Under the same exposure time and penetration depth, the chloride ion content in concrete under two-dimensional (2D) and three-dimensional (3D) diffusion under dry and wet cycles was 1.09~4.08 times higher than that under one-dimensional (1D) diffusion. The correlation coefficients between the simulation results of the multidimensional transport model of chloride ions in concrete under multi-factor coupling and the experimental results were all greater than 0.95, and the model can be utilized to predict the distribution of chloride ion concentration in concrete.Chloride ion erosion is an important factor affecting the durability of marine engineering concrete. In particular, concrete structures in wave splash and tidal zones are subjected to dry and wet cycles and multidimensional diffusion of chloride ions. To investigate the intricate diffusion of chloride ions within concrete under these dynamic conditions, we devised a comprehensive experiment. This experiment encompasses multiple dimensions, involving dry and wet cycles, as well as static immersion. The experiment intends to reveal how chloride ions are distributed in the concrete and clarify the changes that occur in its microstructure. Based on Fick’s second law, the multidimensional diffusion model of chloride ions in concrete under the dry and wet cycles and static immersion was established by comprehensively considering the effects of chloride ion exposure time, environment temperature, relative humidity, and the action of dry and wet cycles. The results show that, under the same conditions, the chloride content in concrete decreases with the increase in penetration depth but increases with the increase in the chloride diffusion dimension and exposure time. Dry and wet cycles and multidimensional diffusion of chloride ions increase the development of cracks and pores in the concrete structure and generate large quantities of C With the implementation of China’s marine power strategy and the development of the marine economy, the demand for diverse types of marine engineering concrete structures is rising. Numerous aggressive ions in the ocean, especially the presence of a large number of chloride ions, which is the main factor causing the corrosion of steel reinforcement and leading to the deterioration of concrete ,3,4,5,6,In the experimental study of chloride ion transport in concrete under the action of dry and wet cycling, Neville  investigIn terms of modeling studies of chloride ion transport in concrete under dry and wet cycling, Ababneh et al.  establisFrom the above studies, it can be seen that domestic and foreign researchers have conducted a lot of studies mainly on the one-dimensional (1D) diffusion test and simulation of chloride ions in concrete under the action of dry and wet cycles; however, the concrete structures of marine engineering are often subjected to two-dimensional (2D) or three-dimensional (3D) diffusion of chloride ions. For this purpose, this paper carries out indoor modeling tests on the multidimensional transport of chloride ions in concrete under the action of dry and wet cycles and static immersion by simulating the concentration of chloride ions in seawater in the Tongan District, Xiamen City, China and tests the microstructural changes in concrete before and after the dry and wet cycling by using Scanning Electron Microscopy (SEM) and X-ray Diffractometry (XRD) to study the effects of dry and wet cycling and multidimensional diffusion on the transport pattern of chloride ions in concrete. On this basis, the multi-dimensional transport model of chloride ions under dry and wet cycles and static immersion is established based on Fick’s second law by considering the effects of dry and wet cycles, time-varying diffusion of chloride ions, ambient temperature, and relative humidity and is verified using the experimental results. The research results can provide a reference for the study of multi-dimensional chloride ion transport mechanisms and the improvement of chloride ion resistance of marine engineering concrete structures under multi-factor coupling.3, crushing index of 8.7%, and particle grading of 5 mm~25 mm. The fine aggregate is natural river sand produced by Xiamen Shunlei Building Material Co., Ltd., Xiamen City, China with an apparent density of 2590 kg/m3 and a fineness modulus of 2.5. The fly ash adopted was grade I fly ash produced by Hejin Longjiang Fly Ash Development and Utilization Co., Ltd., Hejin City, China and its performance meets the requirements of GB/T 1596-2017 [The cement used in this test is Longlin-brand P.O 52.5 ordinary silicate cement produced by Fujian Longlin Group Co., Ltd., Longyan city, China; the product complies with GB 175-2007 , and its596-2017 . S95 sla596-2017 . The watThe design strength grade of concrete for this experiment is C55, and the mix proportion is in reference to the construction mix proportion of a cross-sea bridge in Xiamen; the water-to-binder ratio is 0.3, and the mix proportion of concrete is shown in This experiment mainly simulates the corrosive effect of chloride ion diffusion and diffusion dimension on concrete under the dry and wet cycles in the marine environment, and a total of 80 cubic concrete specimens of 100 mm in size, 3 rectangular concrete specimens of 100 mm × 100 mm × 400 mm, and 6 cylindrical concrete specimens of Φ100 mm × 50 mm were fabricated. And, 3 cubic concrete specimens were used to determine the compressive strength at 7 and 28 days, 3 rectangular concrete specimens to measure the flexural strength