Reveals a Central Role of CD147 during Neutrophil-mediated Tumor Cell Killing of Head and Neck Squamous Cancer Cells.

Human IgA Abs engage neutrophils for cancer immunotherapy more effectively than IgG Abs. Previous studies demonstrated that engineering approaches improved biochemical and functional properties. In this study, we report a novel, to our knowledge, IgA2 Ab against the epidermal growth factor receptor generated by protein engineering and polymerization. The resulting molecule demonstrated a covalent linkage of L and H chains and an effective polymerization by the joining chain. The engineered dimer outperformed its monomeric variant in functional experiments on Fab-mediated modes of action and binding to the Fc receptor. The capacity to engage neutrophils for Ab-dependent cell-mediated cytotoxicity (ADCC) of adherent growing target cancer cells was cell line dependent. Although the engineered dimer displayed a long-term efficacy against the vulva carcinoma cell line A431, there was a notable in-efficacy against human papillomavirus (HPV)- head and neck squamous cell carcinoma (HNSCC) cell lines. However, the highly engineered IgA Abs triggered a neutrophil-mediated cytotoxicity against HPV+ HNSCC cell lines. Short-term ADCC efficacy correlated with the target cells' epidermal growth factor receptor expression and the ability of cancer cell-conditioned media to enhance the CD147 surface level on neutrophils. Notably, the HPV+ HNSCC cell lines demonstrated a significant increment in releasing soluble CD147 and a reduced induction of membranous CD147 on neutrophils compared with HPV- cells. Although membranous CD147 on neutrophils may impair proper IgA-Fc receptor binding, soluble CD147 enhanced the IgA-neutrophil-mediated ADCC in a dose-dependent manner. Thus, engineering IgA Abs and impedance-based ADCC assays provided valuable information regarding the target-effector cell interaction and identified CD147 as a putative critical parameter for neutrophil-mediated cytotoxicity.

Prediction of lymph node status in patients with surgically treated head and neck squamous cell carcinoma via neck lavage cytology: A pilot study.

BACKGROUND: Neck dissection is a standardized surgical procedure for patients with head and neck squamous cell carcinoma (HNSCC) and plays a critical role in the choice of adjuvant treatment based on histopathological findings. Saline irrigation is routinely performed at the end of surgery. However, this irrigant is not used for diagnostic purposes. METHODS: Intraoperative irrigation of the neck dissection wound was performed in 56 patients with HNSCC (N = 93 neck dissections), and the cytological suspension obtained was processed via the liquid-based cytology (LBC) technique, Papanicolaou staining, and immunocytochemical staining. Microscopic preparations were screened for the presence of tumor cells and classified as positive, borderline, or negative. These results were correlated with the histopathological and clinical data. RESULTS: Neck lavage LBC demonstrated high diagnostic value in detecting lymph node metastases (N+) with extracapsular spread (ECS), with a specificity, sensitivity, negative predictive value, and positive predictive value of 93.1%, 100%, 100%, and 80%, respectively. Tumor cells were detected in 4.8% of N- cases, 20% of N+ cases without ECS, and 100% of N+ cases with ECS. Receiver operating characteristic curve analysis showed an area under the curve of 0.8429 for the prediction of N+ (p < .0001) and 0.9658 for the prediction of N+ with ECS (p < .0001). CONCLUSIONS: Differential lavage cytology can provide valid and rapid information on the lymph node status in patients with HNSCC and showed an excellent correlation with histopathology. Thus, neck lavage LBC may facilitate faster and more reasonable planning of adjuvant treatment and help improve the therapeutic management of patients with HNSCC.

Auritidibacter ignavus, an Emerging Pathogen Associated with Chronic Ear Infections.

We describe detection of the previously rarely reported gram-positive bacterium Auritidibacter ignavus in 3 cases of chronic ear infections in Germany. In all 3 cases, the patients had refractory otorrhea. Although their additional symptoms varied, all patients had an ear canal stenosis and A. ignavus detected in microbiologic swab specimens. A correct identification of A. ignavus in the clinical microbiology laboratory is hampered by the inability to identify it by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Also, the bacterium might easily be overlooked because of its morphologic similarity to bacterial species of the resident skin flora. We conclude that a high index of suspicion is warranted to identify A. ignavus and that it should be particularly considered in patients with chronic external otitis who do not respond clinically to quinolone ear drop therapy.

