There is a concern regarding the use of a closed-suction drain (CSD) in two-stage exchange arthroplasty for periprosthetic joint infection as it may decrease the antibiotic concentrations in the joint fluids. The purpose of this study was to identify whether the use of a CSD could reduce local antibiotic concentrations following spacer implantation.n = 160) were collected every 24 h for the first five days following spacer implantation. The antibiotic concentrations of drainage samples were measured by high-performance liquid chromatography, and the bioactivities of the drainage samples against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA) and E. coli were assessed.A prospective, randomized, controlled trial was conducted at our institution between January 2018 and November 2018. We enrolled 32 patients undergoing two-stage exchange arthroplasty for periprosthetic hip infection with an interim cement spacer containing 4-g vancomycin and 2-g meropenem per 40-g methyl-methacrylate cement polymer. Patients were randomized and evenly divided into the study group (non-CSD) and control group (CSD group) by sealed envelopes. Drainage samples of joint fluids (p = 0.917) and meropenem concentration  between the two groups during the first five days following spacer implantation. All joint drainage samples in each group exhibited antibacterial activity against MSSA, MRSA and E. coli.There was no significant difference in the decrease of vancomycin  Periprosthetic joint infection (PJI) is one of the most disastrous complications following total hip arthroplasty (THA) and remains a challenging condition to treat. Two-stage exchange arthroplasty with the implantation of an antibiotic-loaded cement spacer (ACS) and reimplantation of a new prosthesis remains the widely held gold-standard treatment of chronic PJI . The useAlthough several randomized, controlled studies have suggested no inherent benefit with the use of closed-suction drainage (CSD) in primary total joint arthroplasty (TJA), , 7 it isTherefore, we conducted a prospective, randomized, controlled study 1) to evaluate whether the use of CSD could reduce the local antibiotic concentrations following spacer insertion and 2) to identify the association between drainage volume and antibiotic concentrations in the joint drainage.This prospective, randomized, controlled study was registered in the public Clinical Trial Registry (ChiCTR-INR-17014162) and approval was obtained from the Clinical Trials and Biomedical Ethics Committee of our institution (S2017–085-02). The present study adhered to CONSORT guidelines. All participants were enrolled after written informed consent was obtained before randomization.Patients with chronic PJI of the hips and scheduled for two-stage exchange arthroplasty were included. PJI diagnosis was made using the Musculoskeletal Infection Society (MSIS) criteria . PatientAn institutional standard protocol of two-stage exchange arthroplasty was performed in all patients. Patients had their implanted components removed followed by thorough and radical debridement of the unvital bone and soft tissue. A minimum of three sets of cultures were obtained. After irrigation, a cement spacer loaded with two combined antibiotics was then implanted. All bone cement spacers were made intra-operatively by hand-mixing 4 g of vancomycin powder  and 2 g of meropenem powder  per 40 g of methyl-methacrylate cement polymer . Then, liquid monomer was added and mixed for polymerization. The weight of the implanted cement spacer was recorded intra-operatively. A disposable, closed-suction drainage system  was placed in all patients for at least five days. The drains were inserted under the fascia and connected to an evacuator via connector tube. A CSD was placed in all patients after the first-stage surgery to collect drainage for detection of antibiotic concentration. For the study group, the drainage tube remained clamped postoperatively during the study period, which was considered non-use of a CSD. For the control group, the drainage tube was clamped for only 2 h postoperatively and then remained open until removal of the drain. All patients received ceftriaxone (2 g IV) at the induction of anesthesia preoperatively. Intravenous (IV) linezolid (0.6 g IV q 12 h) and ceftriaxone (2 g IV q 24 h) were used in the first five days following spacer implantation. After the study period (5 days following spacer implantation), the antibiotic regimen was decided based on the intraoperative culture sensitivity reports and institutional guidelines.After implantation of the cement spacer, 5-mL fresh aliquots of drainage were collected under sterile conditions every 24 h for the first five days, and the drainage container was changed at the time of drainage collection. After the given study period, the drain was removed if the daily drainage amount was less than 50 mL. Additionally, 10 mL of peripheral venous blood was collected during the first 24 h following implantation of the spacer. All samples were stored and frozen at − 80 °C for no more than three months. The reimplantation was performed after 2–4 weeks of antibiotic holiday and the soft tissue was free of local heat, erythema, swelling, and any infection-related symptoms.18 column . The standard calibration curve consisted of eleven different standard concentrations . The mobile phase consisted of acetonitrile-10.53 mm ammonium acetate  for meropenem and monopotassium phosphate (25 mmol/L)-methanol  for vancomycin. The flow-rate was 1.0 mL/min, and the detection wavelengths were 298 nm and 236 nm for meropenem and vancomycin, respectively. The injection volume was 20 μL, and the temperature of the column was 30 °C. The HPLC system had sensitivities of 0.5 μg/mL for vancomycin and 0.6 μg/mL for meropenem. The concentrations of antibiotics in the drainage samples were determined by comparison with the peak areas of standard curves prepared daily.The concentrations of vancomycin and meropenem in the drainage were measured daily for 5 days by using high-performance liquid chromatography (HPLC) assay carried out on an Agilent 1260 Infinity chromatograph with a Thermo Hypersil CStaphylococcus aureus (MSSA) (ATCC 25923), methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300), and E. coli (ATCC 25922). Inhibitory activity of the disks was determined after 24-h incubation at 37 °C. The diameters of the inhibition zones were measured using a caliper. All samples were tested three times.The bioactivity of the drainage and peripheral venous blood were assessed using an agar disk diffusion bioassay, conducted as described by Hsu et al.  Discs coA noninferiority test was conducted to determine the sample size. Prior study data have indicated 100% antibacterial activity of joint drainage in patients with a CSD in the first week following spacer implantation, , 12, 13 t-test or Mann-Whitney test for continuous variables and the chi-square test for categorical variables. Patients in the control group were further divided into two subgroups based on the median of total drainage volume (400 mL). Univariate linear regression analysis was used to examine the association between drainage volume  and antibiotic concentrations in the joint fluid. β-coefficient and 95% confidence intervals (CIs) were reported. A p value less than 0.05 was considered significant. All of the analyses were performed with the statistical software packages R .Categorical variables were presented as frequencies and percentages and continuous variables as the means and standard deviation (M ± SD). The clinical characteristics between groups were compared with the use of the independent Patient demographics and organism profile at the time of resection arthroplasty are presented in Table and Fig. 2B; Table p = 0.917). The concentration of vancomycin in the non-CSD and CSD groups was 273.9 ± 32.9 and 260.5 ± 12.2 μg/mL, respectively, on the first day and decreased to 110.5 ± 69.1 and 97.5 ± 41.5 μg/mL, respectively, on the fifth day. The decrease of the meropenem concentration did not reach a significant difference between the two groups . The meropenem concentration of the study group and control group was 133.5 ± 21.2 and 127.9 ± 14.1 μg/mL, respectively, on the first day and decreased to 10.7 ± 2.7 and 8.5 ± 7.9 μg/mL, respectively, on the fifth day. The concentrations of vancomycin and meropenem in the serum were too low to be detected by our HPLC system in both groups.Both vancomycin and meropenem were burst released from the cement spacer during the first day of the elution assay in the drainage samples of all patients. The released rates of all the tested samples then gradually decreased by the next time points . When analyzed drainage volumes as a categorical variable (more than 400 mL or not), the results were consistent; there was no association between total drainage volumes and antibiotic concentrations of the fifth day   were not associated with antibiotic concentrations of the fifth day  had similar vancomycin and meropenem concentrations compared to those of the control group (CSD group) up to 5 days following spacer implantation. This result showed that the use of CSD did not affect the local antibiotic concentrations from the antibiotic spacer. Moreover, the result suggested that higher drainage volume did not result in lower antibiotic concentrations detected in the drainage.13 CSD was commonly used following spacer insertion. They inspected the tissue surrounding the spacer in the sixth week following cement spacer insertion. They found the concentration of antibiotics loaded in the cement spacer was still higher than the inhibitory concentration required for treating the pathogens that are responsible for most periprosthetic infections. In another study by Kelm et al.,14 a CSD was used in all patients for seven days following spacer implantation. The mean time of reimplantation was nine weeks, and they detected adequate antibiotic concentrations left over. The results also suggested that the antibiotic levels far exceeded therapeutic requirements against common microorganisms involved in PJI at the time of reimplantation.14 Similarly to our own results, these aforementioned studies have also potentially illustrated that the use of CSD may not be a detriment to the efficacy of antibiotic-loaded spacers. Furthermore, Anagnostakos et al. [Prior studies have shown that local antibiotic concentrations could remain above their effective levels for a long period, both in vitro and in vivo, owing to the continuous antibiotic release from the antibiotic-loaded cement spacer , 14, 15.s et al.  conducte15 Baleani et al. [2 In our study, the combination of vancomycin and meropenem in the bone cement was utilized in accordance with our institutional infection control department, which explained that more than 90% of the organisms isolated from patients with PJI in our institutional were sensitive to one or both antibiotics.The types of antibiotics themselves mixed into bone cement have an impact on local concentrations and elution kinetics. The common antibiotics mixed into the bone cement include gentamicin, clindamycin, vancomycin, tobramycin, aztreonam, meropenem and ampicillin, , 14, 17 i et al.  showed tIt is critical to consider adverse effects owing to antibiotics used. Although vancomycin is one of the most commonly used antibiotics in cement spacers, the renal toxicity of vancomycin is the major concern. Several studies suggested that vancomycin in a cement spacer contributed to acute renal injury after implantation , 20. HowE.coli in the experiment. Other common PJI organisms were not evaluated. Fourth, for detecting antibiotic concentration, we had to use CSD in the study group to collect joint fluid postoperatively. However, the CSD tube kept clamped unless only 5-mL drainage were collected every 24 h for the first five days in the study group. Fifth, the sample size may have been inadequate for conducting subgroup statistical analyses, and the possibility of a type-II error existed. Last, we did not consider the impact of intravenous antibiotics on the release of antibiotics in the spacer. However, the intravenous antibiotic regimen (linezolid and ceftriaxone) was different from the local antibiotic regimen (vancomycin and meropenem) to avoid detection bias.When interpreting our findings, several limitations should be considered. First, given the ethical concerns and risk of organism contamination, we only kept the drains in patients for five days. Additionally, all patients in the non-CSD group opened their CSDs after the study period (5 days) to drain out residual joint fluids due to the requirement by our ethics committee. Therefore, this study was unable to compare postoperative wound complications between groups. Second, the concentration of meropenem decreased dramatically compared to 4antibiotic concentrations would remain higher than the minimum inhibitory concentration over the period of the spacer. Third, we only tested the antibiotic bioactivity of the drainage samples against MSSA, MRSA and In conclusion, this randomized, controlled trial suggested that the use of a closed-suction drainage does not reduce the effectiveness of an antibiotic-loaded spacer in two-stage exchange arthroplasty. Further studies may be necessary to evaluate the outcome of treatment and postoperative complications of two-stage exchange arthroplasty with or without the use of closed-suction drainage.


