The microvasculature plays a critical role in human physiology and is closely associated to various human diseases. By combining advanced microfluidic-based techniques, the engineered 3D microvascular network model provides a precise and reproducible platform to study the microvasculature in vitro, which is an essential and primary component to engineer organ-on-chips and achieve greater biological relevance. In this review, we discuss current strategies to engineer microvessels in vitro, which can be broadly classified into endothelial cell lining-based methods, vasculogenesis and angiogenesis-based methods, and hybrid methods. By closely simulating relevant factors found in vivo such as biomechanical, biochemical, and biological microenvironment, it is possible to create more accurate organ-specific models, including both healthy and pathological vascularized microtissue with their respective vascular barrier properties. We further discuss the integration of tumor cells/spheroids into the engineered microvascular to model the vascularized microtumor tissue, and their potential application in the study of cancer metastasis and anti-cancer drug screening. Finally, we conclude with our commentaries on current progress and future perspective of on-chip vascularization techniques for fundamental and clinical/translational research. The circulatory system plays a vital role to maintain homeostasis in the human body. It comprises a closed network of arteries, veins, and capillaries that allow blood to circulate throughout the body, not only for waste product removal, but also for gas exchange and nutrient transportation, all of which are essential for organ viability. Besides participating in metabolic function, microvasculature in different organ microenvironment has unique biological functions and physical properties, such as maintaining solute and water balance between the blood and tissue compartments, or responding to different deformations and stress fluctuations . RecentlFurthermore, besides the substantial physiological research on constructing and characterizing the microvasculature in homeostatic conditions in these systems, there is a great potential to model pathological conditions to study vascular-related diseases . EspeciaIn this review, we focus on the generation of microvascular networks in 3D engineered tissue constructs and their integration into vascularized microtumor models by combining microfluidics, microfabrication, biomaterials, and tissue engineering technologies. We first discuss the current strategies for tissue vascularization. Next, we highlight relevant factors that induce vascularization inside microfluidic systems. We then provide a brief introduction of selective vascular barrier properties in different human organs and methods to construct and characterize these properties. Then, we review the current, state-of-the-art in vitro vascularized tumor-on-a-chip models in various disease stages, and their potential applications for anti-cancer drug screening. Finally, we conclude with our visions to improve the current approaches to create vascularized microtissues. This review will provide a better understanding of the vascularization process for organ-on-a-chip systems and its applications in cancer biology.In many early studies to understand the basis of vascular biology, 2D models were constructed by plating endothelial cells (ECs) on a flat surface such as Petri dish , porous Briefly, the EC lining methods are achieved by allowing EC to form a monolayer on the inner walls of the microfluidic channel. The major advantage of these methods is that the microvasculature geometry and dimensions can be easily controlled based on different microfabrication techniques with high flexibility. Furthermore, shear stress imposed on the microvessels can be precisely controlled and calculated based on the channel dimensions and the applied flow rate. However, these methods cannot mimic vascular formation in vivo that mainly relies on the natural process of vasculogenesis and angiogenesis to form the complex microvascular networks. Since it is difficult to evenly distribute a high density of ECs inside the microfluidic channels with small diameter due to the blockage, EC lining methods are only suitable to construct large blood vessels with diameter greater than 50 μm . The holThe basic operation procedure of this method is to insert a cylindrical object  into a hydrogel solution and remove it after the hydrogel is fully polymerized to create a single microchannel. Then ECs are seeded onto the inner surface of the microchannel to form a confluent EC monolayer A 11,12,,12,13. BRather than a single microchannel, a single-layer microchannel network can also be fabricated by using standard lithographic patterning method. Zheng et al. developed an interconnected microvascular array by using the additive bonding between a micropatterned collagen gel slab and a flat hydrogel layer B. BrieflIn this method, a multi-layer microchannel network can be fabricated by dissolving or melting the dissolvable gel or solid material embedded in a gel matrix. With the development of 3D printing technology, more complex multi-layer microchannel networks can be interconnected using a wide range of template materials, such as carbohydrate glass , PluroniThe PDMS-based microfluidic chips enable a single-layer microchannel network design with the diameter ranging from 60–200 μm, and different microenvironment factors  can be precisely controlled with the sophisticated microfluidic technologies . In vivoTo solve the problem of non-circular cross section, Bischel et al. developed a “viscous finger patterning” method that took advantage of basic fluidic principles to create 3D lumens with circular cross section inside a PDMS-based microchannel ,30. Briede novo. Therefore, these methods can create a more natural vascular structure than the EC lining methods.Vasculogenesis and angiogenesis are the fundamental processes of vascular development in vivo ,35, as sde novo. Within a microfluidic device, Hsu et al. demonstrated formation of microvascular networks using endothelial colony forming cell-derived endothelial cells (ECFC-ECs) and normal human lung fibroblast (NHLF) mixed in fibrin gel, and embedded inside a series of diamond-shaped tissue chambers  chambers B. Under Angiogenesis is the formation of new blood vessel from pre-existing vessels, which is an important mechanism for vascular network remodeling. Angiogenesis occurs through a series of defined steps, including ECM degradation by matrix metalloproteinases (MMPs), angiogenic stimulus, sprouting, elongation and branching, lumen formation, anastomosis, and finally stabilization or regression . Within To form a perfusable microvascular network, these sprouts need to connect with each other through a process called anastomosis. Yeon et al. established an array of perfusable microvessels from EC monolayer lined on both sidewalls of fibrin gel confined inside a microfluidic channel E 52]. B. B52]. BBy controlling different factors within the microenvironment, different mechanisms to stimulate vascularization can be achieved on a single microfluidic device. Kim et al. presented a microfluidic device with five parallel microchannels that could generate perfusable microvessel network through either vasculogenesis or angiogenesis by seeding the cells and fibrin gel into different channels A 54]. F. F54]. FMicrofluidic system has become an emerging tool to develop microvasculature in vitro due to its advantages in precise control of factors within the microenvironment such as fluid flow at the physiological levels, distribution of different chemical factors, and different ECM properties . These inducing factors can be divided into three main types: Biomechanical factors, extracellular (or diffusible) signaling molecules, as well as cell source and cell-cell interaction. 2 can trigger ECs to sprout and invade into the underlying matrix, independent of cell-cell junction maturation or pressure gradient across the monolayer . . 126]. UTumor microenvironment (TME) plays an important role during the tumor metastasis process, which can be broadly classified into biophysical cues  and biochemical cues . For intramural flow in the bioengineered microvessel models, a critical method is to develop a perfusable and functional microvascular network with either EC lining or vasculogenesis/angiogenesis-based methods. The tumor intravasation/extravasation processes are mainly regulated by the alteration of vessel wall permeability and integrity under the effect of shear stress induced by the intramural flow inside vessel lumen. Therefore, the tumor invasion and metastasis events are unlikely to occur in large vessels like arteries and veins due to the high shear stress along the tight and thick vessel wall. In contrast, the capillaries with a smaller size would easily trap the tumor cells, which are more likely to penetrate through the capillaries due to the thinner walls and lower shear stresses . The intChemokines play a paramount role in the tumor progression. Both tumor cells and stromal cells elaborate chemokines and cytokines. These act either by autocrine or paracrine mechanisms to sustain tumor cell growth, induce angiogenesis and immune response to the tumor . By usinThe main application for in vitro vascularized tumor models is anti-cancer drug screening. Current drug screening methods still heavily rely on 2D cell culture assays or animal models. While 2D cell culture assays fail to replicate the 3D structure and complexity of tissues in vivo, animal models fail to capture the human-specific response to drugs due to intrinsic differences in anatomy and physiology . While 3The widely used strategies for anti-angiogenic therapies are to destroy the tumor vasculature, thereby depriving the tumor of nutrients. However, these methods will also severely compromise the delivery of oxygen to the solid tumor, which induces hypoxia microenvironment to make many chemotherapeutics and radiation less effective. In addition, the interstitial hypertension and nonuniform blood flow induced by the abnormalities and leakiness of tumor vasculature will also accumulate the drugs and oxygen at the concentrated region far from the solid tumors, no matter how much therapeutics and oxygenation are pumped into it. Therefore, another concept for tumor anti-angiogenic therapy is to study the normalization of tumor vasculature, which can temporarily “normalize” the abnormal structure and function of tumor vasculature into the functionally normal blood vessels by using certain antiangiogenic agents to make it more efficient for oxygen and drug delivery . The micIn this review, we have provided an overview of different vascularization strategies based on microfluidic technology. These strategies can be classified into three categories: EC lining-based methods, vasculogenesis and angiogenesis-based methods, and hybrid methods. It is apparent that each strategy carries both advantages and limitations. While the EC lining-based methods enable immediate media perfusion with well-controlled biomechanical factors, it is inefficient and only suitable to create larger blood vessels based on the predefined microchannel dimensions. In contrast, while vasculogenesis and angiogenesis-based methods provide very limited microenvironment control, they are suitable to create a capillary network down to a few micrometers in diameter by utilizing natural morphogenic properties of ECs. Therefore, an ideal strategy for proper tissue vascularization may lie in the combination of more than one technique to realize the hybrid methods. Moreover, multiple vascular inducing factors, such as biomechanical factors, extracellular (or diffusible) signaling molecules, cell source, and cell-cell interaction should be integrated into more complex microfluidic designs simultaneously to closely mimic the native microenvironment in different organs with specific vascular barrier functions. Furthermore, engineered microvessels also play an important role in modeling various human diseases, especially for the cancer research. The construction of vascularized tumor-on-a-chip can serve as a powerful tool to study the mechanisms of cancer metastasis at different stages like tumor angiogenesis, intravasation, and extravasation as well as their potential applications in anti-cancer drug screening and normalization of tumor vessels.While many proof-of-principles studies have demonstrated versatile vascularization strategies and its applications in tumor models, challenges still remain to be solved. For example, there is an urgent need to establish more precise and geometrically controlled methods with more dynamic and flexible on-chip microenvironment control to recapitulate all aspects of vasculature in vivo. To construct a functional vascularized microtissue, interactions between ECs, supporting mural cells, and organ-specific cells with in vivo-relevant cell densities are required. Additionally, current culture media are optimized for a specific cell type when cultured in monolayer. Once these cells are in a complex microenvironment, it is necessary to have a universal blood substitute to equally supplement multiple cell types. Another major consideration is to develop thick, implantable vascularized tissue constructs from microns to millimeters with synthetic biocompatible and degradable scaffold materials for tissue repair or regeneration, as described in the recent AngioChip design . The excTo summarize, although significant progress has been made towards tissue vascularization and related vascularized tumor models in the past decade, numerous challenges remain and will be addressed in future studies with a combination of microfluidics, microfabrication, biomaterials, tissue engineering, and other related technologies. Thus, a multidisciplinary, collaborative approach between engineers and biologists is required to develop more novel microphysiological systems that can closely mimic organ-specific physiology in vivo.