at 28 days, 3 cylindrical concrete specimens to evaluate the chloride diffusion coefficient using the Rapid Chloride Migration Coefficient (RCM) method, and 54 cubic concrete specimens to conduct diffusion of chloride ions tests.To prevent interference from other factors, we used raw materials from the same batch and poured the specimens on the same day. The temperature of the curing room is (20 ± 2) °C, the relative humidity is greater than 95%, and the molding of concrete specimens and their maintenance are shown in Before the chloride ion diffusion test, the concrete specimens should be pretreated. For the 1D diffusion of cubic concrete specimens, 5 faces are coated with epoxy resin and only one exposition surface is kept in contact with the salt solution; for the 2D diffusion of cubic concrete specimens 2, adjacent surfaces are kept as exposition surfaces; and for the 3D diffusion of cubic concrete specimens, 3 two-by-two surfaces are kept as exposition surfaces, and the rest of the surfaces are encapsulated with epoxy resin as shown in − and SO42− in seawater and to take the average of its value as the concentration of the salt solution for the experiment. High-purity industrial chemicals were used for the configuration, and a salt solution of 2.8% NaCl + 0.29% Na2SO4 was used for the dry and wet cycle tests. Referring to the tidal changes in Xiamen in recent years, a dry and wet cycle system of 12 h natural drying + 12 h solution immersion (the dry and wet ratio is 1:1) as a cycle was selected as a comparison group, while the concrete specimens were put into the salt solution for static immersion for 30 days, 60 days, and 90 days, respectively. To ensure the stability of the ion concentration in the solution, the salinity change of the solution was recorded weekly using a seawater salinometer and the solution was replaced once a month for the treatment. The different dimensions of chloride ion diffusion conditions and numbers are shown in In order to make the immersed salt solution as close as possible to the real marine environment, in the experiment, the seawater sampling was carried out in the Tongan District, Xiamen City; the number of samples was three, respectively, to determine the concentration of Cl(1)Compressive and flexural strength testThe compressive and flexural strength of concrete was measured according to GB/T 50081-2019 . A CXYAW(2)Chloride penetration resistance test−12 m2/s and 1.7 × 10−12 m2/s, respectively, and the grade of chloride ion penetration resistance of concrete was RCM-IV, which means the concrete has good chloride penetration resistance.The migration coefficient of chloride ions in concrete was measured according to the requirements of GB/T 50082-2019 , and the(3)Chloride ion content testThe water-soluble chloride content of the concrete was measured after the concrete specimens had been subjected to diffusion of chloride ions for 30, 60, and 90 days. Concrete powder was collected at 1 mm, 10 mm, 20 mm, and 30 mm from the diffusion surface, respectively, and the sampling locations of concrete under 1D, 2D, and 3D diffusion of chloride ions are shown schematically in (4)Microstructure observationsA ZEISS Sigma 300 scanning electron microscope (SEM) from Germany and Rigaku Ultima IV X-ray diffractometer (XRD) from Japan were used to observe the microstructure and chemical composition of the concrete, respectively, and the sampling point was 5 mm from the concrete surface.When SEM was used to observe the microstructure of concrete, the samples were recovered from fractured surfaces to avoid destroying the internal material morphology of the samples. Due to the poor conductivity of the concrete, which will affect the clarity of the observation, it is also necessary to use the Quorum SC7620 sputtering coater to spray gold on the sample. The sample was fixed on the conductive tape when observing the microstructure of the concrete.When XRD was used, a concrete block with a thickness of not less than 0.1 cm was glued to a glass sample stage, a Cu anticathode with a wavelength of 0.154056 nm was used, the test angle was from 5° to 90°, and the scanning speed was selected to be 2°/min.The distribution of chloride ion concentration in concrete specimens under different exposures modes for chloride exposure times of 30, 60, and 90 days is shown in As shown in For the same exposure time and penetration depth, the chloride ion content of concrete under dry and wet cycles was higher than that of concrete under static immersion. This is due to the fact that under dry and wet cycles, chloride ions are transported via capillary absorption and diffusion. During the immersion phase, the capillary action and the concentration difference contribute to the ingress of chloride ions into the interior of the concrete, and during the drying phase, the internal moisture of the concrete migrates outward, the chloride concentration in the pore solution increases, and the difference in the concentration gradient contributes to the migration of chloride ions towards the interior of the concrete, which leads to a higher chloride ion content in the interior of the concrete than that of the static immersion. Taking the 1D diffusion of chloride ions as an example, as shown in As shown in For the effect of exposure time on the chloride ion content, taking the 3D diffusion of chloride ions in concrete under the dry and wet cycles as an example, the variation in chloride ion content in concrete with exposure time at different penetration depths is shown in As shown