The current work presents the complex investigation of the influence of cement and aggregate type on the thermo-mechanical behavior of mass concrete. Six types of cement with different amounts of non-clinker constituents and four types of aggregates are used in experimental tests. Particular attention was given to the low clinker cements with high amounts of siliceous fly ash and ground blast furnace slag. The experimental research covered the determination of thermal, mechanical, and rheological properties of early age concrete with different constituents. Experimental results have been used both to validate the numerical model and analysis of exemplary foundation slab. The results confirm the importance of the concrete mix composition and it has been shown that the early-age volume deformation and possible cracking is the result of the concerted action of thermal and mechanical properties of concrete. The obtained results indicate granite as the best aggregate for mass concrete. Considering the type of cement, much better behaviour of mass concrete has been noted for cements with fly ash and composite cements containing both fly ash and slags than cements only with slag. The temperature rise during cement hydration is still an open problem in the construction of mass concrete structures. Due to the considerable thickness of such structures, the amount of heat generated is significant and the core of the concrete member reaches particularly high temperatures, which is also higher than the temperature of its surface layers. Such non-uniform temperature distribution and its variation in time induces thermal strains. Additionally, shrinkage strains are also observed in early age concrete because of the hydration process and moisture exchange with the environment. Consequently, stresses arise in the concrete structure, which, if not properly controlled, can result in cracking, affecting service life of the structure. This early age cracking of thermal and shrinkage origin may initiate corrosion of reinforcement. Moreover, at a later age, the crack width may increase due to environmental and mechanical loads.The size of early age thermal-shrinkage volume changes and possible cracking depends both on material and technological factors. Among others, concrete mix composition, type of concrete constituents, concrete curing condition, the size of concrete volume, and structure restraint conditions can be specified here ,2. In thHowever, the examination of early-age volume changes in mass concrete cannot be only limited to the hydration heat and strength development. As it was emphasized in ,5,6 thatThis paper is focused on the overall early age behavior of mass concrete structure made of concrete with different constituents. In particular, the influence of cement and aggregate type on the formation of hardening temperature, moisture loss, and stress development in early age concrete has been studied. The work consists of experimental and numerical study. In the experimental part, six types of cement with different amount of non-clinker constituents (fly ash and slag) and four types of aggregates  have been considered. Special attention was paid to the low clinker cements with high amount of siliceous fly ash and ground blast furnace slag. Therefore, cements containing even 68% of non-clinker constituents are used in concrete. The experimental research covered the determination of thermal , mechanical , and rheological (shrinkage and creep) properties of early age concrete with different constituents. First, the obtained experimental results have been used to validate the applied numerical model. Next, the analysis of mass foundation slabs has been performed. The main purpose of this analysis was to indicate that the early-age volume deformation and possible cracking is the result of the concerted action of many factors relating to thermal and mechanical properties of concrete.Two compositions of concrete mix with different cement and aggregate type were used in the experiments, as shown in Six commercial cements with different content of Portland clinker, siliceous fly ash, and/or granulated blast-furnace slag were used for the experimental tests: Portland slag cement CEM II/B-S 32.5R, Portland-fly ash cement CEM II/B-V 32.5R, slag cement CEM III/A 32.5N-LH/HSR/NA, composite cement CEM V/A (S-V) 32.5R-LH/HSR/NA, special composite cement with high amount of non-clinker constituents VLH V/B (S-V), and CEM I 42.5R as a reference cement. The content of non-clinker constituents in the cement compositions varied from 27.1% to 67.7%, as listed in The research program covered the following tests: physical and mechanical properties of cements, hydration heat of cements, compressive and tensile strength of concretes, elasticity modulus of concrete, concrete hardening temperature, thermal conductivity and heat capacity of concretes, concrete shrinkage, and creep. Some results of this extensive research have been already presented, including physical and mechanical properties of cements ,7, hydraConcrete compressive strength was tested after 1, 2, 7, 28, 56, and 90 days of concrete curing. Concrete cubes 150 mm × 150 mm × 150 mm were used according to the procedure enclosed in EN 12390-3 . TensileShrinkage strains were measured on cuboidal samples with the dimensions 100 mm × 100 mm × 500 mm according to the methodology of PN-B-06714-23 , after 2The tests were performed on concretes with the constituents given in As it has been mentioned in the previous section, some results of this extensive research have been already presented ,7,9. NevSignificantly lower early age compressive and tensile strength are observed in concretes made of cements with non-clinker constituents. These values were lower as the addition of non-clinker constituents increased. However, the non-clinker constituents in cement favorably improved the compressive strength of concrete after 28 days. It is also worth noting that the tensile strength of concretes with cement containing fly ash (CEM II/B-V 32.5R) is greater than that of concrete with cement containing slag (CEM III/A 32.5N-LH/HSR/NA), while both cements revealed similar amount of heat evolved during hydration . It confConcrete containing granite, basalt, or limestone aggregates achieved higher average compressive strength than concrete with gravel aggregate. The highest average compressive strength was obtained for concrete with basalt aggregate and in the early age period it was even 33.7% higher than for concrete with gravel aggregate. Concrete with granite or limestone aggregate was characterized by early age strength comparable to concrete with basalt aggregate;Similarly, the average tensile strength of concrete containing granite, basalt, or limestone aggregates was higher than those with gravel aggregate. In the case of concrete with cement CEM I 42.5 R after 2 days, they were higher by 14.7% to 17.9%. However, in the case of CEM III/A 32.5N-LH/HSR/NA, the average tensile strength was higher by 45.0 to 145.0% in comparison to the gravel aggregate, and in the case of cement CEM V/A (SV) 32.5R -LH/HSR/NA, tensile strength was higher by 56.4 to 97.3% compared to concretes with gravel aggregate. After 28 days, the tensile strength of concretes with basalt, granite, or limestone aggregate was higher only by 23.7%.The results of compressive and tensile strength determined for concrete samples with different types of cement and aggregates are shown in The obtained values of modulus of elasticity are plotted in The results of shrinkage tests are plotted in The results of the measured creep strains are depicted in small heat evolved during cement hydration (resulting in low hardening temperature),high thermal conductivity (resulting in fast heat dissipation from the structure),high heat capacity (resulting in lower hardening temperature),small coefficient of thermal expansion (resulting in lower deformation),small shrinkage ,small modulus of elasticity and high creep (decreasing of the arising stresses),high tensile strength (increasing the early age cracking resistance).The best concrete for a massive structure would be the concrete with:the use of cements with a large amount of non-clinker components in mass concrete is beneficial due to reduced hydration heat which decreases the hardening temperature and to a smaller elastic modulus which decreases the arising stresses; nevertheless, the tensile strength of such concrete is much lower and consequently the early age cracking resistance decreases,the use of cements with a large number of non-clinker components results also in lower shrinkage which is preferred in mass concrete,greater early age creep is beneficial in mass concrete as it reduces early age stresses, therefore, in this regard, it is better to use cements containing silica fly ash rather than cements containing ground blast furnace slag which showed lower creep,the effect of aggregate is particularly complex. Considering thermal conductivity, heat capacity and modulus of elasticity concrete with gravel aggregate has the best properties for mass concrete, but simultaneously, the thermal dilation of concrete with this aggregate is the largest ,21. In cReferring the obtained experimental results to the above-mentioned beneficial properties, the following comments can be written:The original numerical model has been developed for the 3D analysis of early age concrete and it can be applied for reinforced concrete structures as foundation slabs and blocks, tank walls, and bridge abutments. The complex analysis of the mentioned structures is run in two stages. In the first stage, temperature and moisture development in time are determined. The original feature of this stage is the application of coupled equations of thermodiffusion. Next, thermal-shrinkage strains are calculated, and these results are used as an input for computation of stresses in the second stage of analysis. In analysis of early age stresses, the viscoelastic material model of ageing concrete is applied. The influence of elevated curing temperatures on concrete mechanical properties as well on the development of hydration heat is considered by introducing equivalent concrete age instead of the real age of concrete ,22,23.The model considers soil–structure interaction and appropriate technological conditions like layered casting, environmental conditions like ambient temperature and humidity, different initial temperature of the concrete layers, and the time of formwork removal. The full thermo-mechanical concrete properties are also considered. For practical application, original computers programs have been developed: TEMWIL for thermal–moisture analysis and MAFEM for stress analysis. Detailed description of the model and computer programs TEMWIL and MAFEM can be found in ,23,24. First, experimental results have been computer program TEMWIL used to validate the numerical model. Validation of the model covered the determination of hardening temperature of concrete and shrinkage and creep strains. Some considerations on the correct description of the development of mechanical properties and proper value of the activation energy of concretes with different constituents have been enclosed in ,25 and wThe results of numerical calculations and experimentally registered temperature of cubic specimens 40 cm × 40 cm × 40 cm  are depi−8 m/s, coefficient of moisture dilatation wα = 0.001/0.0009/0.0006/0.0008 for gravel/granite/basalt/limestone. The other parameters were adopted in accordance with In the validation of shrinkage tests, the best agreement between the results of calculations and the experiment was obtained for the following