Many in vitro studies have shown that tea catechins had vevarious health beneficial effects. However, inconsistent results between in vitro and in vivo studies or between laboratory tests and epidemical studies are observed. Low bioavailability of tea catechins was an important factor leading to these inconsistencies. Research advances in bioavailability studies involving absorption and metabolic biotransformation of tea catechins were reviewed in the present paper. Related techniques for improving their bioavailability such as nanostructure-based drug delivery system, molecular modification, and co-administration of catechins with other bioactives were also discussed. Increased evidence has expanded the role of green tea from a traditional beverage to a source of bioactive ingredients with many health benefits. Green tea is rich in catechins comprised of more than eight polyphenolic compounds. According to different sources, the most abundant catechins in tea are (−)-epigallocatechin gallate (EGCG) and (−)-epigallocatechin (EGC) ,2. In reThere have been many in vitro studies showing that EGCG possesses antioxidant properties and exhibits favorable effects on gene expression, signal transduction and other cell functions . NumerouThe present paper comprehensively reviews the mechanisms leading to low absorption, poor permeability and less stability of tea catechins and also describes the potential for improving the bioavailability of tea catechins through new techniques such as nanoparticle-based delivery systems, structurally modified molecule of catechins, co-administration with other drugs or bioactives. Furthermore, the challenges and future research directions are also discussed.To collect the related references, computerized systematic literature searches were conducted inWeb of Science and Google Scholar databases to retrieve the pertinent studies and reviews. The search keywords used were tea catechins or tea polyphenolsor epigallocatechin gallate (EGCG) in combination with the terms absorption, bioavailability, metabolism, or nanoparticles, chitosan, prodrugs, peracetylate, and synergistic as well as the terms improvementand enhancement. The papers published in the English languagewere exclusively evaluated. No other limitations were applied. The literatures were combed and divided into four main categories: (a) pharmacokinetics of tea catechins, (b) drug delivery system, (c) molecular modification, and (d) synergistic effect with other drugs. Thus, the review is structured. First, into a discussion on the bioavailability of catechins, and then, to provide more thorough insights into the way and mechanism to improve.Only a small fraction of tea catechins present in the intestinal tract after drinking tea can be absorbed, and therefore considered to be bioavailable, i.e., appearing in the blood and tissues or reaching the systemic circulation. The latest study demonstrates that concentration of catechins in green tea infusions is about 3250–4410 mg/L  and apprO-methyltransferase (COMT) before and after being absorbed predominantly in the small intestine and in liver [A fraction of the ingested tea catechins undergoes extensive metabolism by phase II enzymes, such as UDP-glucuronosyltransferases (UGTs), sulphotransferases (SULTs) and catechol-in liver , with thin liver . The catin liver ,33 reporNo specific receptors on the surface of small intestinal epithelial cells have been found to carry EGCG into cells. Thus, the mechanism for catechins being transported across epithelium is principally based on passive diffusion, including paracellular and transcellular diffusions. Cell studies have also suggested that EGCG underwent active efflux after absorption by ATP-depended proteins. EGCG and its metabolites were served as common substrates for two important protein efflux pumps including the multidrug resistance-associated protein (MRP) efflux pumps  and the In brief, many processes including chemical degradation, microbial metabolism, intestinal and hepatic metabolism, membrane permeability, and transporter-mediators may influence the bioavailability of catechins .Nanostructure-based drug delivery system is one of the fastest-emerging areas in improving the bioavailability of drugs. Many studies showed promising EGCG-loaded nano-carriers with sustained release and improved bioavailability even at much lower doses than conventional preparations. Encapsulation materials including lipids ,39, protThe stability of EGCG was improved when bound to bovine serum albumin (BSA) . Both EGA catechin-loaded nanoemulsion-based nanogel showed sustained release profile, resulting in enhanced photoprotection potential to skin due to its improved permeability as well as bioavailability through transdermal route, compared to the conventional gel , in whicMilk proteins, containing caseins and whey proteins, were considered as ideal carriers for delivering catechins. Sodium caseinate adsorbed at the oil water interface, can load high ratios of EGCG ,52. CaseOther proteins such as corn zein protein ,54, soy The presence of hydroxyl groups in EGCG contributes to its strong affinity to proteins by enhancing its interactions with proteins. Although the interactions between catechins and proteins alter the protein structure , leadingDelivery systems based on carbohydrates, including chitosan, cellulose polymers, starch-based materials, gum arabic and sodium alginate, have been widely used in pharmaceutical field to enhance absorption of bioactive compounds, owing to their biodegradability, biocompatible and non-toxic properties. Chitosan is the most widely used material as an EGCG carrier, for it is the most abundant alkaline natural polysaccharide with good biological intermiscibility and film-forming properties. Swiss Outbred mice oral administration of the chitosan-tripolyphosphate nanoparticles enhanced the plasma exposure of total EGCG by a factor of 1.5 relative to free EGCG . In addiLipid carriers incorporating drugs have been found to improve the absorption and circulation time in the body versus stand-alone compounds  and it iCatechins are unstable and highly susceptible to ambient conditions like oxygen, pH changes, metal ions and other stress factors. Nanoparticle-based delivery systems are believed to be plausible options to protect catechins against harsh conditions. The EGCG loaded on lipids showed better stability. Many food formulations are water based, the presence of EGCG on liposomes had the potential to promote the formation of hydrogen bonds between hydrophilic catechins and polar head groups . In vitrAlthough the half-life period of EGCG (5.0–5.5 h) is about two times longer than that of EGC or EC (2.5–3.4 h), it is still too short to exert clinical effect. Sustainable and control release of catechins is a feasible way to improve their bioavailability. However, sustained release capacities of EGCG depend on the carrier systems. About 6.0% and 12.6% EGCG was released from EGCG nanoliposomes at 6 and 24 h, respectively . When EGSome nanoparticles not only enhance the stability of EGCG, but also improve the membrane permeation. Song  reportedIn addition, the drug loaded on nanoparticles can protect the core material from adverse environmental conditions, delay its degradation in the humoral environment, make it easily penetrate various barriers to reach the target organs, which contributes to the controlled liberation of the drugs and improvement of the drug bioavailability. The effects of EGCG nanoparticles are listed in Biochemically, conjugation of the free hydroxyl groups surrounding the molecules influences the efficacy of ingested tea catechins. A molecular modification method using peracetate acid can be used to protect the reactive hydroxyl groups of EGCG. Synthesized peracetate-protected EGCG AcEGCG,  was founIt was reported that AcEGCG increased EGCG stability, resulting in increased bioavailability and enhanced inhibition on the proteasome and growth of breast tumor. Peracetylation also increased the bioavailability of EGCG in esophageal and colon cancer cells , and theAcetate protection of EGCG’s phenol groups is a useful tool for enhancing the stability and improving the bioavailability of EGCG. Furthermore, other chemical modifications that can improve the physiochemical properties of EGCG or reduce its biotransformation may be also useful in improving its bioavailability .It was found that a mixture of tea catechins and ascorbic acid significantly increased tea catechins’ recovery in a simulated in vitro digestion system . AbsorptApart from ascorbic acid, many other bioactive compounds show synergistic interactions with tea catechins. A major challenge for cancer chemotherapy and radiotherapy is time-dependence multi-drug resistance (MDR), as well as treatment interruptions caused owing to various side effects. To overcome this shortcoming, developing novel combination therapies for chemotherapy and bioactive dietary compounds will be a trend in future. The combination of catechins with other drugs which shows synergistic effects might be a promising approach.Tea catechins showed a good coordination with some conventional anticancer drugs. The presence of EGCG significantly increased the pharmacokinetics of orally administered tamoxifen, which was attributed to the decrease in first-pass metabolism in the intestine and liver by inhibiting P-glycoprotein and CYP3A by EGCG . KitagawLow bioavailability of green tea catechins is an important factor leading to the observed inconsistency between in vitro and in vivo studies. Stability, absorption rate and efflux influence the bioavailability. Extreme pH conditions in the stomach and intestinal tract as well as related digestive enzymes are confirmed to be factors inducing instability including degradation and conjugation of catechins. Catechins are considered to be transported across intestinal epithelium principally by passive diffusion, including paracellular and transcellular diffusions because no specific receptors on the surface of small intestinal epithelial cells have been found to carry EGCG into cells, which is the main reason why the absorption rate of catechins is low. The active efflux of partial absorbed catechins decreases the plasma catechins concentration .The bioavailability of catechins can be improved by nanostructure-based drug delivery systems, molecular modification and co-administration with some other bioactive ingredients. Encapsulation of tea catechins on protein-based, carbohydrate-based and lipid-based nanoparticles improved stability, sustainable release and cell membrane permeation of catechins, resulting in increased bioavailability. Molecular modification such as synthesizing peracetylated EGCG (AcEGCG) protects hydroxyl groups on EGCG from oxidative degradation until it is deacetylated into its parent EGCG by esterases in cells , which dThere are still great expectations in the fields of bioavailability research of tea catechins. Disease-targeting and multiple molecular targeting are expected to be improved so as to find more potent, stable and specific active formulation of catechins . Targete