Dual Sec62/Ki67 immunocytochemistry of liquid-based cytological preparations represents a highly valid biomarker for non-invasive detection of head and neck squamous cell carcinomas.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCC) are frequently diagnosed in advanced stages, which limits therapeutic options and results in persistently poor patient outcomes. The aim of this study was to use liquid-based swab cytology (LBC) in combination with dual immunocytochemical detection of migration and proliferation markers Sec62 and Ki67 in order to allow non-invasive early detection of HNSCC as well as to analyse the diagnostic validity of this method for predicting the malignancy of suspicious oral lesions. METHODS: 104 HNSCC patients and 28 control patients, including healthy patients (n = 17), papilloma (n = 1) and leukoplakia patients (n = 10), were included in this study. For all patients, an LBC swab followed by simultaneous immunocytochemical detection of Sec62 and Ki67 was performed. Immunocytochemical as well as cytopathological results were correlated with histological diagnoses and clinical findings. RESULTS: All HNSCC patients (100%) showed dual Sec62/Ki67 positivity, and all control patients except for the papilloma patient were negative for Sec62/Ki67 (96.4%), resulting in a 100% sensitivity and 96.4% specificity of Sec62/Ki67 dual stain for non-invasive detection of HNSCC. The positive predictive value was 99% and the negative predictive value was 100%. Sec62 expression levels showed a positive correlation with tumour de-differentiation (p = 0.0489). CONCLUSION: Simultaneous immunocytochemical detection of Sec62/Ki67 using LBC represents a promising non-invasive and easy-to-apply tool for the early detection of HNSCC in routine clinical practice. This novel technique can help to avoid incisional biopsies and reduce the frequency with which general anaesthesia is used in diagnostic procedures in patients with suspicious oral lesions.

Patterns of immune equilibrium and escape in indolent and progressing tumors.

By comparing indolent/slowly progressing with aggressive/rapidly progressing tumor types, Pandey et al. identify human evidence of immune equilibrium in indolent tumors and immune escape in progressing tumors, suggesting a link between these mechanisms and the epidemiologic phenomenon of overdiagnosis.

Prognostic impact of intra- and peritumoral immune cell subpopulations in head and neck squamous cell carcinomas - comprehensive analysis of the TCGA-HNSC cohort and immunohistochemical validation on 101 patients.

Background: Due to the expanding role of immune checkpoint inhibition in the treatment of head and neck squamous cell carcinoma, understanding immunological processes in the tumor microevironment (TME) has strong translational importance. Though analytical methods for a comprehensive analysis of the immunological TME have constantly improved and expanded over the past years the prognostic relevance of immune cell composition in head and neck cancer TME largely remains ambiguous with most studies focusing on one or a small subset of immune cells. Methods: The overall survival (OS) of the TCGA-HNSC patient cohort comprising 513 head and neck cancer patients was correlated with a total of 29 different immune metrics including a wide spectrum of immune cell subpopulations as well as immune checkpoint receptors and cytokines using RNAseq based immune deconvolution analyses. The most significant predictors of survival among these 29 immune metrics were validated on a separate HNSCC patient cohort (n=101) using immunohistochemistry: CD3, CD20+CXCR5, CD4+CXCR5, Foxp3 and CD68. Results: Overall immune infiltration irrespective of immune cell composition showed no significant correlation with the patients' overall survival in the TCGA-HNSC cohort. However, when focusing on different immune cell subpopulations, naïve B cells (p=0.0006), follicular T-helper cells (p<0.0001), macrophages (p=0.0042), regulatory T cells (p=0.0306), lymphocytes (p=0.0001), and cytotoxic T cells (p=0.0242) were identified as highly significant predictors of improved patient survival. Using immunohistochemical detection of these immune cells in a second independent validation cohort of 101 HNSCC patients, we confirmed the prognostic relevance of follicular T helper cells, cytotoxic T cells and lymphocytes. In multivariable analysis, HPV negativity and advanced UICC stages were identified as additional prognostic biomarkers associated with poor outcome. Conclusion: Our study highlights the prognostic relevance of the immunological tumor environment in head and neck cancer and demonstrates that a more detailed analysis of immune cell composition and immune cell subtypes is necessary to accurately prognosticate. We observed the highest prognostic relevance for lymphocytes, cytotoxic T cells, and follicular T helper cells, suggesting further investigations focusing on these specific immune cell subpopulations not only as predictors of patient prognosis but also as promising targets of new immunotherapeutic strategies.

[Highlights of the ASCO and ESMO annual meetings 2022: radiotherapy of head and neck cancer]. / Highlights der ASCO- und ESMO­Jahrestagungen 2022: Strahlentherapie von Kopf­Hals­Tumoren.