in The concrete without diffusion of chloride ions was used as a comparison group, and the results of electron microscope scans of concrete specimens under different working conditions and concrete without diffusion of chloride ions after 90 days of 3D diffusion of chloride ions are shown in 3A·CaCl2·10H2O; at the same time, the surface of the concrete also produced some fine loose particles, the boundary of the transition zone between the aggregate and the mortar was blurred, and the overall staining adhesion deteriorated, so that more chloride ions entered into the inside of the concrete, which further suggests that dry and wet cycles can significantly enhance the chloride ion transport rate in surface concrete. As shown in From 2 (PDF # 85-1053), CaCO3 (PDF # 87-1863), Ca(OH)2 (PDF # 72-0156), and the C3A·CaCl2·10H2O (PDF # 78-1219).The XRD physical phase change curves of concrete after 90 days of 3D chloride ion diffusion under different working conditions are shown in 3A·CaCl2·10H2O peaks within the concrete specimens. Notably, the C3A·CaCl2·10H2O peaks were more pronounced in the SDW group. This increase in peak height can be attributed to the greater number of wet and dry cycles, which accelerated damage within the concrete. The process led to pore expansion, microcracks, and differences in concentration that facilitated the transport of more chloride ions into the interior of the concrete. Consequently, chloride ions diffused more rapidly inside the concrete due to the influence of these dry–wet cycles and concentration variations, resulting in increased C3A·CaCl2·10H2O formation when reacting with C3A.After 90 days of exposure to varying conditions, we detected characteristic CC0 is the chloride ion concentration in the internal of concrete (unit: %), sC is the chloride ion concentration on the concrete surface (unit: %), D is the chloride diffusion coefficient (unit: m2/s), t is the time of concrete structures’ exposure to the environment (unit: s), x is the depth from the x-axis direction of the concrete surface (unit: mm), and erf(u) is the gaussian error function, which is shown in Equation (2).The transport of chloride ions in concrete under static solution immersion is dominated by migration and satisfies Fick’s second law . The 1D The chloride ion diffusion coefficient is affected by concrete raw material components, service time, external environment, and other factors. A multidimensional diffusion model of chloride ions was established under multi-factor coupling conditions by considering the effects of time factor, chloride ion binding capacity, temperature, relative humidity, and concrete deterioration caused by dry and wet cycling. The diffusion coefficient of chloride ions in the model is expressed by the integrated diffusion coefficient of chloride ions.D0 [d is given in Equation (3).W/B is the water-to-binder ratio.The chloride diffusion coefficient D0  for concK can be introduced when describing the chloride ion penetration of concrete materials under the action of dry and wet cycles [t is the effective diffusion time (unit: s). K is the deterioration effect factor [K in this paper is taken as 2.5. i is the number of dry and wet cycles, stt is the wet time of one dry and wet cycle (unit: s), and gtt is the dry time of one dry and wet cycle (unit: s).For the effect of dry and wet cycles, since dry and wet cycles will lead to the deterioration of concrete materials, the deterioration effect factor t cycles , and thet factor , becausetf of the chloride diffusion coefficient within concrete at the standard curing age can be expressed as Equation (5).t0 is the 28d curing time (unit: s), t is the diffusion time (unit: s), and m is the time decay coefficient, which is given in Equation (6) [FAω is the percentage of fly ash to the mass of cementitious material, FAω/50 ≤ 1, which means that the percentage of fly ash to the mass of cementitious material should be less than 50%. SGω is the percentage of slag to the mass of cementitious material, SGω/70 ≤ 1, which means that the percentage of slag to the mass of cementitious material should be less than 70%.For the effect of chloride diffusion varied with time, Thomas et al.  suggestetion (6) .(6)m=0.Bf can be expressed as Equation (7).eω is the volumetric ratio of evaporable water in concrete, BC is the concentration of bound chloride ions (unit: mol/L), FC is the concentration of free chloride ions in the concrete pore solution (unit: mol/L), and α is the slope of the line.For the effect of chloride binding capacity, Perez et al.  proposedTf is shown in Equation (8).T is the environment temperature; T0 is the reference temperature at age 28d, which is 293.15 K [R is the gas constant, which is 8.314 J/(mol·K); and U is the activation energy during diffusion, which is 35 kJ/mol when the water-to-binder ratio is 0.3 according to the reference [For the effect of environment temperature, Boddy et al.  proposed293.15 K ; R is theference .Hf can be expressed as Equation (9).RH is the relative humidity at the time of the experiment and cRH is the critical relative humidity, generally 75%.For the effect of the environment relative humidity, Bazant et al.  proposedD is modified; assuming that the corrected diffusion coefficient of chloride ions is fD, the modified 1D, 2D, and 3D diffusion equations for chloride ions in the concrete are given in Equations (10)–(12) [fD is the modified integrated diffusion coefficient for chloride ions; m is the time decay coefficient; and y, z is the depth from the concrete surface in the y- and z-axis directions (unit: mm).Taking into account the effects of the diffusion of chloride ions varied with time, the binding effect of chloride ions with concrete, the environment temperature, relative humidity, and the effect of dry and wet cycles, the chloride diffusion coefficient 10)–(12) .