The different drugs and medical devices, which are commercialized or under industrial development for glioblastoma treatment, are reviewed. Their different modes of action are analyzed with a distinction being made between the effects of radiation, the targeting of specific parts of glioma cells, and immunotherapy. Most of them are still at a too early stage of development to firmly conclude about their efficacy. Optune, which triggers antitumor activity by blocking the mitosis of glioma cells under the application of an alternating electric field, seems to be the only recently developed therapy with some efficacy reported on a large number of GBM patients. The need for early GBM diagnosis is emphasized since it could enable the treatment of GBM tumors of small sizes, possibly easier to eradicate than larger tumors. Ways to improve clinical protocols by strengthening preclinical studies using of a broader range of different animal and tumor models are also underlined. Issues related with efficient drug delivery and crossing of blood brain barrier are discussed. Finally societal and economic aspects are described with a presentation of the orphan drug status that can accelerate the development of GBM therapies, patents protecting various GBM treatments, the different actors tackling GBM disease, the cost of GBM treatments, GBM market figures, and a financial analysis of the different companies involved in the development of GBM therapies. Glioblastoma multiform (GBM) is a malignant tumor originating from glial cells. It is the most frequent brain tumor, representing 30% of all central nervous system tumors (CNST), 45% of malignant CNST and 80% of primary malignant CNST. It leads to 225,000 deaths per year in the entire word. It has an incidence of 5 per 100,000 persons, affects 1.5 times more men than women, and is diagnosed at an average age of 64  includes maximal safe resection followed by radiotherapy and chemotherapy using temozolomide (TMZ). Such treatment hardly increases patient survival and leads to a median overall survival (OS) of only 12–18 months following diagnosis  often prevents drugs from efficiently reaching glioblastoma cells, and methods to enable drugs to efficiently cross the BBB should therefore be developed.Efficient treatment against GBM is difficult to develop for a series of reasons that are summarized below. First, GBM is characterized by many dysregulated pathways that can hardly be all blocked and repaired at the same time with a single therapy  is a method that maintains patient awake during the surgical operation that can be carried out using a neuronavigation system, such as the Stealth Station developed by Medtronic  compatible microsurgery and stereotaxic system that enables the surgeon to see GBM lesions and remove them almost simultaneously. Furthermore, due to its surgical tools that are automatically controlled by measuring the forces that they apply on tumor tissue, Neuroarm can precisely remove part of the GBM tumor  can be used to obtain brain maps before a surgical operation. However, since they are not established during the surgical operation, they don't precisely represent brain status or structure during tumor resection, leading to the so-called brain shifts, i.e., discrepancies that have led to numerous side effects such as deformations of cortical and subcortical structures, loss of cerebrospinal fluid (CSF), or brain edema. To improve brain tumor imaging, the following real time techniques have therefore been developed.Positron emission tomography (PET), using for example Siemens EXACT/HR or ADVANCE NXi positron emission tomograph commercialized by Siemens and GE respectively, is a molecular imaging technique that provides information about molecular processes taking place in GBM tumor. In PET, the nucleus of radioisotopes emits positrons that annihilate when they meet electrons, producing photons that are counted on a detector unit. Different types of radioisotopes are used to monitor specific molecular transformations taking place in GBM, for example Fluoro-2-deoxy-D-glucose ([18F]FDG) for measuring glucose metabolism, radiolabeled amino acids ([11C]methionine), and aromatic amino acid  to monitor amino acid transport as well as protein synthesis that are enhanced in glioblastoma tumor, Nitroimidazole derivatives ([18F]fluoromisonidazole and [18F]FAZA38) to detect tumor hypoxia, choline analog ([18F]fluorocholine) produced by high grade glioma and their metastases. With the help of this large variety of radiotracers, PET is able to identify malignant regions with a relatively high resolution (1.5 mm at best), and can therefore guide the surgeon during glioma resection , for example the Cellvizio system developed by Mauna Kea Technologies, is a fluorescent detection method, which was used during GBM surgery in combination with different contrast agents (5-aminolevulinic acid and fluorescein) and enables to distinguish between healthy and glioma cells , which can be carried out with a Sirius 713 Tomograph developed by 4Optics AG, uses near-infrared light penetrating at a depth of up to several millimeters that is reflected to generate cross-sectional images of the brain. Endoscopes could be used to reach glioblastoma tissues during OCT measurements. Different types of OCT endoscopes have been described, integrating side-viewing and forward viewing probes, different scanning mechanism, or being combined with other imaging modalities  resolutions without needing any contrast agent. A study has compared OTC images obtained from healthy and GBM human brain tissues extracted from patients. Lower optical attenuation was found in cancer than non-cancer tissues, suggesting that OCT could discriminate between healthy and tumor tissues during a surgical GBM treatment  can be divided in two categories. A first type of iMRI developed by IMRIS (IMRISneuro), Philips (Ingenia MR-OR), GE healthcare , Odin Medical Technologies (PoleStar magnet), Medtronic Navigation (PoleStar), is directly conceived to be used as iMRI. A second category of iMRI, commercialized by Hitachi Medical System (AIRIS I and II), Siemens Medical Solutions (Magnetom Open Viva), and BrainLAB (BrainSuite), consists in MRI, which have been modified and adapted to be useable in the operation room (OR). iMRI is used to identify GBM cell location during a surgical operation. It can be subcategorized as iMRI of low field strength (0.12–1.5 T), enabling relatively easy and fast real time imaging but without a high resolution, and iMRI of high field strength (1.5–3 T) that are more difficult to use during surgery due to a longer acquisition time, but provide brain tumor images with enhanced resolution. iMRI has been shown to strengthen the safety of surgical procedure by imaging healthy tissues, hence preventing their removal, to increase the percentage of tumor resection, and possibly rather modest improvement in GBM patient survival  are commercialized by large companies that already sell standard MRI equipment, such as Siemens (Siemens 3-T Trio fMRI), Philipps (Achieva 3.0T X-series scanner combined with the Eloquence system), GE Healthcare (BrainWave). fMRI enables to acquire blood oxygen level dependent (BOLD) MRI scans of the brain and hence to detect metabolic changes and abnormalities that are induced by changes in brain oxygen concentration. It complements standard MRI imaging, which only provides morphological information of the cerebral cortex. fMRI is used during brain surgery to detect parts of the brain that need to be kept in place such as those responsible for the production of speech or comprehension, which cannot be seen with standard MRI  equipment, which is commercialized by companies such as Elekta (Elekta Neuromag TRIUX), is a functional neuroimaging technique that maps brain activity by recording magnetic fields produced by electrical currents occurring naturally in the brain. Since the strength of these magnetic fields is very low (~109 lower than the earth magnetic field), it uses very sensitive magnetometers (SQUID sensors) to record them. MEG can be used during GBM surgery to identify locations of brain abnormalities using direct measurements of neuronal activity without necessitating full patient immobilization. However, the main drawback of this technique comes from the high cost of the MEG equipment, which does not seem to be widely used for GBM treatment , commercialized by companies such as Magstim (Rapid) or Nexstim (eXimia), delivers magnetic stimulation to spots on the motor cortex. The resulting electrical activity is monitored by electromyography (EMG). nTMS enables to obtain a map of the motor cortex area and hence to optimize tumor resection by preventing removal or damage of eloquent motor areas. It was also shown that the use of nTMS in GBM patients increases the rate of gross total resections by 17% , developed by Brainlab , slicer (Slicer4), and Medical Analysis and Visualization (MedAlyVis), is a noninvasive imaging technique that measures the diffusion of water molecules in three dimensions within tissue through the application of multiple diffusion gradients. More specifically, it enables visualization of white matter tracts (WMT) often localized near glioma cells , uses an equipment such as Desi 2D developed by Prosolia, which is integrated in the operation room and delineate tumor regions by identifying and characterizing the mass and fragmentation patterns of the molecules involved in GBM at the nanometer scale  to glioblastoma tumors. High energy rays or beams produced outside of the brain are orientated toward the tumor to cover the whole tumor volume  or Image guided radiation therapy (IGRT) use Clinac, Radixact, or Synergy equipment, commercialized by Varian, Accuracy, and Elekta, respectively, that generate X-ray photons of typically 4–20 MV. In this treatment, the glioblastoma tumor is first imaged in 3D using CT, MRI, PET, or PET-CT scan, and a computer program then designs the orientation of the radiation beam applied on patient's head to cover the whole tumor volume while sparing healthy tissues. Patients are typically exposed to 50–90 Gy  uses Radixact (Accuracy), Infinity or Precise treatment system (Electa), Vitalbeam or Clinac (Varian). It is similar to 3D-RT or IGRT, but has the additional feature of allowing an adjustment of the strength of the radiation beam, depending on the targeted region of the glioblastoma tumor. Compared with 3D-RT or IGRT, IMRT enables to deliver higher radiation doses within a shorter period of time without any toxicity increase  uses a HT system, commercialized by Accuray for example. HT is a type of IMRT that uses computed tomography (CT) to guide the X-ray beam to the desired tumor location. HT produces a narrower beam than LINAC used in conventional IMRT. This beam is delivered while the patient is moving enabling to better target different tumor sites without the need for a pause between different patient positions. HT was reported to better spare organ at risks than LINAC during GBM radiation therapy , carried out by Apex or Versa HD (Elekta), Truebeam or ClinaciX system (Varian), Artiste solution, Oncor K or M Class, Primus , is a non-invasive treatment method that uses pencil-thin beams of X-ray radiation that are focused on GBM tumor. Patient's head may be inserted in a frame, an imaging technique such as CT or MRI is used to locate the tumor and deliver the energy at tumor location. Compared with IMRT, SRS presents the advantage of delivering X-ray energy within less sessions (<5) during 6–8 weeks, using higher doses of radiation during each session  that are focused on the GBM tumor with the help of a computer. Gamma knife was reported to be a safe treatment option for patients diagnosed with recurrent GBM. In terms of efficacy, it yielded a median survival after tumor recurrence ranging from 13 to 26 months, which is not significantly better than with other types of radiotherapies. When it was combined with chemotherapy, improved survival may have been observed among GBM patients, but a phase III appears necessary to confirm this result  is carried out with an equipment such as Radiance 330 commercialized by Pro Tom International that generates proton beams, which deliver energy of 70–250 MeV within the tumor location. Compared with X-rays, PRT induces less energy penetration in healthy tissues than X-rays. It enables to reach antitumor efficacy using a lower level of radiation than X-rays and to minimize the exposure of radiations to organs at risks such as the hippocampi, sub-ventricular zones, hearing and visual apparatus, and pituitary gland. Several clinical trials, carried out on GBM patients treated by proton therapy, reported that this therapy was well tolerated, but they did not firmly conclude in an