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.

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. 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. 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.

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.

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.