Choice of surgery in intestinal-type adenocarcinoma of the sinonasal tract: a long-term comparative study.

PURPOSE: Intestinal-type adenocarcinoma (ITAC) is a rare sinonasal malignancy. Curative treatment requires multidisciplinary approach, with surgical options consist of the endonasal endoscopic approach (EEA) and external surgery (EXTS). Here, we provide the post-operative and survival results from a single-center long-term follow-up. METHODS: We report long-term follow-up of 92 ITAC cases treated between 1998 and 2018, treated with EEA (n = 40) or EXTS (n = 52). Survival estimates, post-operative complications and duration of hospitalization were compared between surgical modalities. RESULTS: Baseline characteristics were similar. A higher number of T4b tumors (16%), and subsequently more tumoral invasion (39%), was present in patients undergoing EXTS compared to EEA (3% and 18%, respectively). No difference in Barnes histology subtypes was noticed. Patients undergoing EEA had a shorter post-operative hospitalization stay versus EXTS (4 versus 7 days). Use of EEA was associated to improved disease-specific survival (DSS; 11.4 versus 4.4 years; HREEA = 0.53), especially for patients with T3-4a tumors (11.4 versus 3.0 years; HREEA = 0.41). Patients with T3-4 stage, tumoral invasion, positive surgical margins, mucinous or mixed histology, and prolonged post-operative hospital stay showed poor local relapse-free, disease-free, overall, and DSS. CONCLUSIONS: Long-term follow-up in locally advanced ITAC demonstrates that resection by EEA is correlated with improved DSS compared to EXTS, especially for T3-4 tumors. No significant differences between both treatment modalities was observed regarding per- and post-operative complications, although hospitalization in patients undergoing EEA was shorter than for patients treated with EXTS. These results confirm that EEA should remain the preferred surgical procedure in operable cases of sinonasal ITAC.

Safety assessment of fluorescently labeled anti-EGFR Nanobodies in healthy dogs.

Introduction: Surgical resection is one of the main treatment options for several types of cancer, the desired outcome being complete removal of the primary tumor and its local metastases. Any malignant tissue that remains after surgery may lead to relapsing disease, negatively impacting the patient's quality of life and overall survival. Fluorescence imaging in surgical oncology aims to facilitate full resection of solid tumors through the visualization of malignant tissue during surgery, following the administration of a fluorescent contrast agent. An important class of targeting molecules are Nanobodies® (Nbs), small antigen-binding fragments derived from camelid heavy chain only antibodies. When coupled with a fluorophore, Nbs can bind to a specific receptor and demarcate tumor margins through a fluorescence camera, improving the accuracy of surgical intervention. A widely investigated target for fluorescence-guided surgery is the epidermal growth factor receptor (EGFR), which is overexpressed in several types of tumors. Promising results with the fluorescently labeled anti-EGFR Nb 7D12-s775z in murine models motivated a project employing the compound in a pioneering study in dogs with spontaneous cancer. Methods: To determine the safety profile of the study drug, three healthy purpose-bred dogs received an intravenous injection of the tracer at 5.83, 11.66, and 19.47 mg/m2, separated by a 14-day wash-out period. Physical examination and fluorescence imaging were performed at established time points, and the animals were closely monitored between doses. Blood and urine values were analyzed pre- and 24 h post administration. Results: No adverse effects were observed, and blood and urine values stayed within the reference range. Images of the oral mucosa, acquired with a fluorescence imaging device (Fluobeam®), suggest rapid clearance, which was in accordance with previous in vivo studies. Discussion: These are the first results to indicate that 7D12-s775z is well tolerated in dogs and paves the way to conduct clinical trials in canine patients with EGFR-overexpressing spontaneous tumors.

Current status and future expectations of nanobodies in oncology trials.

INTRODUCTION: Monoclonal antibodies have revolutionized personalized medicine for cancer in recent decades. Despite their broad application in oncology, their large size and complexity may interfere with successful tumor targeting for certain applications of cancer diagnosis and therapy. Nanobodies have unique structural and pharmacological features compared to monoclonal antibodies and have successfully been used as complementary anti-cancer diagnostic and/or therapeutic tools. AREAS COVERED: Here, an overview is given of the nanobody-based diagnostics and therapeutics that have been or are currently being tested in oncological clinical trials. Furthermore, preclinical developments, which are likely to be translated into the clinic in the near future, are highlighted. EXPERT OPINION: Overall, the presented studies show the application potential of nanobodies in the field of oncology, making it likely that more nanobodies will be clinically approved in the upcoming future.

Direct co-registration of [18F]FDG uptake and histopathology in surgically excised malignancies of the head and neck: a feasibility study.