(10)C(xThe modified integrated diffusion coefficient for chloride ions under dry and wet cycles is given in Equation (13).The modified integrated diffusion coefficient for chloride ions under static immersion is shown in Equation (14).We developed a modified multidimensional chloride ion diffusion model using MATLAB R2018b software. The model was applied to simulate concrete specimens exposed to a 90-day immersion, and the comparison between the simulation results in various dimensions and the experimental findings is depicted in As shown in (1)Under the same diffusion conditions, the chloride content of concrete decreases with the increase in penetration depth, and it can be seen that the chloride content of concrete under dry and wet cycling is greater than that of static immersion.(2)Under the same diffusion conditions, the chloride ion content in concrete increases with the increase in diffusion dimension and exposure time. Chloride ion multidimensional diffusion under dry and wet cycles will exacerbate the chloride ion transport rate in concrete and the penetration depth. The chloride ion content in concrete under 2D and 3D diffusion under dry and wet cycles was 1.09~4.08 times higher than that under 1D diffusion.(3)The coupled dry and wet cycles and diffusion of chloride ions increase the development of cracks and pores within the concrete structure, which accelerates the rate of chloride ion transport in the concrete.(4)The correlation coefficients between the simulation results of the multidimensional transport model of chloride ions in concrete under multi-factor coupling and the experimental results were all greater than 0.95, indicating that the model can be used to predict the concentration distribution of chloride ions in concrete.In order to study the effect of dry and wet cycles in the marine environment on the diffusion of chloride ions in concrete, a multidimensional diffusion experiment of chloride ions in concrete under the dry and wet cycles and static immersion was designed, and the distribution pattern of chloride ions and the changes in the microstructure of the concrete across different time periods were measured. Meanwhile, based on Fick’s second law, a multidimensional diffusion model of chloride ions in concrete under dry and wet cycles and static immersion was established by considering the effects of chloride ion exposure time, environment temperature, relative humidity, and dry and wet cycles, which were simulated by using MATLAB software and then verified using the experiment results; the following conclusions were obtained:


MET tyrosine kinase inhibitor that received approval for advanced non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutation. Capmatinib was first discovered in 2011 and has been shown to have promising antitumor activity. Early-phase trials identified a recommended dose of 400 mg twice daily in tablet formulation. The GEOMETRY mono-1 trial showed efficacy in MET exon 14 skipping mutation, leading to FDA approval for capmatinib. Currently, ongoing clinical trials evaluating combination therapy with capmatinib, including amivantamab, trametinib, and immunotherapy, are being conducted to improve efficacy and broaden indications of capmatinib with new drug agents such as antibody–drug conjugates being developed to treat MET dysregulated NSCLC.In this narrative review, we discuss the development of capmatinib, a reversible MET) proto-oncogene has been implicated in multiple solid tumors, including NSCLC, and dysregulation in NSCLC from MET can present most notably as MET exon 14 skipping mutation and amplification. From this, MET tyrosine kinase inhibitors (TKIs) have been developed to treat this dysregulation despite challenges with efficacy and reliable biomarkers. Capmatinib is a Type Ib MET TKI first discovered in 2011 and was FDA approved in August 2022 for advanced NSCLC with MET exon 14 skipping mutation. In this narrative review, we discuss preclinical and early-phase studies that led to the GEOMETRY mono-1 study, which showed beneficial efficacy in MET exon 14 skipping mutations, leading to FDA approval of capmatinib along with Foundation One CDx assay as its companion diagnostic assay. Current and future directions of capmatinib are focused on improving the efficacy, overcoming the resistance of capmatinib, and finding approaches for new indications of capmatinib such as acquired MET amplification from epidermal growth factor receptor (EGFR) TKI resistance. Clinical trials now involve combination therapy with capmatinib, including amivantamab, trametinib, and immunotherapy. Furthermore, new drug agents, particularly antibody–drug conjugates, are being developed to help treat patients with acquired resistance from capmatinib and other TKIs.Non-small cell lung cancer (NSCLC) is a leading cause of death, but over the past decade, there has been tremendous progress in the field with new targeted therapies. The mesenchymal–epithelial transition factor ( EGFR; KRAS G12C; BRAF V600E mutations; ALK, ROS1; RET gene rearrangements; MET alterations, including MET exon 14 skipping mutations, ERBB2 (HER2) mutations, and NTRK 1/2/3 gene mutations [Non-small cell lung cancer (NSCLC) is a leading cause of death, accounting