improvement in patient survival, due to the too small number of treated patients -iodo-4-hydroxybenzenesulfonate]). Gliasite enables the delivery of radiation dose to areas that are most at risk of recurrence. A clinical study carried out on 24 patients suffering from recurrent GBM showed that the treatment was safe, but it did not conclude in improved patient survival compared with other types of radiotherapies . Cotara should then deliver a cytotoxic dose of 131I radiation to the adjacent living GBM cells , commercialized by Novocure, uses Optune consisting in electrodes positioned on patient's head that generate low intensity electric fields alternating at a frequency of 200 kHz, which selectively block tumor cell division during mitosis by interrupting during metaphase and/or anaphase the spindle assembly unusually occurring in healthy cells  has been developed by Monteris . In this treatment, Magnetic Resonance Imaging is first used to localize the GBM tumor, a laser beam is transmitted through fiberoptics toward the tumor region and the resulting thermal energy heats the tumor at an average temperature of 43°C. Thermography enables to monitor and adjust temperature changes during the treatment. The mechanisms by which heat induces tumor destruction remain poorly understood, but possibly involve protein denaturation, membrane dissolution, vessel sclerosis, and coagulative necrosis. MRgLITT can serve to destroy tumor parts located in regions of the brain that are difficult to access and would possibly lead to injury of adjacent functional structures if surgery was used. Visualase and Neuroblate systems operate at relatively similar wavelengths of 980 nm and 1,064 nm, respectively, and powers of 12–15 W. However, the Neuroblate system can more precisely adjust light diffusion in the tumor by using both diffusing and side scattering modes compared with Visualase that only operates with a diffusing mode  an increase in tumor temperature that remained below 43°C, (ii) the destruction of the BBB enabling chemotherapeutic drugs to reach the tumor, (iii) an absence of side effects. The treatment led to 80% of necrotic tumor and to a decrease in tumor diameter. Further assessment of this treatment is however necessary to conclude about its efficacy on a larger number of patients  was developed by the company Nativis. It is supposed to enhance tubulin polymerization and inhibit cell division  focuses ultrasound waves to GBM to heat and ablate these tumors. A first in man study carried out on a patient suffering from recurrent GBM demonstrated that high-power sonications could be applied on GBM with the help of MRI, yielding partial tumor ablation without adverse effects  and progression free survival (PFS) of GBM patients by 15 and 2 months, respectively , which is commercialized by Merck, is an alkylating agent that breaks DNA double-strand and also reduces the activity of a DNA repair enzyme, called O 6 methylguanine-DNA methyltransferase (MGMT), hence promoting GBM tumor cell death  for 5 days every 28-day cycle. In a large phase 3 clinical trial, the efficacy of a treatment using TMZ with concomitant radiation therapy followed by adjuvant TMZ for 6 months was shown to improve median overall survival (MOS) and 2-year survival by ~2 months and 16%, respectively compared with a treatment using only radiation , under development by Del Mar Pharmaceuticals, was reported to cross the BBB, to be absorbed more importantly in cancer than healthy cells, to bind to GBM cell DNA, leading to GBM cell death with more efficacy than other DNA drugs. VAL-083 was shown to be active against MGMT-unmethylated GBM cells which are resistant to treatment with TMZ and nitrosoureas. In a clinical trial, it increased GBM patient OS by 8 months , tyrosine kinase activity, and tumor cell proliferation , which improves penetration through the BBB by transcytosis , which is under development by Buffalo Biolabs and Incuron, is expected to trigger antitumor activity by binding to DNA and inactivating the Facilates Chromatin Transcription (FACT) complex, which repairs transcription and replication mechanisms of DNA. In mice bearing U87 GBM, the administration of 35–70 mg/kg of CBL037 and TMZ was shown to increase mouse maximal survival by 55 days compared with untreated mice , which is commercialized by Genentech for GBM treatment, is a human monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), and has been approved for GBM treatment since 2009 in the USA. However, for patients suffering from GBM, the use of BV does not increase survival by more than 4 months in average and other benefits in terms of improved quality of life have not been demonstrated , which is under development by Millennium Pharmaceuticals, is an inhibitor of type III receptor tyrosine kinase . A first phase II study carried on patients receiving MLN518 with recurrent GBM was closed due to the lack of efficacy of the treatment , hence preventing tumor growth and proliferation. Two phase II studies, which enrolled between 66 and 88 patients, did not show increased survival in patients receiving Enzastaurin compared with untreated patients , under development by AstraZeneca, is an anti-angiogenic drug that inhibits tyrosine kinase with activity against PDGF receptors and c-Kit. Preclinical studies carried out on mice bearing U87, U118, and CNS1 glioblastoma, which received Cediranib orally, showed that this drug did not affect tumor growth, but led to a slight increase in mouse survival by 5–10 days compared with untreated mice , which is under development by Deciphera Pharmaceuticals, is an anti VEGF drug that was designed to overcome BV resistance by targeting proto-oncogene MET, TIE2-expressing macrophages, and VEGFR2. In the GSC17 glioma xenograft model, administration of a combination of altiratinib and bevacizumab significantly prolonged survival compared with treatment using bevacizumab alone, suggesting that Altiratinib could be used to improve bevacizumab therapeutic efficacy , which is under development by Bexion Pharmaceuticals, is made of SapC introduced in DOPS nano-vesicles. It is thought to trigger anti-tumor activity by targeting phosphatidylserine present in large quantity in the outer membrane of tumor associated vasculature and by preventing TGF-β expression and tumor coagulation  is under development by Takeda Pharmaceuticals Internationals that bought Millenium, which originally filed the patent protecting Alisertib. Alisertib acts against the tumor by inhibiting Aurora-A kinase. Mice bearing GB169 or GB30 glioma xenografts received orally TC-A237, resulting in an increased maximum survival by 5–15 days  of the tumor , under development by Celldex, is a vaccine composed of peptides. It was designed to treat patients expressing a mutant of EGFR (EGFRvIII), which is present among 20–30% of GBM patients and is absent on healthy cells. Rindopepimut should therefore specifically target GBM cells. It operates by triggering humoral and cellular responses against EGFRvIII-positive cells , under development by Agenus, is a clinical vaccine containing a heat shock protein peptide complex (HSPPC-96), in particular the heat shock protein gp96. It is a patient specific vaccine fabricated using patient's tumor tissue. It is expected to trigger an anti-tumor immune response, possibly involving CD8+ and CD4+ T cells, as was observed during the prophage treatment of wild type Balb/c mice bearing fibrosarcoma tumors , which is under development by Epitopoietic Research Corporation (ERC), is composed of autologous antigens, surgically removed from patient's tumor tissue, which are administered together with allogeneic antigens coming from glioma tissues resected from other GBM patients. A phase I study showed that 100% of patients treated with Gliovac were still alive 6 months following the beginning of treatment compared with only 33% for the controlled group  found on human leukocyte antigen (HLA) surface receptors coming from primary human GBM tissue. It is designed to activate cytotoxic T cells against tumor cells expressing TUMAP and also to prevent potential tumor escape mechanisms. A phase I clinical trial carried out on HLA-A*02 positive patients seems to have highlighted an anti-tumor immune response, but it did not conclude in any increased survival  vaccine. It contains a combination of autologous tumor antigens with patient's own antigens. Following injection to the patient, DCVax-L should enable DC to present their surface tumor antigen to the CD4 and CD8 T cells and hence to activate these immune cells specifically against the tumor. A clinical phase I/II showed that patients treated with DCVax-L displayed OS and PFS, which were longer than those of the historical control by 21 and 15 months, respectively , which is under development by AbbVie, is an antibody-drug conjugate that preferentially binds to EGFR, which is overexpressed in glioma cell and present in 50% of GBM patients. It then internalizes in cancer cells where it releases an anti-microtubule agent, called monomethyl auristatin F, MMAF, triggering tumor cell death. In a phase I clinical trial, ocular toxicity was observed and it is too early to conclude about any clinical efficacy of Depatux-M , which is under development by Apogenix, is designed to block CD95 pathway by inhibiting CD95 ligand, which consists of the CD95 receptor extracellular domain fused to the Fc domain of IgG. A phase II clinical trial carried out on 91 patients suffering from recurrent GBM showed that APG101 administration combined with radiotherapy increases patient PFS and PFS6 by 2 and 17%, respectively, compared with radiotherapy alone . This suggests that APG101 leads to survival benefit, but this result still needs to be confirmed on a larger cohort of patients within a phase III clinical trial . They were shown to be chemo-radiosensitisers, i.e., to enhance the antitumor efficacy generated both by X-rays and chemotherapy in vitro  designed to target six different tumor associated antigens (TAA). A clinical study carried out on 21 GBM patients has reported larger PFS and OS in patients with increased expression of TAA as well as a decrease or absence of CD133 overexpressed on glioma stem cells in 5 patients following a second resection , which leads to the permanent integration of RRV into the cancer cell genome, and encodes yeast cytosine deaminase, which further converts the antifungal prodrug 5-fluorocytosine (FC) into the anticancer drug 5-fluorouracil, hence mediating local tumor destruction. In mice bearing U87, Tu-2449, TOCA injection seemed to have resulted in tumor disappearance among 40–100% of treated mice, depending on tumor type, quantity of drug injected, and the combination (or not) of TOCA511 with TOCAFC , which is under development by Oryx GmBH, is an oncolytic virus designed to specifically target and destroy cancer cells. A phase I/IIa clinical trial carried out on GBM receiving H-1PV showed that H-1PV was well tolerated, crossed the BBB, spread through the tumor, and possibly triggered an antitumor immune response through antibody formation and specific T cell response. Patient survival seemed to have been prolonged, but a phase III clinical trial is necessary to confirm this result  and genetically engineered models.Glioblastoma cell line xenografts, such as the commercially available GBM immortalized cell lines U87, U251, T98G, and A172, are usually relatively easy to grow, but these cell lines are reported to be quite different from a GBM of a human patient, being circumscribed, having different genotype  are GBM tumors grown orthotopically or subcutaneously on mice by administering either biopsied patient tumor tissue  models involve mice in which certain genes have been inactivated to study genetic alterations involved in GBM tumor initiation and progression. Although GEM models can help understanding the role of tumor microenvironment  or spontaneous (P560) GBM mouse models  , MiR-21, MiR-125b, MiR-181, integrin such as αvβ3 and αvβ5  embedded in a biodegradable co-polymer formed of 1,3-bis-(p-carboxyphenoxy)propane (pCPP) and sebacic acid (SA), is implanted in GBM resection cavity and progressively releases BCNU in the tumor , GBM drugs are eligible to this status and most previously described drugs were given the orphan status by the regulatory agencies of various countries, most frequently by the EMA in Europe and FDA in the USA. This status was originally set up to encourage companies to develop treatments for rare diseases such as GBM for which the chances of generating a profit are undermined by the limited number of patients. Financially, it can provide: (i) partial coverage of clinical trial cost through tax credit reimbursement , (ii) grants through programs that specially support orphan drug development , (iii) discounts on regulatory fees necessary to obtain market authorization in USA, Europe, and Japan. In some countries like Japan, medical expenses can be covered by National Health Insurance in exchange of a control over drug price, a good system that enables both to lower drug development cost and to reach a reasonable drug selling price. Most importantly, the FDA and EMA grant a 7–10 years marketing exclusivity to an orphan drug in the USA and Europe, respectively, by not authorizing similar products to be commercialized during this lapse of time. The orphan status can also give access to scientific advice, which is provided by regulatory agencies to determine the right path toward clinical trials and commercialization and to avoid unnecessary costly and lengthy developments. Finally, it can lead to accelerated drug assessment and approval, which appear essential both to reduce drug development cost and to accelerate treatment access for GBM patients , equipment for positioning the patient during RT (WO2005122993), determination of the dose that needs to be used during RT , robotic system to determine radiation beam trajectory during RT (WO2010120534), system to avoid collisions during treatment (WO2015017630), set-up of a quality assurance system to enable reproducibility of treatment parameters (WO2015044781), equipment to generate beams in several direction with modulated intensity (WO2015062093).Cyber-knife: Radiation equipment , methods to orientate the radiation beam toward the tumor including being in some cases a robotized , system including in some cases a robotic arm for positioning patient , linear accelerator (LINAC) including in some cases a robotic arm coupled to the LINAC , method for determining the volume to be irradiated and/or dose of radiation and/or treatment parameters , imaging methods and apparatus to irradiate tumor region , radiation system with a gantry to image and guide radiotherapy .Gamma-knife: method for collimation of radiation beams (WO1996019262), apparatus for positioning the patient (WO1997017896), method for determining radiation dose (WO1998057705), X-ray/gamma ray radiation apparatus with/without linear accelerator with/without collimator with/without imaging system , surface mountable apparatus for combining radiation and imaging systems (WO2001012066), stereotactic apparatus for guiding radiotherapy (WO2001021085), method for controlling/direction radiation beams (WO2005051215), method for treatment planning , method for fixing patient's head during radiotherapy (WO2009129847), method to enable patient movement during radiation (WO2009137010), method for measuring radiation (WO2010031452).IMRT: Methods for treatment planning , apparatus for sequential generation of modulated beams , dose determination for IRMT (WO2005052721), method for focusing several beams during IRMT (WO2015176265), support system for patients (WO2009033035), IMRT combined with VMAT (WO2011042819).Stereotactic radiosurgery: Apparatus for SRS , laser or other marker for aligning SRS beam , dose estimate for SRS , patient positioning device for SRS , collision prevention system for SRS (WO2017007165).Optune: Method for treating a tumor with an electric field oscillating at different frequencies alone or in combination with other treatments such as photodynamic therapy  for treating tumor cells.Neuroblate/Visualase: MRI guided surgical apparatus that includes a laser that heats the tumor (WO2003051217).Neuroarm: Robot for brain surgery .ABT-414: Composition comprising antibody against Epidermal Growth factor receptor (EGFR) that inhibits Bcl-xL ; composition comprising antibody drug conjugates with specific drug/antibody ratio (WO2014152199).Afatinib: Preparation of various forms/compositions of Afatinib or Afatinib di-maleate , use of Afatinib for cancer treatment .Aldoxorubicin: System of transport of a drug, in which a protein attached to the drug targets a tumor and specifically releases the drug in the tumor under pH changes, , various formulations of doxorubicin .Altiratinib: various kinase inhibitors , derivatives of cyclopropane/cycloproply amides , pyridine/pyridine/pyrimidines derivatives , imidazoline derivatives (WO2014145015), triazol derivative (WO2014145023), with anti-proliferative activity.ANG-1005: Pharmaceutical composition comprising aprotinin fragments Angiopep-1, Angiopep-2, conjugated (or not) to other compounds such as iduronate-2-sulfatase combined (or not) with lysomal enzyme, where this complex can cross the BBB and in some conditions accumulate in lysosomes , paclitaxel, and a tonicity, buffering, bulking, solubilizing agent (WO2009127072).Asunercept: Cancer treatment with an inhibitor of CD95/CD95L in combination (or not) with an immunotherapeutic agent .Au NPs: Metal nanoparticles with various ligands, mainly immunogenic ones .AZD-2171: Production of anti-angiogenic drug , composed of maleate (WO2005061488), modulating the activity of p53 kinase , in combination with gemcitabine (WO2007003933), Mek-inhibitor II (WO2008125820).Bevacizumab (BV): BV in combination with various treatments such as ZD6474 (WO2008037996), campthotecin (WO2010043050), carbonic hydrate (WO2013130354), pyradizanie derivatives (WO2013139423), a parvovirus (WO2016128146), AMP (WO2017045595), immune-conjugates that bind to FORLI (IMGN853) and doxorubicin (WO2017049149), ultrasounds (WO2017080481); BV administration method to increase BV penetration in the brain (WO2011049906); BV preparation with enhanced stability comprising buffering agent and osmotic pressure regulator (WO2016045570).CBL-0137: Method of production of CBL-0137 and use for cancer treatment (WO2015157172).CDX-110: Fabrication and use of antibody vaccine that preferentially binds to GPNMB, MET, EGFR, ALK (tyrosine kinase receptor), and induce immune antitumor activity , peptide-vaccine composition containing KL-H-peptide conjugate (WO2011077309).DCVax-L: Method to increase class I presentation of antigens by human dendritic cell (DC) (WO2001087325), methods to isolate, cultivate, differentiate DC precursor to form immature and/or mature DC preferentially to trigger T1 immune response , tangential flow filtration method to remove and isolate leukocyte from patient's blood (WO2004000444), composition comprising dendritic cells for administration to a patient (WO2004053072).Enzastaurin: Use of Enzastaurin in combination with HDAC inhibitor to treat cancer (WO2010074936).GDC-0084: phosphoinostide/pyrimidine kinase inhibitor and use for anticancer treatment .Gliadel: Carmustine alone or in combination with other drugs, with/without specific solvent, lyophilized or not, for cancer treatment , system for releasing carmustine in the brain using wafer/implant .Gliovac: Tumor vaccine comprising allogenic or xenogeneic tumor cells (WO2007085648).H1-PV: Method of tumor treatment using the parvovirus H1PV .ICT-107: Method of cancer treatment by dendritic cell vaccination comprising tumor associated antigens .IMA950: gp96 carrying antigens to activate DC (WO2002004516), or tumor associated peptides with/without tumor-associated T-helper cell peptide epitotes derived (or not) from survivin, preferentially binding to MHC-I , generating immune antitumor activity.MEDI-3617 and MEDI-575: antibody association with sucrose to prevent antibody self-association (WO20122003470).Mibefradil: Method of preparation of Mibefradil , anti-metastatic activity of Mibefradil (WO2005086971).Nanocell/targoMir: Method for purifying bacterial minicells (WO2004113507), method for targeting mammalian cells with minicells , minicells brain tumor targeting (WO2013088250), combined treatment with minicells and interferon-gamma (WO2015049589).NOX-A12: Spiegelmer, in some cases immobilized .Prophage: Composition comprising a heat shock protein and a saponin or an antigen .SapC-DOPS: Composition comprising combination of saposin C and dioleoylphosphatidylserine for tumor treatment (WO2004096159).SurVaxM: surviving peptide vaccine for tumor treatment .TC-A237: Combination of Mek and Aurora inhibitors (WO2012167247).TMZ: Combined antitumor treatment with TMZ and ATase inhibiting agent (WO1994015615), Cisplatin (W01997007804), interferon , immunocytokine (WO20100078916), VEGFR2 (WO2010093771), methoxyamine (WO2001012199), irinotecan (WO2001054678), thalidomide (WO2002043720), TNF-ALPHA (WO2006026348), kinase inhibitors , bormeol and/or methol (WO2008022535), TMZ administered in microcrystalline suspension (WO2000033823), cancer treatment method with TMZ (WO2000057867), methods for TMZ synthesis , controlled release system containing TMZ (WO2004028534), various formulations/compositions of TMZ and TMZ derivatives , various method of TMZ protocol/administration/dosage for cancer treatment .TOCA-511: Formulation containing 5-fluorocytosine and/or retroviral vectors with immune-stimulating activity for cancer treatment .Val-083: Various derivatives of hexitols for cancer treatment alone or in combination with other drugs .VB-111: Fas-chimera adenovirus vector for cancer treatment (US9200056).At the heart of the GBM community lie the patients. Different structures contribute to the effort for the development of an effective GBM treatment. They consist of medical teams and hospital services dedicated to GBM treatment, EANO and SNO associations that organize conferences on glioblastoma and various means of communication within the glioblastoma community, patient associations, foundations, pharmaceutical companies, regulatory agencies, and various public and private structures that provide funding for research and clinical trials Figure .GBM costs can be divided between direct costs due to stays and treatments carried out at hospital and indirect costs coming for example from work leave and resulting income losses. In the United-States, GBM average direct cost per patient has been estimated as 8,500 $ per month, mainly coming from surgery, imaging, and radiotherapy, while standard chemotherapy only represents 0.1% of this cost .Table Glioblastoma is a very aggressive cancer, leading to patient death a few months only following diagnosis. For operable GBM, surgery remains the most effective initial GBM treatment. However, it does not enable the removal of the entire tumor and the tumor therefore re-grows.GBM treatments that are under development or commercialized include:Methods to improve surgery, such as the maintenance of GBM patients awake during the surgical operation (AWC), the use of a robotized system enabling to improve surgery accuracy (Neuroarm), tools to improve visualization of tumor cells and enable a distinction between tumor and healthy cells using fluorescence imaging , magnetic imaging , DTI-FT or MS.Techniques to improve radiotherapy, using an external X-ray source, which is combined with tumor imaging , modulation of radiation intensity (IMRT), a focalization of the radiation beam at some specific locations of the tumor , an external source of protons enabling to limit the overlap of the radiation beam with the healthy tissue region (PRT), an internal source of X-rays .GBM treatments using different electromagnetic radiation