values assumed in the numerical model: moisture transfer coefficient equal to 2.78 × 10A concrete creep test was also simulated. The calculations considered the development of the mechanical properties of concretes determined during experimental investigations and other experimental data. Good agreement between the results of numerical calculations and the results of experimental tests can be noticed in 2K) (top surface without any protection) and equal to 3.5 W/(m2K) (side surfaces with plywood). Similarly, moisture transfer coefficient was assumed to 2.78 × 10−8 m/s at top surface and to 0.18 × 10−8 m/s at side surfaces. Ambient and initial temperature of the slab were taken as 20 °C. All computational cases are listed in Finally, the complex influence of concrete constituents on the thermo-mechanical behavior has been investigated in mass foundation slabs with the base dimensions 20 m × 20 m and 4 m thickness. The finite element mesh of the slab is shown in In thick foundation slabs, the self-induced stresses resulting from non-uniform volume changes in a cross section are predominant. These stresses have a distinctive distribution during concrete hardening. In the heating phase, the tensile stresses exist in surface layers, while compressive stresses are observed inside the slab. Next, an inversion of the stresses occurs in the cooling phase. In this phase, the tensile stresses are observed in the core of the slab and compressive stresses exist in the surface layers . Thus, i-In case of cements: CEM II/B-V 32.5R and CEM II/B-S 32.5 R, which contain silica fly ash or granulated blast furnace slag of similar amount (about 30%), the higher performance of fly ash was observed. Slabs with CEM II/BV 32.5R cement were characterized by 14.2 °C lower core temperature in relation to CEM II/ BS 32.5R cement. The temperature difference between the core and the surface of the slabs made of CEM II/BV 32.5R did not exceed 20 °C despite the considerable thickness of the slab. Also, tensile stresses at the top surface are much lower than the current tensile strength of concrete. It is worth noting that concrete with CEM II/B-V 32.5R has a low modulus of elasticity and high creep, which is beyond the low hydration heat, also the reason for its low tensile stresses in comparison to CEM II/BS 32.5R,-The use of CEM III/A 32.5N-LH/HSR/NA cement with a slag content of 58.9% does not guarantee early age cracking resistance of the slabs. In this case, the tensile stresses are greater than the tensile strength,-In the case of using CEM V/A (SV) 32.5R-LH/HSR/NA (the content of non-clinker components was 37.8%), a decrease in maximum temperature and center-surface temperature difference was observed in the foundation slab. The mentioned values were at a level similar to that of CEM III/A 32.5N-LH/HSR/NA, in which the addition of the non-clinker component is much higher (58.9%). Tensile stresses are relatively high in relation to the tensile strength, but they have not exceeded it,-The foundation slabs of concrete containing VLH V/B (S-V) 22.5 were characterized by the lowest maximum center temperature as well as the lowest center-surface temperature difference. This is due to the lowest heat of hydration of VLH V/B (S-V) 22.5 of all the analyzed cements. The values of the surface stress were halved in comparison to concrete with cement CEM I 42.5R. This was also due to the much lower modulus of elasticity of concrete with this cement.-The increase in the amount of non-clinker main components in the cement affects the delay of the maximum temperature and maximum tensile strength occurrence. The following relationship is visible: the higher the content of the non-clinker component in the cement, the greater the delay in comparison to the reference concrete with Portland cement CEM I 42.5R. At the same time, it was not noticed that the type of non-clinker component influenced the discussed delay.-It was observed that the type of cement affects the moisture content of concrete in the analyzed period. These differences are the result of the varying amount of water bound in the cement hydration process, which is a direct consequence of the different amount of heat released. It is worth noting that significantly greater moisture loss occurred on the surface of the analyzed slabs, which is consistent with the work , which sThe results of numerical analysis of massive foundation slabs with different cement types are presented in The results of numerical tests are presented in The difference in temperature between the core and the surface exceeded 20 °C in all slabs. Nevertheless, only in case of concrete with gravel aggregate were stresses exceeding the maximum concrete tensile strength observed. The reason is the low tensile strength and higher coefficient of thermal expansion of concrete (resulting from the presence of quartz in the gravel aggregate) compared to concretes with other aggregates. In this case, the lower elastic modulus of concrete with gravel aggregate did not balance the larger thermal deformations. Thus, the complex effect of the concrete mix composition on the thermo-mechanical behavior of massive structures is particularly visible here.The type of aggregate used in the concrete composition affects the time of the occurrence of maximum temperatures and maximum tensile stresses. The shortest time was obtained for concrete with gravel aggregate. In the case of concretes with limestone, granite, or basalt aggregates, the maximum temperature occurred 12, 24, and 36 h later, respectively, in comparison to concrete with gravel aggregate. This is due to the different thermal conductivity of these concretes. Similarly, the maximum tensile stresses occurred 24, 36, and 48 h later than for concrete with gravel aggregate.The use of gravel aggregate in the concrete is the least favorable due to the values of maximum stresses in the analyzed foundation slabs, and due to the relatively short time of their occurrence. Regarding the mentioned properties, the granite aggregate in the concrete composition seems to be the most optimal. The analyzed foundation slabs made of this concrete were characterized by the lowest maximum temperature and tensile stresses. Occurrence of maximum temperature and maximum stresses is also delayed. The use of basalt and limestone aggregates is also more advantageous than gravel aggregate.This research presents the results of experimental and numerical studies on the overall early-age properties and behavior of mass concrete structures. Since concrete is a heterogeneous material whose behaviour depends on the properties of its constituents, the cement and aggregate type has been studied. Although in some works ,29 the pThe use of cements with non-clinker main components in mass concrete, especially with a large number of them (>35%), reduces the maximum hardening temperature and generated stresses and delays the time of their occurrence. The presented results show that the use of cements with addition of siliceous fly ash in concrete is more advantageous than cements containing granulated blast furnace slag in mass concrete. Experimental tests and numerical analysis of foundation slabs made of concretes containing cements with silica fly ash showed that the maximum temperature and tensile stress are lower, which results from the lower hydration heat of these cements, lower elasticity modulus of concrete, less shrinkage, and greater creep compared to concretes with cements containing granulated blast furnace slag.It should be noted that the conclusions regarding the benefits of using cement with non-clinker main components in massive structures are not new. However, they were mainly related to limiting the hardening temperature of concrete. Furthermore, the composition of the concrete was usually determined in terms of limiting the maximum temperature and ensuring adequate compressive strength of the concrete without a comprehensive analysis of all its properties. Similarly, other beneficial properties of such cements  are not raised very often.Based on the analyses and experimental tests, the tested cements may be ordered from the most to the least favorable based on early thermal behaviour in mass concrete: VLH V/B (SV) 22.5; CEM II/BV 32.5R; CEM V/A (SV) 32.5R-LH/HSR/NA; CEM III/A 32.5N-LH/HSR/NA; CEM II/BS 32.5R; CEM I 42.5R. Therefore, considering the type of cement, much better behaviour of mass concrete has been noted for cements with fly ash and composite cements containing both fly ash and slags than cements with slag only.silica fly ash above 15% reduces DEF, and with content above 30%, DEF does not occur,granulated blast furnace slag in the amount of 17.5% limits DEF and is preventative above 25–30%.It is also worth mentioning that curing temperature exceeding 65–70 °C can lead to delayed ettringite formation (DEF) and consequently to possible later damage of the concrete. In this respect, as it was indicated in ,31 that The significant influence of aggregate type on the stress development in the mass structures has also been highlighted. The conducted analysis revealed that the gravel aggregate, consisting mainly of quartz, can be considered as the worst aggregate, while granite aggregate may be treated as the best. Therefore, the proper selection of aggregate is also important for reducing early-age cracking in mass concrete. Simultaneously, the effect of the aggregate is very complex and all thermal and mechanical properties should be carefully considered.Thus, the results confirm that the early-age volume deformation and possible cracking is the result of the concerted action of thermal and mechanical properties of concrete whose depend primarily on the concrete constituents. Finally, despite the fact that the research program was relatively extensive, it requires continuation by others in the field of tensile creep testing, as concrete exhibits higher creep under tension ,33 and t