for an estimated 1.8 million deaths according to GLOBOCAN in 2020 [utations ,8,9,10. MET) gene is located in human chromosome 7 (7q21–q31), comprising 21 exons and 21 introns, and encodes a protein that is approximately 120 kDa in size. The ligand for MET is hepatocyte growth factor (HGF), which is a soluble cytokine and is synthesized by mesenchymal cells, fibroblasts, and smooth muscle cells [The mesenchymal–epithelial transition factor -dependent inhibition of mTOR which then decreases the sensitivity of NSCLC cells with wild-type EGFR to TKI and thereby represses the expression of liver kinase B1 (LKB1) [MET dysregulation can occur via gene mutation, most notably the MET exon 14 skipping mutation seen in about 3–4% of adenocarcinoma and 2% of squamous cell carcinoma but in higher frequencies in adenosquamous carcinoma (6%) and pulmonary sarcomatoid carcinoma (9–22%) [In cancer, the -catenin   . Finally (9–22%) . MET exon 14 skipping mutations are processes in which the 47-amino-acid juxtamembrane domain is deleted, altered, or disrupted by intronic regions surrounding exon 14, leading to fusion in mature mRNA between exon 13 and exon 15 [MET exon 14 skipping mutations have been shown to be exclusive from other driver mutations but coexist with other MET amplification or copy number gains [MET gene, which is defined as a gain in copy number (GCN), has been seen both de novo and as an acquired resistance mechanism [MET amplification is seen in EGFR-acquired resistance and can occur with or without the loss of T790M [n = 78), MET amplification was seen in  of samples, EGFR C797S  of cases, and 15 patients having >1 resistance-related genomic alteration [MET amplification is also considered an acquired resistance mechanism of ALK inhibitors, as MET amplification has been observed in about 15% of next-generation ALK inhibitor resistance [MET exon 14 skipping mutations and MET high-level amplification have been shown to portend poor prognosis [MET inhibitors, a retrospective study by Awad et al. showed that the median OS was 8.1 months [MET exon 14 skipping mutations are seen more frequently in females than in males, and the median age of MET exon 14 skip mutation patients ranged from 71.4 to 76.7 years [MET exon 14 skip mutation patients tend to be smokers, with only about 36% being never smokers in a previous retrospective analysis [ exon 15 ,20. MET er gains . Meanwhiechanism . MET ampof T790M . In the teration ,24. MET sistance . Both MErognosis . Without1 months . MET exoin 14/78,% of sampanalysis .MET tyrosine kinase inhibitors have been developed to treat MET-dysregulated NSCLC, classified as Type I, Type II, and Type III inhibitors. Type I inhibitors compete with ATP for the binding of the ATP-binding pocket of the active conformation of MET. Specifically, Type Ia inhibitors such as crizotinib interact with the Y1230 residue in the hinge region and are dependent on binding with the G1163 residue [ residue ,29. Type residue ,30,31,32 residue ,34,35. T residue .MET exon 14 skip mutations in metastatic NSCLC on 10 August 2022 and by the European Medicines Agency (EMA) on 20 June 2022 specifically for those patients who have received immunotherapy or platinum-based chemotherapy or both [This review specifically focuses on capmatinib (INC280), which received U.S. Food and Drug Administration (FDA) approval for  or both ,38. HereMET TKI to show efficacy in MET exon 14 skipping mutation in advanced NSCLC. The PROFILE 1001 trial showed an overall response rate (ORR) of 32% (95% CI 21–45) among 65 response-evaluable patients, with a median duration of response (DOR) of 9.1 months (95% CI 6.4–12.7) and a progression-free survival (PFS) rate of 7.3 months (95% CI 5.4–9.1), with two additional Phase II crizotinib trials showing ORR of around 30% [MET Type Ib TKIs such as capmatinib, and thus treatment for MET dysregulation has shifted towards MET Type Ib TKIs [ALK- and ROS1-positive advanced NSCLC by the FDA and EMA [Prior to capmatinib, crizotinib was the first ound 30% ,40,41. H Ib TKIs . Current and EMA ,44.MET of over 1000 fold [MET amplification and HGF expression in vitro were also associated with capmatinib sensitivity in vitro [Capmatinib was first reported in 2011 by Liu et al., who showed that in both in vivo and in vitro mice studies using human cell lines, capmatinib had a 10,000-fold selectivity for c-met over a large panel of human kinase . They sh000 fold . Further000 fold . MET ampin vitro .MET. Capmatinib has an average IC50 value of 0.13 nM and a cell-based IC50 of 0.3–0.7 nM in lung cancer cell lines [max) obtained about 1–2 h after a 400 mg dose is given. There is similar absorption when taken with and without food. The effective elimination half-life is 6.5 h. The plasma protein binding is 96% [Capmatinib is a selective Type Ib ATP-competitive tyrosine kinase inhibitor targeting ll lines ,46  by 42%, with no change in Cmax. Coadministration with rifampicin, a strong CYP3A inducer, decreased capmatinib AUC0-INF by 67% and decreased Cmax by 56%. Coadministration with protein pump inhibitors (rabeprazole) decreased capmatinib by AUC0-INF 25% and decreased Cmax by 38%. Coadministration with rosuvastatin, a BRCP substrate, increased rosuvastatin AUC0-INF by 108% and increased Cmax by 204% [In drug interaction studies, coadministration with itraconazole, a strong CYP3A inhibitor, increased capmatinib’s area under the curve  twice a day (b.i.d.) as a tablet. The median duration of treatment exposure was 7 weeks (range 0.4–32.3 weeks), with disease progression being the primary reason for the discontinuation occurring in 38 patients (86.4%). There were two drug-limiting toxicities (DLTs), which consisted of Grade 2 suicidal ideation in a patient taking 600 mg po b.i.d. and Grade 3 depression in a patient taking 400 mg po b.i.d. . AnotherMET-dysregulated NSCLC, which included 40 patients with prior systemic therapies. All patients discontinued treatment, mostly due to disease progression (69.1%), with a median duration of 10.4 weeks. While the overall response rate (ORR) by RECIST for the entire cohort was 20%, MET with a gene copy number ≥6 had an ORR of 47%, with median progression-free survival (PFS) of 9.3 months, and all patients with MET exon 14 skip mutations had a response. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%) [EGFR-mutated, MET-dysregulated NSCLC in combination with gefitinib, an EGFR TKI, in patients with acquired EGFR TKI resistance. The ORR across the cohort was 27%, with a 47% ORR in patients with a MET copy number ≥6. The drug was relatively well tolerated, with the most common Grade 3–4 adverse event being increased amylase and lipase levels (6% in both). The R2PD was capmatinib 400 mg po b.i.d. plus gefitinib 250 mg po daily [Schuler et al. investigated 55 patients with advanced ng (31%) . Anotherpo daily  , Cohort 1 consisted of MET amplification with (a) GCN ≥ 10 (n = 69) or (b) GCN 6–9 (n = 42); Cohort 2 consisted of MET amplification with GCN 4–5 (n = 54); Cohort 3 consisted of MET amplification with GCN < 4 (n = 30); Cohort 4 consisted of MET exon 14 skipping mutation with any GCN (n = 69); and Cohort 6 consisted of MET amplification with GCN > 10 (n = 3) or MET exon 14 skipping mutation with any GCN (n = 31) who had received one line of therapy (n = 34). In the untreated group, Cohort 5a consisted of MET amplification with GCN ≥ 10 (n = 15); Cohort 5b consisted of MET exon 14 skipping mutation with any GCN (n = 28); and Cohort 7 consisted of treatment-naïve MET exon 14 skipping mutation with any GCN (n = 23). MET exon 14 skipping mutation patients had a slightly higher median age (71 years) than patients with MET amplification (60–70 years) on diagnosis. Patients with MET exon 14 skipping mutation were more likely to be women and to have never smoked [The GEOMETRY mono-1 trial was a multicohort Phase II study in patients with MET exon 14 skip mutations, ORR was seen in 41% (95% CI 29–53) of 69 previously treated patients and 68% (95% CI 48–84) of 28 previously untreated patients. The median duration of response (DOR) was 9.7 months (95% CI 5.6–13.0) among the treated patients and 12.6 months (95% CI 5.6—not reached) in previously untreated patients. Most patients (82% in treated and 68% in untreated) had a response at the first tumor evaluation following the start of capmatinib therapy. The median PFS was 5.4 months (95% CI 4.2–7.0) in previously treated patients and 12.4 months (95% CI 8.2—not reached) in previously untreated patients. Notably, 12 of 13 patients with exon 14 skipping mutations who had brain metastasis had intracranial disease control. The primary reason for discontinuation was progressive disease (58% in previously treated patients and 46% in untreated patients) [Among patients with In patients with GCN < 10, the cohorts were closed due to futility, as PFS for GCN 6–9 and 4 or 5 was only 2.7 months. In GCN ≥ 10, there was activity; the ORR was 29% (95% CI 19–41) in previously treated patients and 40% (95% CI 16–68) in previously untreated patients, but this fell below the predefined clinical efficacy. The median DOR was 8.3 months (95% CI 4.2–15.4) in treated patients and 7.5 months (95% CI 2.6–14.3) in untreated patients. The median PFS was 4.1 months (95% CI 2.9–4.8) in treated patients and 4.2 months (95% CI 1.4–6.9) in untreated patients [Across all cohorts, the most reported adverse events were peripheral edema, nausea, and vomiting. Overall, 67% of patients had adverse events of Grade 3 or 4; the most frequent of these were peripheral edema, nausea, vomiting, and increased blood creatinine level. Treatment-related adverse events led to the discontinuation of treatment in 39 patients (11%), with treatment-related peripheral edema leading to discontinuation in 6 patients (2%) [MET exon 14 skipping mutation patients that focused on 19 patients in the cohort who had previously received immunotherapy (IO) showed ORR 57.9% , with a median DOR of 11.2 months (95% CI 3.35—not reached). Safety findings were similar, according to which capmatinib showed efficacy irrespective of prior treatment with IO and was also well tolerated in post-IO patients [The post hoc analysis involving 69 patients . Moreovepatients . There wpatients .MET exon 14 skipping mutation and brain metastasis patients; of the 68 patients that fit the criteria, the real-world response rate was 90.9%, with 87.3% intracranial response along with a median PFS rate of 14.1 months [MET exon 14 skipping mutation who were treated with capmatinib from March 2019 to December 2021 [A recent real-world analysis was carried out that investigated 1 months . Anotherber 2021 . The ORRber 2021 .MET-dysregulated, advanced NSCLC, with promising ORR and PFS seen in MET exon 14 skip mutations, though the results showed a lack of effect in MET GCN < 10, leading to FDA and EMA approval for capmatinib only in advanced NSCLC with MET exon 14 skipping mutations. Subsequent real-world data have shown response to capmatinib among patients with MET exon 14 skipping mutations, with IO exposure and brain metastasis [Thus, the