At the 2022 annual meetings of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO), several studies on radiation therapy for head and neck squamous cell carcinoma (HNSCC) were presented. Among the main topics were new concepts for treatment de-escalation with the goal of reducing side effects. Radiotherapy alone for nasopharyngeal carcinoma with an intermediate-risk profile was found to be noninferior to chemoradiotherapy with cisplatin while improving tolerability. In the phase II DIREKHT trial for adjuvant radiotherapy, individualized deintensification concepts of radiation dose or volume were implemented. Overall, this treatment resulted in excellent levels of locoregional control with a minimal side effects profile. In subgroup analysis, however, an increased locoregional recurrence rate was observed for tumors of the oral cavity. In 2022, as in the previous year, there was a continued focus on the role of immune checkpoint inhibitors in combination with platinum-based chemoradiotherapy in the first-line treatment of locally advanced HNSCC. In the HNSCC-15-132 trial, sequential application of the PD­1 inhibitor pembrolizumab to chemoradiotherapy was not significantly, but numerically superior to concomitant application. The phase III KEYNOTE-412 trial evaluated the efficacy of concomitant and sequential additive pembrolizumab therapy compared to additive placebo in 804 patients with locally advanced HNSCC. The observed benefit in terms of event-free survival in the pembrolizumab group marginally missed statistical significance, probably due to the particular study design. In addition, new 5­year overall survival data from the phase II trial of chemoradiotherapy in combination with the inhibitor of apoptosis proteins (IAP) antagonist xevinapant versus placebo were presented. The xevinapant group continued to demonstrate a significant survival advantage and a sustained response to treatment.

The 3q Oncogene SEC62 Predicts Response to Neoadjuvant Chemotherapy and Regulates Tumor Cell Migration in Triple Negative Breast Cancer.

In the absence of targeted treatment options, neoadjuvant chemotherapy (NACT) is applied widely for triple-negative breast cancer (TNBC). Response to NACT is an important parameter predictive of oncological outcomes (progression-free and overall survival). An approach to the evaluation of predictive markers enabling therapy individualization is the identification of tumor driver genetic mutations. This study was conducted to investigate the role of SEC62, harbored at 3q26 and identified as a driver of breast cancer pathogenesis, in TNBC. We analyzed SEC62 expression in The Cancer Genome Atlas database, and immunohistologically investigated SEC62 expression in pre- and post-NACT tissue samples from 64 patients with TNBC treated at the Department of Gynecology and Obstetrics/Saarland University Hospital/Homburg between January 2010 and December 2018 and compared the effect of SEC62 on tumor cell migration and proliferation in functional assays. SEC62 expression dynamics correlated positively with the response to NACT (p ≤ 0.01) and oncological outcomes (p ≤ 0.01). SEC62 expression stimulated tumor cell migration (p ≤ 0.01). The study findings indicate that SEC62 is overexpressed in TNBC and serves as a predictive marker for the response to NACT, a prognostic marker for oncological outcomes, and a migration-stimulating oncogene in TNBC.

Differential nasal swab cytology represents a valuable tool for therapy monitoring but not prediction of therapy response in chronic rhinosinusitis with nasal polyps treated with Dupilumab.