sources such as the electric field blocking the mitosis of tumor cells (Optune), or laser thermotherapy locally heating the tumor .Therapies targeting specific parts of the tumor .Drugs against angiogenesis .A kinase inhibitor (GDC-0084)Immunotherapies such as vaccines , antibodies , check point inhibitors (NOX-A12).Nanotherapies miRNA targeting (TargoMIR)Glioma stem cell targeting (ICT-107)Gene Therapy (TOCA511)Virus (ParvOryx)Among these treatments, Optune seems to be the only one with some efficacy  demonstrated in a phase III clinical trial. Many of them are still at a too early stage of development to be able to firmly conclude about their efficacy.Several ways to improve the efficacy of GBM treatments have also been suggested. Early diagnosis methods could be developed enabling the treatment of smaller tumors possibly easier to eradicate. More preclinical trials could be carried out on large animals such as dogs whose relatively large tumor sizes could lead to a better estimate of the human dose than mouse studies. Drug delivery could be improved to better enable GBM drugs to reach the tumor. For intravenous injection, new methods shall be developed to allow GBM drugs to cross the BBB. For intra-tumor administration, a better diffusion of the drug should be obtained, for example by using CED.At an industrial level, the development of GBM therapies has been facilitated by the orphan drug status that applies on GBM drugs due to the low prevalence of GBM. Several analyzed companies seem to earn a large number of patents protecting their GBM treatment and may be able to generate revenues when/if they firmly demonstrate some efficacy with their GBM drug, as it is the case for Novocure that has announced a large revenue in 2016 Table .This review describes industrial developments of GBM drugs and medical devices at different stages of developments, i.e., which were tested in:early clinical trials not yet enabling to conclude about their efficacy on a large cohort of patients .phases II or III clinical trials resulting in an absence of efficacy .phase III clinical trials demonstrating some modest efficacy pre-clinically mainly showing tumor growth retardation on tumors originating from PDX and/or immortalized cell lines .Cells showing decrease in GBM cell survival or proliferation Optune is the only recently developed GBM drug that has shown some efficacy  on a large cohort of patients.Among the approaches tested for GBM treatments that have led to preclinical efficacy or clinical efficacy on a limited number of patients are:drugs targeting of various types of molecules such as T-type channel (Mibefradil), DNA , microtubule (ANG-1005), EGFR (Afatinib),Anti-angiogenic drugs ,Immunotherapies Glioma stem cell targeting (ICT-107)Gene therapy (TOCA 511 combined with TOCAFC)Virus (ParvOryx)More clinical trials are necessary to determine if these drugs are efficient (or not) on a large number of patients.Traditional approaches fail to treat efficiently glioblastoma. Surgery does not completely remove glioblastoma without damaging the brain. Radiation therapy cannot be used beyond a certain threshold dose, which is insufficient to completely eradicate glioblastoma. Chemotherapy has shown limited efficacy and can be very toxic.According to the author, one of the most interesting therapeutic approaches is to expose the tumor to an external energy source, such as an alternating electric or magnetic field, to repeatedly induce antitumor activity. Ideally, these sources should be chosen to be able to carry out the treatment until the tumor has fully disappeared. They should also be sufficiently compact, inexpensive, and easy to use so that patients can carry out the treatment at home, possibly with the help of a nurse. Ultimately, it is desirable that the use of the hospital environment is minimized to reduce costs and allow the treatment of as many patients as possible at a reasonable cost for each patient.Immunotherapy approaches have also raised an enormous interest, but failed until now to show antitumor efficacy on humans. This may be due to the complex immune mechanisms that are not yet fully described and understood. These approaches should be pursued, maybe by trying to reactivate the immune system against the tumor several times until the tumor has fully disappeared.Finally, on the one hand more effort should be spent to develop a proper preclinical model, without which treatment efficacy cannot be properly assessed. On the other hand, methods should be developed to diagnose glioblastoma earlier. The author thinks that those steps are prerequisites to develop an efficient glioblastoma treatment.Due to the proximity of the author with the two companies Nanobacterie and Magforce, the latter are not analyzed in this review. The patents were quoted by their publication number.The author confirms being the sole contributor of this work and approved it for publication.EA has been working with the company Nanobacterie.


Kidney transplantation is the current treatment of choice for patients with end-stage renal disease. Innovations in transplantation and immunosuppression regimens have greatly improved the renal allograft survival. Based on recently published data from the Scientific Registry of Transplant recipients, prevalence of kidney transplants is steadily rising in the United States. Over 210,000 kidney transplant recipients were alive with a functioning graft in mid-2016, which is nearly twice as many as in 2005. While successful renal transplantation corrects most of the electrolyte and mineral abnormalities seen in advanced renal failure, the abnormalities seen in the post-transplant period are surprisingly different from those seen in chronic kidney disease. Multiple factors contribute to the high prevalence of these abnormalities that include level of allograft function, use of immunosuppressive medications and metabolic changes in the post-transplant period. Electrolyte disturbances are common in patients after renal transplantation, and several studies have tried to determine the clinical significance of these disturbances. In this manuscript we review the key aspects of the most commonly found post-transplant electrolyte abnormalities. We focus on their epidemiology, pathophysiology, clinical manifestations, and available treatment approaches. End-stage renal disease is associated with a variety of metabolic and electrolyte derangements. Although most of these abnormalities resolve with kidney transplantation, a new plethora of electrolytes and acid-base abnormalities are noted. With rising prevalence of kidney transplantation, even the general nephrologist and internists have to address these abnormalities. An important study conducted by Einollahi et al. shed some light about the most common electrolyte disorders encountered after kidney transplantation, but the exact incidence and prevalence of these disorders vary from study to study . The autHyperkalemia is a common complication in renal allograft recipients found with a reported incidence ranging from 25 to 44% in kidney transplant recipients on calcineurin inhibitors[CNIs] . SimultaPotassium (K+) is the most abundant intracellular cation with a concentration of 150 mEq/L compared to just 4 mEq/L in the extracellular compartment. This difference in concentration between compartments is maintained by the Na-K-ATPase pump. Since the ratio between the intracellular and extracellular K+ concentration is the main determinant of the resting membrane potential then maintaining K homeostasis, i.e., maintaining a relatively constant plasma K+ concentration, is critical for cell function . Figure Hyperkalemia is usually asymptomatic until cardiac complications develop. Excitable tissues like cardiac and skeletal muscle are the most commonly affected organs. Hyperkalemia causes increased potassium conductance and shortens the duration of the action potential making the heart more susceptible to arrhythmias. Arrhythmias like sinus arrest, sinus bradycardia, ventricular fibrillation and asystole can be caused by hyperkalemia . Peaked Limiting the use or lowering the dose of drugs that increase potassium levels may not always be feasible in the immediate post-transplant setting. Initial approach should include dietary modification and addition of thiazide or loop diuretic if volume status permits. Fludrocortisone has mineralocorticoid properties and causes sodium reabsorption and potassium excretion in the distal nephron. Studies indicate that fludrocortisone can ameliorate persistent hyperkalemia and metabolic acidosis in transplant recipients, but it can result in fluid retention , 16. SodMetabolic acidosis after kidney transplantation is not an uncommon finding. It has been reported with varying prevalence from 12 to 58% . While iWhen present, metabolic acidosis is predominantly of the normal anion gap variant. In addition to the common pathogenic factors acting in any form of chronic kidney disease, there are other mechanisms specific to the kidney transplant status. Both proximal and distal (including type 4) renal tubular acidosis can be seen in kidney transplant recipients . Diarrhe+-V-ATPase pumps and anion exchanger (AE1) and decrease in renal function are postulated to be the factors responsible for association between rejection and metabolic acidosis  , 27. Tubacidosis . Experimacidosis . Cyclospacidosis   and 1,25-dihydroxyvitamin D3 by acting on receptors in the gut, kidney, and bone. Calcium is essential for cellular signaling, nerve impulse transmission, coagulation, muscle contraction, and bone mineralization . The disTertiary hyperparathyroidism is a very common cause of post-transplant hypercalcemia. A successful kidney transplant eliminates the stimuli that usually induce parathyroid overactivity in dialysis patients. Yet parathyroid involution does not always occur immediately, especially in patients with severe pre-transplant hyperparathyroidism, probably due to the presence of underlying parathyroid hyperplasia or adenoma, causing persistent and sometimes significant hypercalcemia. The improvement in production of calcitriol post-transplant, further stimulated by the inappropriately high PTH levels and low phosphorous levels, also is considered an important factor for the development of hypercalcemia. Steroid therapy and the resorption of soft-tissue calcium phosphate deposition formed in dialysis patients are also hypothesized as potential contributors for post-transplant hypercalcemia , 42–44 .The clinical manifestations of hypercalcemia range from anorexia, nausea, constipation, polyuria, polydipsia, and nephrocalcinosis in mild cases to cognitive difficulties, drowsiness or obtundation in severe cases in the general population . Given tKDIGO guidelines recommend that we apply the same principles for managing the mineral bone disorders in patients with chronic kidney disease stages 3–5 to managing bone mineral disorders after renal transplant. However, no specific guidelines are offered by KDIGO pertaining to the management of metabolic derangements in kidney transplant recipients with normal renal function. The first treatment option nowadays for post-transplant hypercalcemia is a calcimimetic, cinacalcet being most commonly used. Calcimimetics induce changes in conformation of the calcium receptor and thus increase sensitivity to extracellular calcium and cause reduction in PTH secretion and thereby decrease calcium levels in tertiary hyperparathyroidism . If therEvenepoel et al. studied the effect of cinacalcet in a placebo-controlled trial for management of post-transplant hypercalcemia due to persistent hyperparathyroidism. They demonstrated that cinacalcet normalizes serum calcium and lowers PTH levels while placebo treatment led to no significant changes in these parameters and the discontinuation rate was quite low. However, after 1 year of treatment, the cinacalcet group had several other outcomes similar to placebo