Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding GGCX gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype–phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one GGCX mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations—a frequent problem in orphan diseases—we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype–phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.

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.

Background/Purpose: We analyzed complications and functional outcomes and aimed at identifying prognostic factors for functional outcomes and complications in patients who underwent salvage total laryngectomy (STL) for residual, recurrent, and second primary squamous cell carcinoma (SCC) of the larynx and hypopharynx after initial (chemo)radiation. Methods: Retrospective cohort study of patients who underwent STL in four major Belgian reference hospitals between 2002 and 2018. Prognostic factors for functional outcomes and complications were identified with uni- and multivariable analysis. Results: A total of 405 patients were included in the final analysis. STL was performed for residual tumor (40.2%), local recurrence (40.5%), or second primary laryngeal or hypopharyngeal SCC (19.4%). Early postoperative complications were experienced by 34.2% of patients: postoperative hemorrhage occurred in 5.4%, wound infection in 16.2%, and clinical pharyngocutaneous fistula (PCF) in 25.5% of patients. Early readmission proved necessary in 15.1% of cases, most often due to late PCF development (72.2%). Patients achieved total peroral intake in 94.2% of cases. However, subjective dysphagia was reported by 31.3% of patients during follow-up. Functional speech, defined as functional communication by speech without additional aids, was reported in 86.7% of cases and was most often achieved by tracheo-esophageal puncture (TEP) (94.1%). In a multivariable model, lower preoperative hemoglobin (<12.5 g/dl) was identified as an independent prognostic factor for higher overall complication rate. No risk factors were found significant for clinical fistula formation. Vascularized tissue augmentation did not significantly prevent clinical PCF. Patients with positive section margins, patients initially treated with surgery combined with adjuvant RT (vs. radiotherapy alone), and those developing PCF after STL were less likely to achieve total peroral intake. Postoperative dysphagia proved more likely in patients who developed a PCF postoperatively, and less likely in patients who underwent STL without partial pharyngectomy and in patients with myocutaneous pectoralis major (PM) flap reconstruction, compared to muscle onlay PM flap. Achieving postoperative functional speech proved most likely in patients with smaller tumors (lower pT classification) and free section margins. Conclusion: Substantial complication rates and favorable functional outcomes are reported after STL.

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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.