Introduction: Chronic Rhinosinusitis with nasal polyps (CRSwNP) is a common chronic disease with a high impact on patients' quality of life. If conservative and surgical guideline treatment cannot sufficiently control disease burden, biologicals can be considered as a comparably new treatment option that has revolutionized CRSwNP therapy since the first approval of Dupilumab in 2019. With the aim to select patients who benefit from this new treatment and to find a marker for therapy monitoring, we investigated the cellular composition of nasal mucous membranes and inflammatory cells of patients suffering from CRSwNP and undergoing Dupilumab therapy using non-invasive nasal swab cytology. Methods: Twenty CRSwNP patients with the indication for Dupilumab therapy have been included in this prospective clinical study. In total, five study visits were conducted with ambulatory nasal differential cytology using nasal swabs starting with the beginning of therapy and followed by visits every 3 months for 12 months. First, these cytology samples were stained with the May-Grunwald-Giemsa method (MGG) and the percentage of ciliated cells, mucinous cells, eosinophil cells, neutrophil cells, and lymphocytes was analyzed. Secondly, an immunocytochemical (ICC) ECP-staining was performed to detect eosinophil granulocytes. Additionally, during each study visit the nasal polyp score, SNOT20 questionnaire, olfactometry, the total IgE concentration in peripheral blood as well as the eosinophil cell count in peripheral blood were recorded. The change of parameters was evaluated over one year and the correlation between clinical effectiveness and nasal differential cytology was analyzed. Results: In both MGG (p<0.0001) and ICC analysis (p<0.001) a significant decrease of eosinophils was seen under Dupilumab treatment. When patients were divided into a Eo-low- (<21%) and Eo-high- (≥21%) group according to the percentage eosinophils in nasal swab catology in the first study visit, the Eo-high-group showed a greater change of eosinophils over time (Δ17.82) compared to the Eo-low-group (Δ10.67) but, however, no better response to therapy. The polyp score, SNOT20 questionnaire, and total IgE concentration in peripheral blood showed a significant decrease during the observation period (p<0.0001). Discussion: Nasal swab cytology as an easy-to-apply diagnostic method allows detection and quantification of the different cell populations within the nasal mucosa at a given time. The nasal differential cytology showed a significant decrease of eosinophils during Dupilumab therapy and can therefore be used as non-invasvive method for monitoring therapy success of this cost intensive therapy and potentially can allow an optimized individual therapy planning and management for CRSwNP patients. Since the validity of initial nasal swab eosinophil cell count as a predictive biomarker for therapy response was limited in our study, additional studies including larger number of participants will be necessary to further evaluate the potential benefits for clinical practice of this new diagnostic method.

Transorbital embolization of cavernous sinus dural arterio-venous malformations with surgical exposure and catheterization of the superior ophthalmic vein.

PURPOSE: Cavernous sinus dural arterio-venous malformations (dAVF) represent a pathologic connection between branches of the internal and/or external carotid artery and the cavernous sinus. Standard endovascular approaches for dAVF treatment are transvenous embolization through the inferior petrosal sinus or the facial vein and transarterial embolization. These approaches are not always successful or feasible, and alternative techniques are required. Here, we present a case series of a minimally invasive transorbital approach with surgical exposure and catheterization of the superior ophthalmic vein for transvenous fistula coiling. METHODS: 14 patients with dAVFs (Barrow Type B to D) that were treated at a tertiary care medical center over a period of 13 years were included in the study. Patients with persisting dAVF associated symptoms were selected for this approach when conventional endovascular interventions were not successful or not feasible. The surgical procedure was performed under general anaesthesia. RESULTS: A successful transorbital approach was performed in all 14 cases. In 12 of 14 patients a catheter assisted successful embolization of the fistula was performed using platinum coils with no relevant residual fistula flow. In two cases, a spontaneous thrombosis of the fistula during the surgical procedure required no further embolization. No postoperative therapy-associated complications were observed. CONCLUSION: The described approach is an effective method to embolize dAVFs in selected cases when catheter assisted transvenous and/or transarterial embolization is not successful or not feasible. In this case series we demonstrate an excellent success rate with no therapy-associated major complications.

Expression of 3q Oncogene SEC62 Predicts Survival in Head and Neck Squamous Cell Carcinoma Patients Treated with Primary Chemoradiation.

Primary chemoradiotherapy (CRT) is an established treatment option for locally advanced head and neck squamous cell carcinomas (HNSCC) usually combining intensity modified radiotherapy with concurrent platinum-based chemotherapy. Though the majority of patients can be cured with this regimen, treatment response is highly heterogeneous and can hardly be predicted. SEC62 represents a metastasis stimulating oncogene that is frequently overexpressed in various cancer entities and is associated with poor outcome. Its role in HNSCC patients undergoing CRT has not been investigated so far. A total of 127 HNSCC patients treated with primary CRT were included in this study. The median follow-up was 5.4 years. Pretherapeutic tissue samples of the primary tumors were used for immunohistochemistry targeting SEC62. SEC62 expression, clinical and histopathological parameters, as well as patient outcome, were correlated in univariate and multivariate survival analyses. High SEC62 expression correlated with a significantly shorter overall survival (p = 0.015) and advanced lymph node metastases (p = 0.024). Further significant predictors of poor overall and progression-free survival included response to therapy (RECIST1.1), nodal status, distant metastases, tobacco consumption, recurrence of disease, and UICC stage. In a multivariate Cox hazard proportional regression analysis, only SEC62 expression (p = 0.046) and response to therapy (p < 0.0001) maintained statistical significance as independent predictors of the patients' overall survival. This study identified SEC62 as an independent prognostic biomarker in HNSCC patients treated with primary CRT. The role of SEC62 as a potential therapeutic target and its interaction with radiation-induced molecular alterations in head and neck cancer cells should further be investigated.