treatment: no improvement in bone mineral density (BMD), no improvement in biomarkers of high bone turnover and both groups had comparable and stable estimated GFR . When thIn renal transplant recipients, hypomagnesemia is reported with high prevalence with lowest serum magnesium concentration noticed around second month post transplantation. In 20% of the renal transplant recipients, hypomagnesemia might persist several years after transplantation . The incMagnesium is the fourth most abundant cation in the body and the second most abundant intracellular cation after potassium . Around Use of CNIs is associated with an inappropriate and significant increase in fractional excretion of calcium and magnesium. CNIs induce renal magnesium wasting by downregulation of magnesium transport proteins in the distal tubule Figure . CNIs inMagnesium is an essential cofactor for critical enzymatic reactions, and hence has a role in various physiological functions involving the neuromuscular and cardiovascular systems. Magnesium plays a role in PTH-induced release of calcium from bone and in severe hypomagnesemia also might cause diminished PTH secretion . HypomagThere are studies showing association of hypomagnesemia with vascular stiffness and decreased graft survival in patients with CNI toxicity –70. GuptIt has been well established that there is a strong association between hypomagnesemia and insulin resistance in the general population. Due to increasing awareness about post-transplant diabetes, several studies looked at hypomagnesemia after renal transplantation and its relation with post-transplant diabetes. Intracellular Magnesium regulates enzymes and ion transport channels in pancreatic beta cells and plays a role in insulin receptor phosphorylation. Conversely, insulin activates the renal magnesium channel TRMP6 that plays a role in magnesium reabsorption in the kidney and hence plays a role in magnesium homeostasis. Consequently, it is suggested that a vicious cycle may ensue in hypomagnesemic patients with diabetes in which low magnesium levels causes insulin resistance and insulin resistance reduces serum magnesium concentrations .p < 0.05)  in their study was associated with a quantitatively increased risk of post-transplant diabetes, based on time-fixed, conventional time-varying, and rolling-average time-varying Cox proportional hazards models.  .p = 0.02), and study had the drawback that fasting plasma glucose levels were higher in the control group already at baseline. In addition, no significant differences were noted in other measures of glycemia i.e., area under the glucose curve during an oral glucose tolerance test and in insulin resistance as expressed by Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR). The trial was also underpowered to evaluate the effect of magnesium supplementation on the risk of post-transplant diabetes. Of note, one in four patients in the treatment group had persistent hypomagnesemia despite reasonably high doses of magnesium oxide  are the major regulators of phosphate homeostasis and they involve a complex interplay between intestinal absorption, internal redistribution, and renal excretion of phosphate. FGF23 is a recently characterized phosphaturic hormone that is produced in osteoblasts in response to increased phosphate levels. FGF23 causes suppression of vitamin D 1α hydroxylation, increase in renal phosphate excretion, and decreases gut absorption of phosphate causing a decrease in serum phosphate levels. Vitamin D increases phosphate absorption in gut and kidney while PTH increases renal excretion of phosphate .FGF23 and PTH are found to be at elevated levels in chronic kidney disease and end stage renal disease patients in response to elevated phosphate levels. After successful kidney transplantation, elevated FGF23 levels and other phosphatonins might take some time to come down and this persistent elevation is considered to play a key causative role in the phosphaturia and hypophosphatemia seen in the kidney transplant recipients , 86. TacHypophosphatemia, especially in the severe forms is known to cause predisposition to hemolysis, rhabdomyolysis, respiratory failure, muscle weakness, seizures, and myocardial depression . There iThough no specific guidelines exist for the management of post-transplant hypophosphatemia, patients are usually treated with oral phosphate supplements and the treatment is well tolerated. However, intervention studies are scarce for the treatment of post-transplant hypophosphatemia and phosphate supplementation in these patients is not always considered benign. There is a theoretical risk that phosphate supplementation can in turn increase PTH and FGF23 synthesis and hence worsen hyperparathyroidism and cause further phosphate wasting in patients with a well-functioning allograft , 92. ThiThere is high incidence and prevalence of a spectrum of acid–base and electrolyte disorders in renal transplant recipients. Understanding the pathophysiological effects of these disorders and knowledge of the current available evidence regarding therapy is crucial for making effective clinical decisions in this vulnerable population. Additional research in both fundamental and clinical domains is necessary to ensure an evidence-based approach for the management of these disorders.VP has written the sections of hyperkalemia, metabolic acidosis, hypocalcemia, hypomagnesemia, and hypophosphatemia with some contribution of HR-B. VP and HR-B contributed equally to developing the tables, introduction, and conclusions. HR-B developed all the figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Silica continues to represent an intriguing topic of fundamental and applied research across various scientific fields, from geology to physics, chemistry, cell biology, and particle toxicology. The pathogenic activity of silica is variable, depending on the physico-chemical features of the particles. In the last 50 years, crystallinity and capacity to generate free radicals have been recognized as relevant features for silica toxicity. The ‘surface’ also plays an important role in silica toxicity, but this term has often been used in a very general way, without defining which properties of the surface are actually driving toxicity. How the chemical features  and configuration of the silica surface can trigger toxic responses remains incompletely understood.Recent developments in surface chemistry, cell biology and toxicology provide new avenues to improve our understanding of the molecular mechanisms of the adverse responses to silica particles. New physico-chemical methods can finely characterize and quantify silanols at the surface of silica particles. Advanced computational modelling and atomic force microscopy offer unique opportunities to explore the intimate interactions between silica surface and membrane models or cells. In recent years, interdisciplinary research, using these tools, has built increasing evidence that surface silanols are critical determinants of the interaction between silica particles and biomolecules, membranes, cell systems, or animal models. It also has become clear that silanol configuration, and eventually biological responses, can be affected by impurities within the crystal structure, or coatings covering the particle surface. The discovery of new molecular targets of crystalline as well as amorphous silica particles in the immune system and in epithelial lung cells represents new possible toxicity pathways. Cellular recognition systems that detect specific features of the surface of silica particles have been identified.Interdisciplinary research bridging surface chemistry to toxicology is progressively solving the puzzling issue of the variable toxicity of silica. Further interdisciplinary research is ongoing to elucidate the intimate mechanisms of silica pathogenicity, to possibly mitigate or reduce surface reactivity. Guides and examples of good practice such as those proposed by the European Network on Silica (NEPSI) are recognized as valuable and necessary instruments to complement regulatory measures [Almost 60% of the Earth’s crust is made of silica, mainly in its crystalline form. Crystalline silica (CS) is thus a key industrial product, present in many materials extracted from the ground, and an essential component of numerous products of our daily life, including ceramics, glass, paints, plastics, aids in industrial processes, and in many construction products. Industrial sectors involved with CS include producers or users of sand, gravel, and aggregates, industrial minerals, coal, cement and plaster. Thus, workers are exposed to silica in many occupational settings, and excessive inhalation of respirable CS particles has long been associated with an increased risk of respiratory and systemic diseases. Silicosis is probably the most ancient occupational disease, but obstructive lung diseases, lung cancer or autoimmune diseases are other adverse manifestations related to silica exposure. Effective preventive measures, mainly based on exposure reduction, are available to reduce the occurrence of silica-associated diseases . The recmeasures . The dirThe exact mechanism governing the pathogenicity of silica particles remains, indeed, one of the most puzzling issues in toxicology, despite extensive research efforts during the last century carcinogenicity in humans was not detected in all industrial circumstances studied. Carcinogenicity may be dependent on inherent characteristics of the silica or on external factors affecting its biological activity or distribution of its polymorphs”. Several publications followed, including “The quartz hazard: A variable entity” [The need for interdisciplinary collaboration in the search for the structure-toxicity relationship of silica particles became clear and urgent after IARC monograph n° 68 . While i entity” , “Surfac entity” , and “Va entity” . VariabiIn the same period, the need for new and efficient materials prompted the chemical community to develop the production of nanomaterials, including amorphous silica (AS) nanoparticles . As a coRecent developments in the surface chemistry of silica, cell biology and toxicology have provided new avenues to extend and improve our understanding of the variable reactivity of silica particles. New tools and models are also available to explore the interactions between silica particles and cells. This, collectively, creates a unique momentum for finally elucidating the main mechanisms of silica toxicity. A focused workshop was jointly organized in Torino (September 2018) by the ‘G. Scansetti’ Center of the University of Torino  and the Louvain centre for Toxicology and Applied Pharmacology (Belgium) to gather both the new and older generations of researchers active in the field, from different horizons and across a range of disciplines, including chemistry, geology, biophysics, biology and toxicology. The aim of the workshop was to discuss recent research on the understanding and prediction of silica toxicity through surface characterization, particle toxicology or preparation of safer materials. This Commentary illustrates how interdisciplinarity can contribute to the understanding of the intimate mechanisms of silica pathogenicity.2) and siloxane bridges (≡Si-O-Si≡) i≡) Fig. . Strainethermogravimetric analysis, coupled with mass-spectroscopic analysis of evolved gas, allows determination of the total  silanol content. Titration of hydroxyl groups on the particle surface with appropriate reagents such as lithium aluminium hydride  yields the amount of surface silanols. Not all surface silanol groups are, however, accessible due to steric hindrance. A prerequisite to every quantitative analysis is, therefore, a thorough sample pre-treatment, removing physisorbed water at a temperature of 140–150 °C and application of a vacuum. Such a characterization procedure is illustrated by the example of pyrogenic AS, produced by flame spray