This study aimed to assess the regularity of the choroidoscleral interface (CSI) using a novel parameter, CSI irregularity index, before and after epiretinal membrane (ERM) surgery. This study included 36 patients with idiopathic ERM who underwent pars plana vitrectomy and ERM removal. All subjects underwent ocular examinations at baseline and at 1, 2, 4, and 6 months after surgery. The regular contour of the CSI was found in 14 patients (38.9%); mean CSI irregularity index was 14.84 ± 11.01 in this group. The irregular contour of the CSI was found in 22 patients (61.1%); mean CSI irregularity index was 33.96 ± 20.64 in this group. The CSI irregularity index decreased gradually after ERM surgery, and was correlated with postoperative best-corrected visual acuity. The CSI irregularity index could serve as a surrogate marker to quantitatively represent the CSI morphology. We observed the gradual decrease of the CSI irregularity index after ERM surgery in quantitative manner. This study showed correlations between the CSI irregularity index and visual outcomes after ERM surgery. Our results suggest that the CSI irregularity index might be an intuitive anatomic indicator of the CSI and might be useful as a possible prognostic marker for patients undergoing ERM surgery. Surgical removal of ERM is the only option in eyes that require treatment4. Surgical removal of ERM in symptomatic patients can improve visual acuity (VA) by more than 2 Snellen lines and reduce metamorphopsia in 70-90% of cases8. However, in some cases, VA improvement may be limited after successful ERM removal9. Thus, previous studies have attempted to identify prognostic factors that indicate which patients exhibit a better outcome following ERM surgery16. Many studies have focused on the relationship between central foveal thickness and visual outcome after ERM surgery; however, the results have been inconsistent14. Outer retinal layer damage, including disruption of the ellipsoid zone (EZ) or cone outer segment tip (COST), has been associated with poor visual outcomes after ERM surgery15. In recent years, inner retinal deformation has been suggested as an important prognostic factor in ERM. Inner retinal irregularity index and inner retinal layer thickness were reportedly associated with poor visual outcomes; in contrast, retinal contraction was associated with good visual outcomes after ERM surgery16. However, a recent systematic review revealed that many discrepancies exist between studies; thus, an overall prognosis prediction model is still needed17.Epiretinal membrane (ERM) is one of the most common retinal diseases, characterized by fibrocellular tissue proliferation on the inner retinal surface19. In previous reports, the regularity of the choroidoscleral boundary was evaluated in macular hole20 and ERM19. Michalewski et al.19 suggested that there may be a relationship between choroidal thickness and structure and the presence of idiopathic ERM. With recent advances in optical coherence tomography (OCT), precise visualization of the choroid and the choroidoscleral interface (CSI) have become possible. In the literature, irregular CSI has frequently been reported in patients with ERM; moreover, patients with irregular CSI recovered VA more rapidly after ERM surgery19. However, there is limited information regarding CSI before and after ERM surgery; notably, previous researchers have evaluated CSI solely in a qualitative manner.The role of the choroid in the pathogenesis of ERM is not well-known. However, recent studies have suggested that ERM might involve more complex etiopathology than solely vitreoretinal interface changesThe aim of this study was to quantitatively assess the regularity of CSI using a novel parameter called CSI irregularity index. Additionally, this study evaluated the effectiveness of the CSI irregularity index as a predictive prognostic marker for postoperative outcome in patients with idiopathic ERM.P = 0.774, 0.094, and 0.130, respectively). Further, there were no significant differences in sex, age, presence of diabetes or hypertension, symptom duration, axial length, intraocular pressure, best-corrected visual acuity (BCVA), or refractive error between the two groups . Figure P < 0.001 for trend).We analyzed 36 eyes of 36 patients. The demographic and clinical characteristics of the patients with ERM are depicted in Table P = 0.012, P = 0.049, P = 0.045, P = 0.017, P = 0.035 for before surgery and 1, 2, 4, 6 months postoperatively, respectively). EZ/COST defect grade was correlated with BCVA solely at baseline (P = 0.007). CSI irregularity index was correlated with BCVA at 4 and 6 months after ERM surgery . However, central foveal thickness and central choroidal thickness did not show any correlation with BCVA at any time points .Table P = 0.001), EZ/COST defect grade , and CSI irregularity index  exhibited correlations with postoperative BCVA. Multiple regression analysis showed that inner-retinal irregularity index was strongly correlated with postoperative BCVA . Central choroidal thickness, EZ/COST defect grade and CSI irregularity index did not exhibit significance in the multiple regression analysis model . The factors are independent each other because there is low degree of intercorrelation (multicollinearity) in the multiple regression analysis.Table For each observer, there was a high intra-observer agreement for the CSI irregularity index . Furthermore, there was a high inter-observer agreement between the 2 investigators for the CSI irregularity index .To the best of our knowledge, this study is the first to quantitatively analyze the choroidoscleral interface. We observed reduction of CSI irregularity after ERM surgery, and the CSI irregularity index was correlated with postoperative visual outcome.16. With the advent of the SS-OCT device, changes in choroidal structures have been assessed in recent studies22. ERM might lead to choroidal thickening and choroidal vasculature changes through a variety of possible mechanisms. Tangential traction caused by epiretinal membrane can affect the retinal pigment epithelium and choroid. Another possible explanation of the choroidal changes is that the mechanical stretching of the RPE may increase the expression of vascular endothelial growth factor, which might lead to choroidal hyperpermeability or choroidal vascular rearrangement. Further, low-grade chronic inflammation might be present in the choroidal layer, which might cause choroidal vascular changes.Inner-retinal layer distortions other than outer retinal changes have gained attention for predicting the visual prognosis after ERM surgery, because ERM is primarily an inner retinal disease20 and ERM19. Michalewska et al. reported that an irregular choroidoscleral boundary was more frequently observed in diseased eyes, such as those with ERM; moreover, patients with an irregular outer choroidoscleral boundary recovered visual function more rapidly after ERM surgery18. To quantitatively assess these findings, we developed a novel parameter called CSI irregularity index. In the regression analysis, the CSI irregularity index showed positive correlations with postoperative BCVA. However, this new parameter is not more robust than the inner-retinal irregularity index for prediction of visual outcome. We can utilize this index as one of multiple prognostic markers in ERM surgery. Excellent intraobserver and interobserver repeatability was observed for CSI irregularity index, as indicated by the ICC values.In this study, we analyzed correlations of the CSI irregularity index and several OCT-derived parameters in ERM, as well as visual outcomes after ERM surgery. Our study showed that CSI irregularity index decreased gradually after ERM surgery. Transient, sudden decline of the CSI irregularity index at 1 month after ERM surgery might be due to residual gas tamponade effect. In previous reports, the regularity of the choroidoscleral boundary was evaluated in macular hole25, exhibiting a bowl-shaped contour27. The CSI may either be regular or irregular, even in healthy eyes, particularly when temporal inflection of CSI occurs with focal thinning of the choroid26. Dolz-Marco and colleagues hypothesized that this inferotemporal inflection could be related to the inferior oblique muscle causing inward compression of the choroid28. In diseased eyes, higher CSI irregularity index (or an irregular CSI) might be result from focal dilation of choroidal vessels. This might be due to tractional force caused by the ERM itself. Another factor is the status of vitreous oxygenation after vitrectomy. After removal of the vitreous, which is oxygen-consuming tissue, the retina and choroid are exposed to a more highly oxygenated environment. These may result in reduction of choroidal thickness and CSI irregularity index after vitrectomy18.In the macular area, the choroid typically is thickest at the subfovea; choroidal thickness decreases gradually toward the temporal side and more steeply toward the optic nerve16. Second, gas tamponade with 14% perfluoropropane (C3F8) was conducted for each patient at the end of the surgery. The gas tamponade procedure was performed at the surgeon’s discretion to avoid immediate postoperative hypotony. Third, the follow-up period after ERM surgery was relatively short. Changes in retinal and choroidal structure and morphology could last up to 12 months after ERM surgery29. Fourth, the shape of the CSI could differ on the basis of the location of the OCT sections, even within a single patient. Furthermore, when measuring the CSI irregularity index, manual determination of the CSI should be conducted. There were many cases of artifacts in CSI tracking when using the automated segmentation layer line. In our study, two independent observers repeated the CSI tracking to ensure accuracy, and inter-observer agreement between the 2 investigators was high. However, this part should be supplemented in order to adopt this approach in clinical practice.Our study had some limitations. First, due to the nature of the retrospective study design, cataract surgery was performed at the surgeon’s discretion; thus, some patients underwent cataract surgery, while others did not. However, previous studies reported that cataract surgery did not affect visual prognosis after ERM surgeryIn conclusion, we developed a novel surrogate marker, the CSI irregularity index, for quantitative representation of CSI morphology. We quantitatively observed gradual reduction of the CSI irregularity index after ERM surgery. This study revealed correlations between the CSI irregularity index and visual outcomes after ERM surgery. Based on our results, the CSI irregularity index might constitute an intuitive anatomic indicator of the CSI and might be useful as one of multiple prognostic markers of ERM surgery.This was a retrospective cohort study of consecutive patients with idiopathic ERM who underwent uncomplicated pars plana vitrectomy and ERM removal between December 2016 and March 2018 at Seoul St. Mary’s Hospital in Korea. Exclusion criteria for the study were as follows: (1) secondary ERM , (2) high myopia , (3) eyes with a history of any intraocular surgery, ocular trauma, or laser treatment, (4) the presence of other retinal diseases, including glaucoma, age-related macular degeneration, or coexisting macular hole, and (5) media opacity that significantly affect OCT image. Patients were also excluded if they exhibited ERM in both eyes.This study adhered to the tenets of the Declaration of Helsinki. Institutional Review Board (IRB)/Ethics Committee approval was obtained from the Catholic University of Korea. It waived the requirement to obtain informed consent because of the retrospective nature of the study.3F8) was conducted for each patient.One experienced vitreoretinal surgeon (Y.H.P.) performed all of the operations. A standard 3-port pars plana vitrectomy was performed using a 25-gauge trocar and cannula . In patients with a visually significant cataract, cataract operation was performed before vitrectomy. For each patient, ERM and the internal limiting membrane (ILM) were peeled with end-gripping forceps. ILM peeling was performed after staining of the ILM with 0.05% indocyanine green dye; the area of ILM peeling was as large as a 2- or 3-disc diameter, with the fovea as the center. At the end of the surgery, gas tamponade with 14% perfluoropropane , slit-lamp biomicroscopy, funduscopy, pneumatic tonometry, axial length measurement with partial coherence interferometry  and OCT. OCT imaging was performed using a swept-source (SS)-OCT device .30. We obtained a six-line radial pattern scan  centered on the fovea from each eye. We performed OCT image acquisition between 2 and 5 PM to exclude known diurnal variations of choroidal thickness or choroidal vasculature.We performed SS-OCT examination on all study subjects. The detailed OCT acquisition methods were described in a previously published articleWe obtained retinal and choroidal thicknesses using in-built OCT software. The software automatically created thickness maps in accordance with ETDRS sectors and we used the central retinal and choroidal thicknesses of the innermost 1-mm circular area for analysis. For each OCT scan, all automated segmented layer lines could be manually adjusted to avoid possible segmentation errors.16. Disruption of the EZ/COST line was detected when there was a loss of a