PURPOSE: Recent technical advancements in PET imaging have improved sensitivity and spatial resolution. Consequently, clinical nuclear medicine will be confronted with PET images on a previously unfamiliar resolution. To better understand [18F]FDG distribution at submillimetric scale, a direct correlation of radionuclide-imaging and histopathology is required. METHODS: A total of five patients diagnosed with a malignancy of the head and neck were injected with a clinical activity of [18F]FDG before undergoing surgical resection. The resected specimen was imaged using a preclinical high-resolution PET/CT, followed by slicing of the specimen. Multiple slices were rescanned using a micro-PET/CT device, and one of the slices was snap-frozen for frozen sections. Frozen sections were placed on an autoradiographic film, followed by haematoxylin and eosin staining to prepare them for histopathological assessment. The results from both autoradiography and histopathology were co-registered using an iterative co-registration algorithm, and regions of interest were identified to study radiotracer uptake. RESULTS: The co-registration between the autoradiographs and their corresponding histopathology was successful in all specimens. The use of this novel methodology allowed direct comparison of autoradiography and histopathology and enabled the visualisation of uncharted heterogeneity in [18F]FDG uptake in both benign and malignant tissue. CONCLUSION: We here describe a novel methodology enabling the direct co-registration of [18F]FDG autoradiography with the gold standard of histopathology in human malignant tissue. The future use of the current methodology could further increase our understanding of the distribution of radionuclides in surgically excised malignancies and hence, improve the integration of pathology and molecular imaging in a multiscale perspective. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05068687.

High-Resolution 18F-FDG PET/CT for Assessing Three-Dimensional Intraoperative Margins Status in Malignancies of the Head and Neck, a Proof-of-Concept.

The surgical treatment of head and neck malignancies relies on the complete removal of tumoral tissue, while inadequate margins necessitate the use of adjuvant therapy. However, most positive margins are identified postoperatively as deep margins, and intraoperative identification of the deep positive margins could help achieve adequate surgical margins and decrease adjuvant therapies. To improve deep-margin identification, we investigated whether the use of high-resolution preclinical PET and CT could increase certainty about the surgical margins in three dimensions. Patients with a malignancy of the head and neck planned for surgical resection were administered a clinical activity of 4MBq/kg 18F-FDG approximately one hour prior to surgical initiation. Subsequently, the resected specimen was scanned with a micro-PET-CT imaging device, followed by histopathological assessment. Eight patients were included in the study and intraoperative PET/CT-imaging of 11 tumoral specimens and lymph nodes of three patients was performed. As a result of the increased resolution, differentiation between inflamed and dysplastic tissue versus malignant tissue was complicated in malignancies with increased peritumoral inflammation. The current technique allowed the three-dimensional delineation of 18F-FDG using submillimetric PET/CT imaging. While further optimization and patient stratification is required, clinical implementation could enable deep margin assessment in head and neck resection specimens.

The Prognostic Value of CD206 in Solid Malignancies: A Systematic Review and Meta-Analysis.

An increased presence of CD206-expressing tumor associated macrophages in solid cancers was proposed to be associated with worse outcomes in multiple types of malignancies, but contradictory results are published. We performed a reproducible systematic review and meta-analysis to provide increased evidence to confirm or reject this hypothesis following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The Embase, Web of Science, and MEDLINE-databases were systematically searched for eligible manuscripts. A total of 27 papers studying the prognostic impact of CD206 in 14 different tumor types were identified. Meta-analyses showed a significant impact on the overall survival (OS) and disease-free survival (DFS). While no significant differences were revealed in progression-free survival (PFS) and disease-specific survival (DSS), a shift towards negative survival was correlated with increased CD206-expresion. As a result of the different tumor types, large heterogeneity was present between the different tumor types. Subgroup analysis of hepatocellular carcinoma and gastric cancers revealed no heterogeneity, associated with a significant negative impact on OS in both groups. The current systematic review displays the increased presence CD206-expressing macrophages as a significant negative prognostic biomarker for both OS and DFS in patients diagnosed with solid cancers. Because a heterogenous group of tumor types was included in the meta-analysis, the results cannot be generalized. These results can, however, be used to further lead follow-up research to validate the specific prognostic value of CD206 in individual tumor types and therapeutic approaches.

Identifying non-otologic risk factors for tinnitus: A systematic review.

BACKGROUND: The origin of tinnitus has been attributed to a peripheral auditory lesion, inducing bottom-up changes and resulting in the perception of a "phantom sound." However, non-auditory factors can co-exist as well, and can even lie at the origin of tinnitus development. An increasing body of literature focuses on psychological, (neuro)muscular, cardiovascular and many other influences and their respective associations with tinnitus prevalence. OBJECTIVE OF REVIEW: The purpose of this study was to provide a comprehensive description of these non-otologic risk factors, and to summarise the evidence in literature about their link with tinnitus. TYPE OF REVIEW: A narrative systematic review was conducted, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. SEARCH STRATEGY: The MEDLINE, Embase and Web of Science databases were systematically searched for eligible articles, supplemented with manual search methods and grey literature search. Epidemiological studies reporting on the relationship between various non-otologic risk factors and tinnitus were included. EVALUATION METHOD: Quality assessment was performed using the Hoy & Brooks tool. RESULTS: Fifty-five studies were included. Studies were of variable quality, with poor tinnitus definitions and evaluations or questionable sampling of the study population as main contributing factors for high risk of bias. Multiple associated factors have been identified, including cardiovascular, psychological, neurological, musculoskeletal and dietary factors. CONCLUSIONS: The current literature review identified multiple risk factors that could be of significant importance for tinnitus development, maintenance or aggravation. While causality remains uncertain, this systematic elaboration of possible tinnitus comorbidities/risk factors can help provide direction for future research, and can direct clinicians to identify patients at risk and treat relevant symptoms accordingly.