pyrolysis at different flame enthalpies, resulting in a range of flame temperatures and particle synthesis times [2), indicating a fully hydroxylated surface. This value was reduced down to ~ 4 OH/nm2 for silica made in long and ‘hot’ flames. Moreover, ‘cold-flame’ silica exhibited a higher proportion of hydrogen-bonded vs. isolated silanols and more physisorbed water than ‘hot-flame’ silica of similar average primary particle diameter. Interestingly, the above surface chemistry differences translate to lower in vitro cytotoxic activity in human monocytes for ‘cold-flame’ silica, compared to the ‘hot-flame’ sample of the same specific surface area but with lower surface silanol density [Surface silanols can be detected and quantified by several complementary methods, including thermal gravimetric analysis, titration, zeta (ζ)-potential, magnetic resonance, and vibrational spectroscopies. While infrared and Raman spectroscopy alone can provide a qualitative picture of the silanol groups present in silica samples, they fail at quantification, unless they are combined with additional measures such as H/D isotopic exchange (see below). Careful is times . Thereby density .infrared (IR) spectroscopy. IR spectroscopy is widely and easily applicable, and the O-H stretching frequency vibrations (νOH) are highly sensitive to inter-silanols interactions, which depend on the distance between ≡Si-OH groups [Recent experimental and modeling advances also revealed silanol arrangements, exposed by CS particles, using H groups . Of noteH groups , 33 allomolecular dynamics simulations can also be used to explore the structure and reactivity of different silica surfaces, including CS and AS. Ab initio simulations allow simulating interfaces, including electronic structure aspects as well as dynamics, and finite temperature effects, which are essential to describe realistic conditions. The acidity of different types of silanols depends on the local environment, also including electrolyte solutions [Ka around 8.5, and more acid ones, forming out-of-plane hydrogen bonds, and exhibiting and acidity constant around 5 [Ka’s of the surface silanols follow a combination of the cationic and anionic Hofmeister series in the order pKa (neat solution) < pKa (NaCl solution) < pKa (NaI solution) < pKa (KCl solutions) [−. The change in the pKa is the result of both water destructuring by alkali halides, as well as of the specific cation/SiO− interaction, depending on the electrolyte [Ab initio olutions . With abaround 5 . When moaround 5 . In morelutions)  which isctrolyte . Additioctrolyte . Such inctrolyte .Molecular dynamics simulations are also a valuable tool to investigate interactions at the biotic/abiotic interface. Despite the increase in available computational resources, these methods still suffer from a debilitating timescale problem that greatly reduces the number of phenomena that can be investigated, i.e. properly targeting free energy. So-called ‘enhanced’ sampling methods have been introduced to alleviate this problem , and havAtomic force microscopy (AFM) is another approach to elucidate interactions between the biological environment and solid materials such as silica particles. AFM is, to date, one of the most popular techniques to characterize the biophysics of biological interactions [ractions . From itractions . The traractions . Single-A significant bridge between surface chemistry and toxicology has been established by recent studies examining the relationship between silanols and pathogenic responses to silica particles. Particle toxicology studies often start with basic membranolytic tests, using red blood cell membrane damage (haemolysis) as a proxy for more complex mechanisms of toxicity. Quartz is highly haemolytic and often used as a positive control in haemolysis tests. Early investigations on the membranolytic potential of quartz focused on a systematic analysis of the physico-chemical properties of silica particles relevant for membranolysis . These sNext, membranolysis of phagolysosomes was identified as an early key event promoting activation of the inflammasome in macrophages and epithelial cells , 50. ThiA further piece to the puzzle was added by using respirable as-grown quartz crystals, obtained via an innovative hydrothermal synthesis procedure , 58. UnlThe presence of impurities within the crystalline structure of silica particles is another determinant of the variable pathogenic activity of silica , 22, espAs the physico-chemical determinants of silica toxicity appear linked to surface silanol groups, chemical blocking of these reactive groups might represent a strategy to render silica less toxic, and to increase workers’ safety. As already mentioned, several approaches were considered to modify, mask or inactivate the surface of CS particles with different compounds, including dipalmitoyl lecithin , Al lactSeveral studies explored the role of the silica surface in the toxicity of the reference CS sample, DQ12, modified with polyvinyl-pyridine-N-oxide (PVNO) or Al lactate. In an in vivo rodent model, these surface modifications reduced the ability of DQ12 to induce a persistent pulmonary inflammation, DNA damage in alveolar epithelial cells and lung tissue remodelling, including fibrosis, whereas particle clearance from the lung was increased , 28, 43.There are currently concrete efforts to bring preventive CS surface coating into industrial application. Two EU projects have developed and implemented, at an industrial scale, cost-effective coating technologies, based on stable, covalent masking of surface silanol groups to inhibit CS toxicity , 64. BotRecent research on the interaction between silica particles and cell receptors has revealed that AS nanoparticles affect the function of cellular ionic channels . AS nano2+ influx, and TNF-α release, which occurs within the first minutes of cell exposure to silica [Innate immune system recognition is also a sophisticated mechanism which promptly recognizes silica particles and engages crescendo immune and tissue responses. Major progress has been achieved in recent years regarding recognition of microorganisms by the innate immunity, notably by integrating a set of distinct receptors designated pattern recognition receptors (PRRs), which serve as sensors for monitoring the extracellular and intracellular compartments for microbial residues. After infection, this elaborate system also detects debris from dying cells  and perturbations in cytoplasmic homeostasis . Decades ago, such a PRR-mediated sensing system did not appear plausible for silica particles because they were considered different from biological structures such as bacterial cell-wall components or viral nucleic acids. The discovery that scavenger receptors  sense silica particles in macrophages  shifted o silica . Howevero silica . The pronew physico-chemical methods can finely characterize and quantify silanols at the surface of silica particles;computational modelling is unravelling some of the molecular mechanisms behind the interactions between silanols and biomolecules or cellular membranes;force microscopy with ad hoc functionalized tips offers unique opportunities to explore the interactions between cells and the surface of silica particles;fracturing of silica particles induces a perturbation of the regular crystalline face, generating, upon contact with atmospheric components, specific silanol populations (slightly-interacting and isolated silanols), which impart membranolytic and inflammatory activity to the respirable CS particles;impurities at the surface of some CS , including substitution of Al and/or Na and occlusion of particle surfaces by Al-rich accessory minerals, likely influences the H-bonding potential of silanols at the particle surface and can reduce toxicity;the toxicity of CS particles can effectively be reduced by surface coating processes masking silanol functionalities, also at the industrial level;the discovery of new molecular targets of silica particles  in the immune system and in epithelial lung cells allows exploration of new toxicity and surface-driven pathways for these particles.The workshop illustrated how the puzzling issue of the variable toxicity of silica can be progressively unravelled by interdisciplinary research bridging surface chemistry to toxicology. It highlighted several key aspects that will fuel further interdisciplinary research for the elucidation of the intimate mechanisms of silica pathogenicity for possible mitigation or reduction of surface reactivity, and hence prevention of adverse health effects:


Camptocormia has been reported in a plethora of diseases comprising disorders of the central nervous system, the peripheral nervous system, and the neuromuscular junction as well as hereditary and acquired myopathies. In sporadic late onset nemaline myopathy concomitant axial myopathy is common, but reports about camptocormia as the only presenting symptom in this condition are very rare. Notably, sporadic late onset nemaline myopathy is a potentially treatable condition in particular when associated with monoclonal gammopathy of unknown significance, HIV or rheumatological disorders.We report the case of a 62-year-old female patient, who presented with slowly progressive camptocormia. Comprehensive work-up including neurological work-up, laboratory tests, MR-imaging, muscle biopsy and genetic testing led to the diagnosis of sporadic late onset nemaline myopathy.Our case report highlights that sporadic late onset nemaline myopathy has to be considered in patients presenting with isolated camptocormia and comprehensive work-up of camptocormia is mandatory to ascertain the individual diagnosis, especially in consideration of treatable conditions. Camptocormia is characterized by involuntary forward flexion of the thoracolumbar spine. In contrast to spinal deformities due to skeletal disorders, forward flexion in this condition typically increases in upright and resolves in supine position . CamptocWe report the case of a 62-year-old female patient of European origin, who presented with slowly progressive camptocormia. Her progressive inability to walk upright started at the age of 52 years and was accompanied by generalized myalgias, which were independent of exertion. Her family history was negative for neurological and neuromuscular disorders and neurological examination at age 60 revealed isolated axial muscle weakness resulting in camptocormia Fig. a. DuringCamptocormia as the presenting symptom has been reported in a wide variety of primary myopathies including inflammatory myopathies, amyloid myopathy, myotonic dystrophy, muscular dystrophies , metabolic myopathies , mitochondrial myopathies and toxic myopathy , 4.In the reported patient with initially isolated camptocormia, our diagnostic work-up led to the diagnosis of sporadic late onset nemaline myopathy, which is defined as a late-onset and subacutely evolving muscle disorder. Schnitzler et al. recently published a systemic overview comprising a large cohort of 76 patients with SLONM, excluding patients with HIV infection . In thisThough SLONM is rare, it is potentially a treatable condition. Patients with SLONM associated with HIV-infection or rheumatological diseases often show good clinical response to immunosuppressive therapy . In SLONRegular check-ups including physical examination with special attention to cardiac and pulmonary testing are mandatory in SLONM-patients. Diagnostic work-up must repetitively address MGUS, HIV-infection  and rheuWhole body muscle MRI is a reliable diagnostic tool for detecting myopathy in patients with camptocormia and might further help to choose the site for muscle biopsy . In our Our case report highlights that myopathy and in particular SLONM has to be considered in all patients with isolated camptocormia. SLONM should especially be suspected when camptocormica is combined with MGUS, HIV or rheumatological disease . In all