hyperreflective line at the fovea31. We graded the disruption of the EZ/COST line in accordance with the global disruption scale, as described previously33. Grade 0 was assigned when the line was intact, Grade 1 was assigned when the focal disruption of the line was 200 microns or less, and Grade 2 was assigned when the disruption was greater than 200 microns.The inner-retinal irregularity index was calculated as the length of the inner plexiform layer divided by the retinal pigment epithelial layer length using ImageJ software , as described previously18. We compared the parameters according to these 2 groups. After importing images into Matlab software, the image was pre-processed to remove background noise, with the thresholding filter in Matlab used to differentiate intensity between background and the signal from the CSI. The contour of the CSI was subsequently extracted and curve-fitted using a third-order polynomial. The Polyfit function was used to fit the coordinates by following the least square principle. The polynomial curve was used for curve fitting with the Curve Fitting Tool in Matlab software. The order of polynomial function was determined to identify the best approximation to the shape of the CSI. In addition, the shape of the CSI was approximated as a smooth curve without any sharp point. The definition and a representative image of measurement of the CSI irregularity index are shown in Fig. We developed a new parameter to quantitatively assess the irregularity of CSI for SS-OCT images. CSI irregularity index is defined as the weighted sum of differences at each measured point between the CSI on optical coherence tomographic image and its best-fit spherocylinder. Briefly, the horizontal OCT scan image passing through the central fovea was imported into Matlab R 2017b software . Before importing images into Matlab software, the CSI was manually delineated by two masked observers (M.K. and R.Y.K.). At first, the graders judged the CSI irregularity in an intuitive manner. CSI may be either be bowl-shaped (regular) or follow the natural oval shape of the globe or be inflective (irregular)34.The CSI was independently assessed by two masked graders (M.K. and R.Y.K.). We evaluated both intra- and inter-observer reliability for assessing CSI irregularity index. The reliability of the CSI irregularity index was assessed by the absolute agreement model of the intraclass correlation coefficient (ICC). A high ICC value (ICC ≥ 0.8) indicates the good agreement between the investigatorsP < 0.05.We expressed categorical data as absolute numbers, and continuous data as mean ± standard deviation . We conducted statistical analysis using the Statistical Package for the Social Sciences for Windows version 23.0 . The normality of data distribution was confirmed using the Kolmogorov–Smirnov test. Demographic and clinical data of patients were compared by independent t-test, chi-square test, and Fisher’s exact test. To investigate the relationships between the BCVA and predictive prognostic factors, we used Spearman rank correlation coefficient for the central foveal thickness, central choroidal thickness, inner-retinal irregularity index, EZ/COST defect grade, and CSI irregularity index. Univariate and multivariate regression analysis were conducted to assess the correlation between the 6-month visual outcome and predictive prognostic factors. Statistical significance was assumed when


This paper examines the influence of dosing method and material characteristic of superabsorbent polymers (SAP) used for internal curing, on the selected concrete properties. A new method of introducing SAP into the concrete mix and its impact on the shrinkage and compressive strength of concrete was studied. It was shown that the method of dosing SAP to the concrete mix and the differences in the properties of the tested SAPs have a significant impact on the course of changes of selected properties of the tested concrete composites. In order to compare tested series with each other and with other published results on the subject, a new method of including SAP mass content in the concrete mix, as a percentage of absorbed mixing water, was presented. The effectiveness of internal curing using different types of SAP under different dosing methods was presented as a percentage difference in tested concrete properties between modified series and reference series. Superabsorbent polymers (SAP) can be described as cross-linked hydrogel networks ,2,3. SAPAssuming such a model of an interaction within SAP, its their absorption capacity is limited not only by lowering the osmotic pressure due to water absorption, but also by the influence of external pressures resulting from the change of the SAP volume ,4 and thSAP as a component of concrete is difficult to classify using the current criteria, due to the non-standard parameters that characterize its role in the concrete mix. According to the quantitative criterion, SAP may be included in the group of concrete admixtures according to EN 206 standard, because its dosage is usually 0.3–0.6% of binder mass . IntroduThe published research on SAP in concrete technology focuses primarily on the assessment of the impact of various types of SAP on the mechanical properties and durability of concrete composites, as well as on the properties of concrete mixes ,7,8,9,10The issue of SAP’s adequate preparation and insertion method into the concrete mix is, in the authors’ opinion, crucial in the context of obtaining the optimal internal curing effect in relation to the basic characteristics of concrete, including primarily autogenous shrinkage and mechanical features. Autogenous shrinkage is one of the parameters that reduce the durability of concrete composites with low water-binder ratio ,22,23,24Despite the fact that the use of SAP as an internal curing agent is aimed at improving the durability of a concrete composite, such as reduction of linear changes, SAP can also have an influence on the mechanical parameters of concrete composites. Due to the theoretical mechanism of SAP activation, involving the absorption of mixing water from a concrete mix by a previously unsaturated SAP, changes in the course of hydration ,30,31 orAnalyzing the published research results, the decrease in compressive strength is visible as the proportion of water absorbed in the total amount of mixing water increases ,36,37,38tot—total water-binder ratio, (we/c)—ratio of entrained water to the mass of the binder and (weff/c)—effective water-binder ratio, where weff is the total mass of water used in the concrete mix, minus the mass of water entrained in the modifier serving as the internal curing agent [In the vast majority of tests carried out, the methodology known from other methods of internal concrete curing is adopted. It consists of introducing an additional volume of water to the concrete mix, which corresponds with the absorption capacity of the applied SAP mass. This fact influences the method of calculating the water-binder ratio. Usually, with respect to concrete composites with SAP addition, three variants of this coefficient are distinguished: (w/c)ng agent ,39.tot or (w/c)eff. In most studies, water intended for absorbtion by SAP is not included in the effective water-binder ratio. It is a result of adopting a similar methodology as with other internal curing agents. This leads to a situation where the assessment of the SAP influence on the properties of the concrete composite is carried out by modifying two parameters simultaneously: mass SAP content in the tested composition and additional water needed to fully activate the modifier. Such a methodology makes it difficult to draw correct conclusions as to what the real impact of SAP on the properties of concrete composites is. It can be argued that with the introduction of additional water to the concrete mix, without the use of SAP, an increase in the water-binder ratio is obtained. This results in the deterioration of mechanical properties and an increase of porosity of the concrete, leading to a reduction in shrinkage deformations. The introduction of additional water into the concrete mix will therefore affect the same parameters on which the influence of SAP is tested. The adoption of such a methodology leads to conclusions based on two phenomena occurring simultaneously and affecting the same properties of a concrete composite, making it impossible to properly determine the impact of SAP itself on the above-mentioned parameters.The problem of unambiguous determination of w/c affects the interpretation of published research results on the impact of SAP on strength parameters. In the vast majority, published results represent a reduction of compressive strength as the content of SAP in the concrete mix increases . The bigThe aim of the conducted research was to determine the impact of SAP material characteristics and an alternative to the commonly used method of dosing SAP to concrete mix on the effectiveness of internal curing. The percentage change in compressive strength and linear change caused by shrinkage deformations in relation to the reference series was assumed as a means to measure effectiveness. As part of the experiment, two types of SAP were used, differing in material characteristics and the potential to absorb water in different environments. After preliminary absorption tests of the used modifiers, ten series of specimens were made with differing mass content of used SAP and different dosing methodologies. Specimens were tested for compressive strength and linear changes caused by shrinkage deformations.The CEM I 42.5 R cement used for the preparation of the tested concrete mixes has been compliant with the requirements of EN 197 . MineralTo study the influence of SAP on selected properties of a concrete composite, two types of SAP with different grain sizes and properties were used, as seen in The methodology of the research on the impact of SAP on the development of the linear changes caused by shrinkage deformations was carried out using the Amsler apparatus. It was conducted on prismatic specimens with a square cross-section of 100 × 100 mm and a length of 500 mm (Polish standard PN-84/B06714/23 ). The coThe methodology of the conducted research on the impact of SAP on compressive strength after 28 days was developed in accordance with EN-12390-3  using 15The consistence tests of the concrete mix were made using slump test according to EN 12350-2 .The conducted research included an assessment of the impact of the method of dosing SAP to the concrete mix on the formation of selected concrete composite parameters. Two dosing methods were included: by adding non-activated SAP to the other dry components of the concrete mix, as seen in In the case of the method R, the absorption of the mixing water by the SAP takes place with the addition of water to the remaining components of the concrete mix, i.e., the activation of SAP takes place in a highly active electrochemical concrete mix environment. Due to the reversible nature of water absorption by SAP, its ability to absorb water strongly depends on the environment  in which this phenomenon occurs. In the concrete mix environment, the ability of SAP to absorb the mixing water is limited to 10–15% of the absorption achieved in the environment of tap water. This ultimately leads to a much lower intensity of curing, due to the relatively small amount of water being desorbed from the activated SAP particles during the hydration process.Method O omits the stage of absorption of mixing water from a concrete mix and focuses on maximizing the desorption potential of previously absorbed tap water. Thanks