Precision surgery:the role of intra-operative real-time image guidance - outcomes from a multidisciplinary European consensus conference

Developments within the field of image-guided surgery are ever expanding, driven by collective involvement of clinicians, researchers, and industry. While the general conception of the potential of image-guided surgery is to improve surgical outcome, the specific motives and goals that drive can differ between the different expert groups. To establish the current and future role of intra-operative image guidance within the field of image-guided surgery a Delphi consensus survey was conducted during the 2(nd) European Congress on Image-guided surgery. This multidisciplinary survey included questions on the conceptual potential and clinical value of image-guided surgery and was aimed at defining specific areas of research and development in the field in order to stimulate further advances towards precision surgery. Obtained results based on questionnaires filled in by 56 panel experts (clinicians: N=30, researchers: N=20 and industry: N=6) were discussed during a dedicated expert discussion session during the conference. The outcome of this Delphi consensus is indicative of the potential improvements offered by image-guided surgery and of the need for further research in this emerging field, that can be enriched by the identification of reliable molecular targets

Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not?

All human cells, including cancer cells, need oxygen and nutrients to survive. A widely used strategy to combat cancer is therefore the starvation of tumor cells by cutting off the blood supply of tumors. Clinical experience indeed shows that tumor progression can be delayed by anti-angiogenic agents. However, emerging evidence indicates that in certain experimental conditions, hypoxia as a result of pruning of the tumor microvasculature can promote tumor invasion and metastasis, although these findings are contextual and debated. Genetic studies in mice unveiled that vascular-targeting strategies that avoid aggravation of tumor hypoxia or even promote tumor oxygenation might prevent such an invasive metastatic switch. In this article, we will discuss the emerging link between hypoxia signaling and the various steps of metastasis.status: publishe

Identification of a chronic non-neurodegenerative microglia activation state in a mouse model of peroxisomal β-oxidation deficiency

The functional diversity and molecular adaptations of reactive microglia in the chronically inflamed central nervous system (CNS) are poorly understood. We previously showed that mice lacking multifunctional protein 2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, persistently accumulate reactive myeloid cells in the gray matter of the CNS. Here, we show that the increased numbers of myeloid cells solely derive from the proliferation of resident microglia and not from infiltrating monocytes. We defined the signature of Mfp2(-/-) microglia by gene expression profiling after acute isolation, which was validated by quantitative polymerase reaction (qPCR), immunohistochemical, and flow cytometric analysis. The features of Mfp2(-/-) microglia were compared with those from SOD1(G93A) mice, an amyotrophic lateral sclerosis model. In contrast to the neurodegenerative milieu of SOD1(G93A) spinal cord, neurons were intact in Mfp2(-/-) brain and Mfp2(-/-) microglia lacked signs of phagocytic and neurotoxic activity. The chronically reactive state of Mfp2(-/-) microglia was accompanied by the downregulation of markers that specify the unique microglial signature in homeostatic conditions. In contrast, mammalian target of rapamycin (mTOR) and downstream glycolytic and protein translation pathways were induced, indicative of metabolic adaptations. Mfp2(-/-) microglia were immunologically activated but not polarized to a pro- or anti-inflammatory phenotype. A peripheral lipopolysaccharide challenge provoked an exaggerated inflammatory response in Mfp2(-/-) brain, consistent with a primed state. Taken together, we demonstrate that chronic activation of resident microglia does not necessarily lead to phagocytosis nor overt neurotoxicity. GLIA 2015.status: publishe

Microplastic Exposure by Razor Clam Recreational Harvester-Consumers Along a Sparsely Populated Coastline

Microplastics (MPs) are anthropogenic contaminants found in coastal and marine environments worldwide. Pacific razor clams (Siliqua patula), important for local indigenous culture, economy, gastronomy and food security along the United States West Coast, are subjected to myriad environmental stressors including predation, storm events, disease, toxins, and MPs. This study aimed to determine MP burdens in Olympic Coast, Washington Pacific razor clams and estimate annual MP exposure of recreational razor clam harvester-consumers from eating this species. We quantified suspected MP burdens in Pacific razor clams collected from eight tribal, recreational, and commercial harvest areas on the Olympic Coast in April 2018. We administered questionnaires to 107 recreational razor clam harvesters during the same timeframe to determine consumption patterns, preparation styles, knowledge and concerns about MPs, and demographics. Razor clams containing suspected MPs, primarily microfibers, were found at all eight sites. Average suspected MP burden differed by sample type (whole = 6.75 ± 0.60, gut-tissue = 7.88 ± 0.71, non-gut tissue = 4.96 ± 0.56, and cleaned samples = 3.44 ± 0.25). FTIR analyses of a random subset of microfiber-type MPs in whole and cleaned clams indicated material types of polyethylene terephthalate, cellulose acetate, cellophane, polyester, nylon, and cellulose. The average number of razor clams consumed per meal by Olympic Coast recreational razor clam harvesters was 4.27 ± 0.27, which varied by gender and ethnicity, but not income or age. Harvesters ate 0–209 meals/year of razor clams (16.2% harvested but did not eat razor clams), and most respondents (88.3%) fully cleaned razor clams before consuming them. Annual suspected MP exposure for razor clam harvester-consumers was 60– 3,070 for cleaned and 120–6,020 for whole clams. Our findings suggest Olympic Coast recreational razor clam harvester-consumers are exposed to low levels of MPs from eating razor clams. MP exposure can be reduced by roughly 50% if clams are cleaned before consumption. Our work serves as an important reference in the growing portfolio of Pacific Northwest microplastic research, to inform future MP attenuation recommendations and development of human health standards for this type of pollution

Phospholipase C gamma 1 (PLCG1) R707Q mutation is counterselected under targeted therapy in a patient with hepatic angiosarcoma

Hepatic angiosarcoma is a rare and aggressive vascular neoplasm. Pathogenic driver mutations are largely unknown. We present the case of a patient with recurrent hepatic angiosarcoma, who initially showed good response to sunitinib, followed by progression. Using comprehensive molecular techniques, we explored the potential mechanisms of resistance. By low-read-depth whole-genome sequencing, the comparison of copy number aberrations (CNAs) of the primary tumor to the skin metastatic lesion that developed after progression on sunitinib, revealed high-level amplification of the 4q11-q13.1 region (containing KIT, PDGFRA and VEGFR2 genes) that was sustained in both lesions. Whole exome sequencing on the germline, primary and metastatic tumor DNAs, resulted in 27 confirmed mutations, 19 of which (including TP53 mutation) presented in both primary and metastatic lesions. One mutation, ZNF331 frameshift deletion, was detected only in the primary tumor. In contrast, seven other mutations, including phospholipase C-gamma1 (PLCG1) R707Q mutation, were found only in the metastatic tumor, indicating selection of cells with the resistant genotype under sunitinib pressure. Our study supports the notion that PLCG1-R707Q mutation may confer VEGFR2-independent signaling and may thus cause resistance against VEGF(R)-directed therapies. This case illustrates also the advantages of using next-generation technologies in identifying individualized targeted therapy.status: publishe