GEOMETRY mono-1 trial evaluated tastasis ,56.MET alterations, namely tepotinib and savolitinib [MET exon 14 skipping mutations in advanced NSCLC after the open-label Phase II VISION study [MET exon 14 skipping mutations who require systemic therapy following immunotherapy and/or platinum-based therapy [MET exon 14 skipping mutations were followed, and the ORR was 46% (95% CI 36–57), including 44.2% (95% CI 29.1–60.1) in untreated patients and 48.2 (95% CI 34.7–62.0) in previously treated patients. The median DOR was 11.1 months (95% CI 7.2—not reached), and the PFS was 8.5 months (95% CI 5.1–11.0) [Two other MET selective Type Ib inhibitors have been investigated in olitinib ,31. Tepo therapy . In thisMET exon 14 skipping mutations who had positive pulmonary sarcomatoid carcinoma or other NSCLC subtypes and received savolitinib [MET exon 14 skipping mutations in patients who have progressed after or who are unable to tolerate platinum-based chemotherapy [Meanwhile, a Phase II, single-arm, open-label study in China involved 84 patients with olitinib . The ORRolitinib   2+ and 3+, the ORR outcomes ranged from 14% to 68% [MET overexpression has been the MET/chromosome 7 centromere (CEP7) ratio, in which ORR outcomes range from 33% to 67% [One of the challenges in the success of finding successful % to 68% ,50,51,59MET amplification have been that gene copy number gains can occur through both polysomy and amplification and thus the gene copy number could be a result of polysomy, not true amplification [MET/CEP7 ratio >5 is reliable for MET inhibitor response, but the issue is that many below this ratio have other oncogenes and may not be truly MET-addicted cases [Some thoughts as to the lack of reliability in fication ,60,61. Afication ,61. A pred cases .MET alterations, only 2 of the 18 patients who also received tissue testing were found to have MET alterations in the tissue [MET alterations on ctDNA testing, but only 17.8% of the 26% total also had MET alterations on tissue testing [MET alterations have been found in both circulating-free DNA (cfDNA) and circulating tumor cells (CTCs) both at diagnosis and at resistance to EGFR TKIs [MET amplification in tumor tissue [MET dysregulation is captured on diagnosis but then also on acquired resistance because sometimes patients may not have adequate tissue for testing, which limits them only to liquid biopsy testing, or clinicians may choose to only perform liquid biopsy testing upon the progression of the disease. Thus, finding a trustable biomarker, whether it is a specific MET GCN or MET/CEP7 ratio threshold that can be used in both tissue testing and ctDNA testing, will go a long way towards determining which MET amplification patients would benefit from capmatinib and other MET-targeted agents and to ensure that as many MET exon 14 skipping mutations are detected as possible.Another challenging aspect of finding a reliable companion diagnostic assay has been the discrepancy between circulating tumor DNA (ctDNA) and tumor next-generation sequencing (NGS) testing. Ikeda et al. studied the ctDNA of 438 patients, and among the 31 patients with e tissue . Another testing . Overall testing . Yet, MEGFR TKIs . Moreover tissue . This alMET exon 14 skipping mutations, there is also some variability in the ORR, with ranges from 32% to 64%, though these studies do originate from patients on different lines of therapy and different MET TKI inhibitors [MET inhibitor [In hibitors ,31,41. Hhibitors ,67. The nhibitor ,67.In the GEOMETRY mono-1 trial, across all cohorts, the most reported adverse events were peripheral edema, nausea, and vomiting. Notably, 67% of patients had adverse events of Grade 3 or 4; the most frequent of these were peripheral edema, nausea, vomiting, and increased blood creatinine level. Treatment-related adverse events led to the discontinuation of treatment in 39 patients (11%), with treatment-related peripheral edema leading to discontinuation in 6 patients (2%) [n = 9), alanine aminotransferase (n = 7), and peripheral edema (n = 6) being the most common serious adverse side effect. There was one death in the study due to tumor lysis syndrome, likely treatment-related [In the VISION study, 28% of patients had Grade 3–4 adverse events, with peripheral edema (7%) being the greatest . Other G-related  Table 5n = 9, alMET exon 14 skipping mutations despite the National Comprehensive Cancer Network (NCCN) recommending capmatinib as first-line therapy in advanced NSCLC with MET exon 14 skipping mutations [MET exon 14 skipping mutation and compares the efficacy of capmatinib with docetaxel [MET inhibitor, including 15 with MET exon 14 skipping mutation. The DCR was 80%. Notably, circulating tumor DNA analysis was carried out on these patients, and a secondary MET mutation was detected in four patients with MET D1228H and Y1230H, along with three patients having MAPK signaling alterations [MET inhibitors have not been directly compared with Type Ia MET inhibitors.Although capmatinib has been approved by both the FDA and EMA, there has not been a Phase III trial comparing capmatinib versus chemotherapy and immunotherapy in the first-line setting for utations . In pretocetaxel . Furthererations . FurtherMeanwhile, the challenge remains in finding reliable combinations to both improve the efficacy of capmatinib and broaden the indications of capmatinib use beyond MET exon 14 skipping mutations . Within population subgroups, there are ongoing studies on capmatinib in Asia, which may give insight into its efficacy within