to the prior activation of SAP in the tap water environment, a much higher initial degree of SAP saturation with water can be achieved, and thus it significantly increase the desorption potential in a highly electrochemically active environment. The time between preparing and adding the mixture of SAP and mixing water to the rest of components of the concrete mix depends on the material characteristics of tested SAP. In the case of SAP M mixture, it was added to the concrete mix within 5–10 min after activation. In the case of SAP D, 24 h were needed to achieve full SAP activation. Nonetheless, the authors’ observations suggest that the period between SAP activation and addition to the mix could be significantly longer, without compromising the impact of SAP on the concrete properties.The hypothesis that prompted the authors to check the efficiency of the method O in comparison to the widely used method R was the idea of using differences in SAP absorption potentials in environments with different electrochemical activity to intensify the internal curing process. Assuming these differences, one can expect changes in the course of desorption of water from SAP activated in various environments. In order to illustrate hypothetical changes in the course of absorption and desorption of water during the hydration process, modified Powers charts were developed. These charts allow a schematic representation of changes in the phase distribution in the cement matrix during the course of hydration, as shown in In the case of concrete with a specific water-cement ratio, the distribution of phases during hydration proceeds in accordance with the empirical model developed by Powers and Brownyard  in 1948,tot in the case of max is reached, the aforementioned balancewill be restored. This fact means entraining some of the absorbed water in the SAP structure even after achieving the maximum degree of hydration.If the (w/c)tot is kept the same as in option (b), SAP activation takes place at the expense of a portion of the mixing water. However, the absorption process takes place in the tap water environment. A mixture of activated SAP and remaing mixing water is added to the rest of components of the concrete mix. Assuming the same mass content of the applied SAP as in case (b), the increase in the percentage of absorbed mixing water is caused by the absorption potential of SAP in the tap water environment approximately 10 times higher than in the cement paste environment. With such defined initial conditions and using the full absorption potential of the SAP mass used from the moment of SAP introduction into the mix, only rapid desorption of water from the SAP will occur. It is caused not only by stress in the concrete, but also by a highly active electrochemical environment. This will contribute to significant reductions in linear changes in the initial phase of hydration. Considering the compressive strength development by entraining a significant fraction of the mixing water in the SAP’s structure during concrete hardening, the water migration beyond the concrete would decrease, thus the maximal degree of hydration would increase. By maintaining the porosity at a similar level as in the example unmodified with SAP, shown in If in the case of The first step in designing compositions of concrete mixes tested in the research program was the determination of the absorption capacity of SAP used. The SAP used in the study, shown in The absorption of water by the SAP M led to the formation of a homogeneous mixture of saturated SAP in a liquid state. It had increased viscosity in relation to the viscosity of tap water. However, the SAP D did not form a homogeneous mixture after saturation—it was possible to remove the excess of non-absorbed water from between the swollen grains of the SAP. In addition, at the stage of preparation for carrying out absorption tests, an observation was made regarding the mechanism of absorption of SAP M. It forced the application of absorption capacity assessment methods other than the one commonly used in the literature. SAP M, added to the tap water in a non-dispersed form, tended to rapidly absorb water at the interface between the water and SAP layers. This resulted in creating conglomerates consisting of an activated SAP layer on the outside and non-activated in the center from which the water supply was cut off by the saturated outer layer. This phenomenon made it impossible to correctly assess the absorption capacity on the basis of the teabag method test , consistDue to the absorption mechanism of the SAP D, a standard teabag method test was carried out as part of the assessment of the SAPs absorption potential of tap water environment . It reflIn the case of the SAP M, an alternative method for assessing the water absorption capacity had to be developed. Due to the different absorption mechanism, the teabag method was considered too inaccurate and not reflecting the conditions that characterized the tested methods of SAP dosing to the concrete mix. Instead of assessing the absorption potential of the SAP M itself, the assessment of the properties of the mixture of SAP and tap water was conducted. More specifically, a study of viscosity of the mixture depending on the mass of water to the mass of SAP ratio was conducted. This action was taken due to the assumed method of dosing the SAP M, i.e., by adding a mixture of SAP M and the mixing water to the dry components of the concrete mix. By observing the viscosity changes depending on the mass of SAP M to the water mass ratio, it was possible to estimate the practical absorption of the SAP, in conditions in which it was added to the concrete mix.It was problematic to determine the absorption potential of the SAP M with the method of introducing unsaturated SAP into the concrete mix. The water absorption capacity of SAP in the concrete mix environment is strongly impaired in comparison with the absorption in the tap water environment. It is caused by the highly electrochemically active nature of such environment. In the literature, this problem is usually solved by preparing a solution of a cement paste with a water-cement ratio of 5–7  or by prDue to the long activation time of the SAP D, no studies on the effect of the addition of the above-mentioned unsaturated SAP to the dry components of the concrete mix were made, since the determination of the actual absorption capacity under such dosing conditions would be extremely inaccurate.The absorption of the SAP D was determined by performing the teabag method test, as seen in The absorption potential of the SAP M in the tap water environment was determined based on the authors’ method of measuring the viscosity changes resulting from the change of the water to SAP M mass ratio in the mixture tested. The rapid drop in the viscosity of the mixture, visible in In order to investigate the effect of an alternative method of dosing SAP on the formation of concrete composite properties, ten concrete mix compositions were developed. Those included a reference series, not modified with SAP and nine SAP modified mixes. Reference series’ composition represented a concrete with low w/c ratio and with a substantial mass of the binder. It was designed that way in order to increase the contribution of the autogenous shrinkage to the total shrinkage of the concrete. Also, by composing binder solely from CEM I the influence of other mineral additions on the tested concrete properties was mitigated. Six of them were modified with the SAP M and three with SAP D. The developed compositions also differed in mass content of the SAP used. As part of the analysis developed on the basis of the results of laboratory tests, the percentage of the mixing water absorbed by the SAP in each of the tested series of specimens was considered as a comparative parameter.All tested series of specimens were characterized by the same total water-cement ratio set at 0.3, the same aggregate composition and the same amount of binder used, as seen in Series of specimens modified with SAP differed only in the quantitative SAP content in a given concrete composite and the method of dosing SAP into a concrete mix. A total of nine compositions have been prepared containing SAP M or SAP D .tot, was 0.3, so that it would be possible to compare the results obtained as a result of the research with the results of the reference series. The total water content in SAP modified mixes was always the same as in the reference mix, shown in tot on a constant level in all prepared series of specimens the only variables affecting changes in the properties of the tested concrete composites were the quantitative content of SAP in a given specimen series and the percentage of water absorbed by SAP.In each of the designed compositions the total water-cement ratio—(w/c)Initially the influence of SAP D was to be tested in dosages allowing the absorption of 25, 50 and 75% of the mixing water successively. However, during the preparation of the SAP DO 50 mix, a significant decrease in consistence was observed. Based on this observation, it was assumed that the mix with 75% of the mixing water absorbed by the SAP D, will be extremely dry and it would impossible to compact it on the vibrating table. Due to this, a decision was made to change the dosages allowing the absorption of 12.5, 25 and 50% of the mixing water successively.Conducted experiments consisted of compressive strength tests, the study of linear changes caused by shrinkage deformations and tests of the consistence of concrete mixes. In addition to the research, a representation of the results of individual specimen series was developed, as part of the analysis of the results. It was prepared in reference to the reference series and a previously presented summary of published research on the range of reduction of linear changes. Aforementioned representation of the results was presented as a function of the absorbed percentage of mixing water, shown in To determine the effect of the addition of SAP on the consistence of the concrete mixes, a slump test was performed, the results of which are presented in As part of the determination of the effect of the addition of SAP on average compressive strength, a destructive test was carried out in accordance with the EN-12390-3 standard. The results of this test are presented in In order to analyze the impact of SAP on the shaping of linear changes caused by shrinkage deformations it was decided to present the results of tests on two different types of graphs. The first of them, shown in The second type of prepared graphs illustrates the partial changes between the series containing SAP and the reference series for the first 31 days of measurements. This method of presenting research results allows the following of the course of shaping the linear changes of individual specimen series and to determine the activation time of SAP, shown in All of the tested concretes containing SAP were characterized by showing smaller linear changes caused by shrinkage deformations than the reference concrete composite. The biggest reduction, reaching 43% after 31 days, was achieved by the SAP MO 75 mix.Taking into account the characteristics of the course of changes of the concrete series tested for linear changes, the obtained results, as seen in In the case of mixes containing SAP MR dosed according to the method of adding non-activated SAP to the remaining dry components of the mix, one can see the confirmation of the correctness of the model used in the presentation of research results in the literature, seen in The results of the tests for linear changes caused by shrinkage deformations for SAP D modified mixes, where SAP D was added as the mixture of a previously activated SAP and the remainig mixing water, allowed to observe the influence of another variable on the internal curing. Although SAP D was added to the concrete mix in the same way as the SAP M in the MO series, it was characterized by a different grain size, absorption potential and different mechanism of water absorption. These differences resulted in a change in the efficiency of reduction of linear changes, seen in It can be concluded that SAP DO series were characterized by the lowest reduction in linear changes caused by shrinkage deformations despite the higher mass content of SAP in the concrete mix—in the case of the SAP DO 50 series it was 0.204% of the binder mass. Despite the larger mass content of the SAP in the concrete mix, it obtained a smaller reduction in linear changes than concrete composites of the MO series. The mechanism of water absorption in the case of SAP D may be responsible for such a phenomenon. SAP D did not form a homogeneous mixture with the added mixing water, so the reduction of linear changes occurred locally. It resulted in a rapid desorption of absorbed water and led to reducing the final efficiency of linear change reduction.The method of adding previoulsy activated SAP M to the concrete mix increased the compressive strength by almost 10% compared to the reference series. This increase could be observed in the case of absorption of 25–30% of the mixing water by SAP. This influence of SAP in the applied method of dosing is probably caused by several factors. The first of these factors is the even distribution of SAP in the structure of the cement matrix. Assuming such a behavior of the SAP M, the cement matrix structure is densified along with the release of the absorbed water—as the absorbed water is released evenly in the entire volume of the concrete composite, the global degree of hydration increases. Another factor allowing as explanation as to why the changes in compressive strength differ depending on the SAP dosing methods used is the mechanism of water absorption by the tested SAP samples. When a pre-saturated SAP is added to the dry components of the concrete mix, a homogeneous mixture of activated SAP and water is obtained. In the case of the addition of non-activated SAP to the concrete mix, SAP conglomerates may form , due to With the increase in the percentage of mixing water absorbed by SAP above 60% in the MO series of mixes the compressive strength of the material starts to deteriorate. It can therefore be concluded that the change of the methodology of adding SAP to the concrete mix allows modification of the influence of SAP on the compressive strength only in a given range of dosages. Beyond this range there is an almost linear decrease in strength characteristic. Also, the change from effective water-cement ratio mainly reffered to in literature  to totalThis conclusion would suggest that a different approach to internal concrete curing with SAP investigated in this paper could mitigate SAP’s negative effects on the pore phase distribution in hardened concrete. However, as aforementioned mitigation is reached by lowering the dosage of SAP in the mix, the anti-shrinkage efficiency of the modifier drops as well. The reach of this mitigation should be investigated further by studying the actual pore phase distribution in microstructure of concretes, modified with SAP, with different material characteristics and using different dosing methods. The analysis of compressive strength results of SAP MR and SAP MO series, seen in In the case of SAP MR series of concrete mixes, results fit in the trend of literature research results ,32,33,38In the case of the tested series of SAP DO specimens, one can observe a decrease of the compressive strength as the percentage of mixing water absorbed by SAP increases. The reason for the decrease in strength can be explained by the increase in the porosity of the concrete composite after the desorption of the SAP characterized by a considerable grain size. SAP D probably contributes to the formation of a large pore network, which despite the local increase in cement hydration degree at a direct proximity from the SAP particles, have a negative impact on the heterogeneity of tested concrete composites.In order to determine the optimal composition and the method of dosing SAP, a graph, seen in SAP is used as an additives in order to reduce linear changes caused by shrinkage deformations, therefore the optimal composition of a concrete mix modified with SAP was defined as the composition contributing to the greatest reduction of linear changes while maintaining or increasing the compressive strength in relation to a reference series. With such assumptions, the concrete composite of SAP MO 50, characterized by the largest reduction of linear changes and increased compressive strength in relation to the reference series, was considered an optimal composition of the concrete mix tested in the research program.The pre-saturation in tap water environment of SAP with fine graining allowed an increase in the efficiency of internal curing. In the case of SAP M with a small grain size compared to the same mass of SAP M applied to the concrete mix as non-activated, the increase of both the reduction of linear changes and the compressive strength compared to the reference series was observed.Regardless of the type of SAP used, its mass quantity and the amount of absorbed mixing water resulting from the dosing method, the SAP addition to the concrete mix reduced the linear changes of the concrete, especially in the first 7 days.Increase or lack of decrease in compressive strength as a result of modifying the concrete composite with pre-saturated SAP M depended on the amount of water absorbed by the SAP.The increase of SAP content in a concrete mix caused a decrease in the liquidity of the concrete mix, regardless of the type of SAP used, its mass quantity and the amount of the mixing water absorbed resulting from the dosing method.The use of SAP D particles characterized by the non-activated grain size of 2.0–2.5 mm, even if pre-saturated with tap water, resulted in a significant decrease in compressive strength and the significantly higher variation of the test results than in the case of SAP M modified compositions or reference series. This suggests an increase in material heterogeneity.The highest reduction in linear changes caused by shrinkage deformations in series modified with SAP occurred during the first week of measerments, potentially increasing the durability of the concrete at an early phase of concrete hardening, i.e., reducing cracking risk in first days after demoulding.On the basis of conducted research on the effectiveness of internal curing with the use of SAP with different material characteristics, in different dosages, and using different methods of its introduction into a concrete mix with a composition typical for concretes in which the internal curing is recommended and applied, the following conclusions were made:


Primary sarcoma of the breast is rare. Surgery has been the only curative treatment available. Recently, neoadjuvant chemotherapy including anthracycline/ifosfamide has been reported effective for patients with high-risk sarcomas in a prospective trial.A 52-year-old Japanese woman presented with a mass in her left breast. The 10 cm tumor was fixed to her chest wall on examination. A skin biopsy was performed which showed leiomyosarcoma. Neoadjuvant chemotherapy was given and the tumor became mobile. A mastectomy and axillary dissection were performed with surgically negative margins. After neoadjuvant chemotherapy, the amount of necrosis was profoundly influenced by chemotherapy, and the histological effect of neoadjuvant chemotherapy was assessed in reference to pre-neoadjuvant chemotherapy magnetic resonance imaging.In contrast to many other cancers, the evaluation of various treatments and of the histological effect of neoadjuvant chemotherapy for sarcoma has been difficult due to the rarity of these tumors. We report the case of a patient with a breast sarcoma, treated with neoadjuvant chemotherapy and discuss the appropriate pathological evaluation and therapeutic management. Breast sarcoma is a rare entity; it is a heterogeneous group of uncommon neoplasms arising from mesenchymal tissues of the breast. Breast sarcomas accounted for 0.0006% of all breast malignancies . Over thSurgery with an adequate resection margin is the only potentially curative therapy for patients with sarcomas. However, a recent randomized trial provided evidence to support the use of neoadjuvant chemotherapy for patients with high-risk soft tissue sarcomas of the extremities and trunk by European sarcoma groups , 6. We dA 52-year-old Japanese post-menopausal woman was referred with a left breast mass, which had rapidly increased in size. Bleeding from her chest wall started about 6 months prior to presentation. The tumor measured 10 cm in its greatest dimension. It was non-mobile, contained an oozing skin ulcer and was fixed to her chest wall  plus ifosfamide (2000 mg/m2 on days 1 to 5) with mesna uroprotection (400 mg/m2 × 3 on days 1 to 5). We explained to our patient the treatment strategy and got written informed consent. She completed this regimen without major adverse effects. After neoadjuvant chemotherapy, there was no significant change in the size and enhanced pattern on MRI, even though at the completion of neoadjuvant chemotherapy the tumor became mobile.Based on the results of the European sarcoma trial, we decided to administer three cycles of doxorubicin  to shrink the tumor and allow negative surgical margins after resection.Recently, neoadjuvant chemotherapy has been used more frequently to treat patients with soft tissue sarcomas. Having been treated with neoadjuvant chemotherapy, soft tissue sarcomas such as gastrointestinal stromal tumors are likely to result in necrosis, intra-tumor hemorrhage, or myxoid degeneration, which differs from malignancies not treated that way . The necIt is necessary to have a grading system to objectively monitor the regression of soft tissue sarcomas following neoadjuvant treatment, but there is no accepted standard system to date. The European Organisation for Research and Treatment of Cancer - Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) proposed that therapeutic response should be evaluated by the change on pathological findings of stainable tumor cells and necrotic area for the entire tumor following neoadjuvant chemotherapy . They reIn the present patient, after excluding pre-treatment necrosis from evaluation, 30% of the tumor was necrotic and over 50% of the area was regarded as having stainable tumor cells. According to the proposed EORTC-STBSG tumor regression grading scheme, this patient’s therapeutic grade is “E”. The EORTC-STBSG concluded that less than 5–10% of stainable tumor cells is a good responder and correlates with favorable survival [Lymphatic spread is uncommon in sarcomas. In a prospective analysis of 1722 soft tissue sarcomas, lymph node metastases were present in 2.6% of patients . In the There is no consensus regarding the use of adjuvant radiation therapy, also. Radiation therapy may reduce the risk of local recurrence but does not result in a survival advantage. In a study of extremity soft tissue sarcomas, a cohort study and a retrospective study reported that postoperative radiation therapy may improve the survival advantage in large (> 5 cm) high-grade lesions , 13. DueOutcomes of the larger and most recent series on “breast sarcomas” are provided in Table en bloc resection with negative margins is the only potentially curative therapy. Neoadjuvant chemotherapy for aggressive high-grade lesions is widely accepted as a therapeutic option and its benefits have been reported. We believe that breast sarcomas could be treated in the same way as other soft tissue sarcomas in terms of adjuvant chemotherapy and radiotherapy. The generalized application of this approach will be difficult to assess because of the rarity of these lesions.For patients with soft tissue sarcomas, an


An overactivation of hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) axis promotes tumorigenesis and tumor progression in various cancer types. Research data recently evidenced that HGF/MET signaling is also involved also in the immune response, mainly modulating dendritic cells functions. In general, the pathway seems to play an immunosuppressive role, thus hypothesizing that it could constitute a mechanism of primary and acquired resistance to cancer immunotherapy. Recently, some approaches are being developed, including drug design and cell therapy to combine MET and programmed cell death receptor-1 (PD-1)/programmed cell death receptor-ligand 1 (PD-L1) inhibition. This approach could represent a new weapon in cancer therapy in the future. Physiologically, MET RTK is activated by a serum ligand, the hepatocyte growth factor (HGF), which is produced predominately by stromal cells and fibroblasts. MET activation triggers, through subsequent phosphorylations, various intracellular signaling cascades, including proliferation and survival pathways such as the extracellular signal-regulated kinase 1 and 2 (ERK1/2)/mitogen-activated protein kinases (MAPK) and the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and inflammation pathways such as signal transducer/activator of transcription (STAT) and nuclear-factor-κB (NF-κB) [The Physiologically, the HGF/MET pathway plays a main role in embryonic development, sustaining stem cell growth in early phases ,3 and reAn over-activation of the HGF/MET axis promotes tumorigenesis and tumor progression in various cancer types . This haMET as a proto-oncogene in tumorigenesis.Taken together, these findings elucidate a leading role of MET expression explored in clinical settings revealed that it is a mediator of anti-cancer drugs resistance, like EGFR inhibitor resistance in non-small cell lung cancer (NSCLC) [Moreover, changing in  (NSCLC) ,14 and c (NSCLC) , and als (NSCLC) , such as (NSCLC) , breast  (NSCLC) , and CRC (NSCLC) .MET role as a marker of resistance to anti-tumor therapy and bad prognosis mainly relies on its ability in inducing EMT, and consequent changes in gene and protein expression phenotype in cancer cells, which become more malignant and highly invasive . In the Among the main so-called hallmarks of cancer identified by Hanahan and Weinberg , there tIn particular, PD-L1 is an extracellular protein that downregulates immune response primarily in peripheral tissues through binding to its two receptors, PD-1 and B7.1. PD-1 is an inhibitory receptor expressed on T-cells following T-cell activation, which is sustained in states of chronic stimulation, such as in chronic infection or cancer ,34. TheiThe overexpression of PD-L1 on cancer cells has been reported to block anti-tumor immunity, resulting in immune escape , and bloResearch data has demonstrated that HGF/MET signaling is also involved in immune responses ,37,38; nHGF itself is also able to control the migration of B and T lymphocytes, and to counteract the anti-inflammatory effect of TGF-β ,46; as aMoreover, HGF itself induces the expansion of all blood cell types precursors, in cooperation with other hematopoietic stimuli .Specifically, in the context of cancer, the role of HGF/MET is very complex: HGF is secreted by cancer cells themselves, and also by stromal cells. Its oncogenic and pro-metastatic effects are well known and studied, while very recently, the interest in its effect on the immune system in cancer is increasing, due to the direct therapeutic implications in the clinical scenario of new immunotherapy drugs .First of all, MET itself can be recognized as a tumor-associated antigen (TAA) by CD8 cytotoxic T-cells, and this mechanism can trigger immune system activation against cancer cells that overexpress MET .+) that control cytotoxic CD8+ T-cells. It has been shown that HGF is able to increase this function, thus suggesting a positive role in anti-cancer immunity [+ T lymphocytes, and the increase of T reg cells result in the inhibition of the immune response [Until now, the most widely investigated role of MET is that which is played on DCs. These are involved in the presentation of TAAs, and they induce the activation of regulatory T-cells  , and thiMET overexpression is very common in several types of solid cancers, and there are numerous experimental and clinical evidences of its role in mediating resistance to conventional anti-tumor therapies, thus making MET a very attractive druggable target [MET overexpression is also often a negative prognostic factor itself, due to its intrinsic ability to induce cell cycle progression, cell migration, invasion, EMT, and angiogenesis [e target . MET oveogenesis . CurrentMoreover, in EGFR-driven lung cancer and CRC, MET activation is a very common cause of resistance to anti-EGFR drugs ,15,20,62In the last few years, the clinical scenario of anti-cancer therapies has seen a dramatic change with the introduction of immunotherapy agents. Immunotherapy is a kind of biologic cancer treatment that boosts the natural immune defenses of the patient to fight tumor cells. This includes monoclonal antibodies against negative immune checkpoints molecules, oncolytic virus therapy, T-cell therapy, and cancer vaccines . Immune MET exon 14 mutation (about 4%). These patients may benefit from MET-targeted therapy, as already anticipated by data from an expansion cohort of the phase I study of the MET-ALK inhibitor crizotinib (PROFILE 1001) [MET exon 14-skipping alterations or MET amplification. A very interesting study by Sabari et al. retrospectively investigated the effectiveness of immune checkpoints inhibitors in MET exon 14-mutated NSCLC patients, and showed that, despite them expressing high PD-L1 levels, treatment responses were very rare, with very short durations of response and progression-free survival, and they were also lower than those observed with MET-targeted therapy [MET exon14-mutated NSCLC patients showed very low TMB levels, similarly to BRAF and ROS1 mutant NSCLC, which represent other sub-groups of patients with an absence of clinical benefits from immunotherapy [+ T-cells and to induce tumor cell killing in NK/T-cell lymphoma (NKTCL) cell lines. In particular, in this model, MET elicited a specific anti-tumor immune response, with three novel identified MET-induced T-cells epitopes. The activation of T-cells was stronger in the presence of MET-inhibitors, since they caused a reduction of the synthesis of TGF-beta, which is immune-suppressive, from tumor cells. Additionally, the presentation of MET-derived peptides by major histocompatibility complex class II (MHCII) to CD4+ T-cells was influenced by chaperon processing and autophagy, thus proposing an innovative potential role of autophagy inducers as immune activators. Finally, since HGF/MET stimulation increases the proliferation of NKTCL cells in vitro, MET inhibition again displayed a dual role: direct tumor killing for MET-dependent cell survival, and anti-tumor immune activation [In lung cancer, PD-L1 expression on tumor tissue, defined by immunohistochemistry and tumor mutational burden, based on whole exome sequencing analysis, are the only two positive biomarkers for the response to anti PD-1/PD-L1 immunotherapy, while variants in EGFR and STK11 genes were found to be associated, with no benefit in NSCLC patients ,75,76. ALE 1001) ; other o therapy . Interesotherapy . In our otherapy . It is botherapy . Thus, aotherapy  demonstrotherapy  showed ttivation .Recently, some approaches are under development, including drug design and cell therapy. A novel dual inhibitor of MET and PD-1 was designed by Sun et al.  and testhttps://www.ema.europa.eu/human-regulatory/research-development/scientific-guidelines/multidisciplinary/multidisciplinary-cell-therapy-tissue-engineering (accessed on 12 November 2018).Another MET-targeted immunotherapy approach that has already been tested in preclinical mesothelioma models is the MET chimeric antigen receptor (CAR) T-cell immunotherapy . CAR T-cIn the study of Thayaparan et al., T-cells have been engineered to express HGF as a chimeric antigen to target MET-expressing cancer cells . The effPreviously, Frigault et al. engineered novel CARs coding for immune signals molecules, such as CD28, ICOS, and 4-1BB, by using common cancer genes including MET as a referral to design the promoters to be transfected in T-cells .Only preliminary data are available for MET CAR T on human samples: they come from the data of intra-tumor injection of MET CAR T-cells in breast cancer tumors. After injection, these tumors displayed necrosis, loss of MET, and infiltration of macrophages, which are markers of inflammation .These data confirm the good activity of the CAR T method, and suggest subsequent evaluations in other cancer types with a significant MET expression, thus introducing a very innovative therapeutic potential of MET targeting.From clinical datasets, only few datasets are already available on the resistance to the currently used anti-PD-1/PD-L1 immunotherapy, and further studies are needed to select and identify subpopulations of patients that can derive clinically consistent benefit from these drugs.The HGF/MET pathway plays many distinct roles with an impact on tumor aggressiveness. Among these, a poorly explored one is that on the immune system. Considering the previously cited references, it is evident that this role is not sufficiently understood. Indeed, currently available data are quite contradictory, at least in some circumstances. For example, IDO1 upregulation appears to favor tumor growth , while tVarious preclinical data support the immunological mechanisms and the potential efficacy of combining MET-inhibitors with immunotherapy; in a clinical context, dose-limiting toxicities could be an issue for this combination, and no data are currently available on their safety in humans. As a consequence, we can only make hypotheses on the probable side effects. Besides class-effect adverse events of MET targeting agents  ,65, HGF/Another issue to be considered is the selectivity of action of the putative combination (anti-MET + anti-PD-1/PD-L1 or MET-CAR-T-cells). Indeed, the MET receptor is expressed with a plethora of normal cells, which implies the possibility of safety concerns to the effect on normal besides tumor cells. Too little data are now available; thus, further studies should help to quantify the off-target effects of these therapies. Other interesting approaches rely on the possibility of improving immune checkpoint inhibitor delivery through the use of nanotechnologies ,91.In conclusion, the HGF/MET pathway is one of the most important pro-oncogenic, pro-angiogenetic, and pro-metastatic signals in various cancer types. Interestingly, from various studies, its activation emerges as one of the main mediators of resistance to anti-cancer therapies, including the novel anti-PD-1/PD-L1 immunotherapies, thus reinforcing the potential of MET-targeted therapies and giving the rationale for testing them in combinational strategies or integrated innovative approaches, like CAR-T therapy, in multiple cancer types.