specific Asian subgroup populations, including one in China  and one in India (NCT05110196). For early-stage NSCLC, the GEOMETRY-N (NCT04926831) study is a Phase II, two-cohort, two-stage study evaluating the efficacy and safety of neoadjuvant and adjuvant capmatinib therapy in improving the major pathological rate (MPR) and outcomes in patients with MET exon 14 skipping or high-level MET amplification NSCLC . As therEGFR mutation or ALK rearrangements. However, the trial closed due to concerns from the drug sponsor of tolerability in patients [MET pathway, as MET expression has been found to be implicated through its pathway with MET/HGF and is involved in the regulation of the inflamed tumor microenvironment, leading towards the upregulation of inhibitory molecules such as PD-L1 and the downregulation of immune stimulators such as CD137, CD252, and CD70 [Currently, there is a Phase I/Ib trial underway that investigates capmatinib and trametinib, a MEK inhibitor (NCT05435846), which may be of benefit to patients with progression on crizotinib. Meanwhile, there has not been much success with capmatinib in combination with immunotherapy due to limited activity and tolerability. A retrospective study at two academic institutions showed an ORR of 17% (95% CI 6–36) in MET exon 14 skip mutations receiving PD-L1 blockade . A Phasepatients . Finallyand CD70 .MET amplification, as observed in about 15% of patients who received first-line osimertinib and in 12–22% of patients receiving second-line osimertinib [EGFR mutant, MET-amplified Stage IV or recurrent NSCLC. Meanwhile, NCT03040973 is a rollover study currently accruing in patients who were part of a Novartis-sponsored clinical trial to continue receiving capmatinib as a single agent or in combination with other treatments.Another important role of capmatinib in the future is in patients with acquired mertinib . As mentmertinib ,77. The As with all TKIs, it will be important to note the recurring resistance mechanisms with capmatinib to aid with future directions. Previous studies have shown that in Type I MET TKIs, secondary mutations at residue Y1230 may cause resistance, as Type I MET TKIs do interact with Y1230, specifically Y1230C ,78,79. HMET signaling pathway may provide the answer for treatment in the post-capmatinib treatment setting [EGFR and MET is a promising combination that can be considered in conjunction with capmatinib. In the CHYRSALIS study specifically involving patients with MET exon 14 skipping mutation whose disease had progressed or had declined standard-of-care therapy, the ORR was 21% (4/19) in patients with prior MET inhibitor therapy and 46% (5/11) in patients with no prior MET inhibitor therapy. The median DOR was not reached, and 67% (8/13) had DOR ≥ 6 months [EGFR exon 19 deletion or L858R NSCLC who had progressed on an EGFR TKI, ORR with amivantamab and lazertinib, an EGFR inhibitor, was 36% (95% CI 23–51), and 39% had a DOR ≥ 6 months [MET exon 14 skipping mutation or MET amplification and may provide a promising new combination. Another promising class of novel drugs includes antibody–drug conjugates (ADCs) in which the monoclonal antibody binds to a specific protein and can deliver a cytotoxic drug to its intended target [EGFR wild-type [While switching to Type II MET TKIs has been believed to help overcome resistance to capmatinib, novel drugs that can bypass the  setting . Amivant6 months . Meanwhi6 months . An ongod target . telisotild-type . ABBV-40Finally, it is worth noting the tolerability of capmatinib, as 67% of patients in the GEOMETRY mono-1 trial had a Grade 3 or 4 toxicity, and 42% of patients had serious adverse events .Thus, future directions in capmatinib and other combinations and novel agents in MET-dysregulated NSCLC will focus on the efficacy of these drugs, tolerability, and given the multiple new drugs, the sequence of these agents. MET in NSCLC has proven challenging when it comes to finding therapeutic options given the lack of activity and reliability of biomarkers. Capmatinib, a Type Ib MET TKI that is not dependent on G1163, as crizotinib is, has proven to have efficacy, as shown in the GEOMETRY mono-1 study. Subsequent post hoc analyses have shown similar efficacy regardless of the prior treatment used and patient-reported improvement in quality of life. In addition, real-world analysis has shown similar efficacy with a promising intracranial response. The Foundation One CDx assay has been shown to be a reliable companion assay and remains the only FDA-approved assay for MET-targeted therapies. However, there have been no completed Phase III studies comparing capmatinib to first-line chemotherapy and immunotherapy or second-line chemotherapy. Furthermore, there was a notable percentage of Grade 3–4 toxicities. Future studies include investigations of capmatinib with MEK inhibition, combination therapy with amivantamab, and new classes of drugs, particularly ADCs. Capmatinib’s role in a perioperative setting in early-stage NSCLC may provide further treatment options for early stage patients with MET exon 14 skipping NSCLC, but the sequencing of these drugs and tolerability will be key factors, along with finding a more reliable biomarker.The dysregulation of


After 28 days an average compressive strength of 42.7 MPa, a corresponding flexural load of over 2000 N, and a modulus of rupture of 6.2 MPa were obtained. The conclusion is then drawn that altering the sequence of mixing ingredients becomes a mandatory process with scoria aggregates to obtain high-quality lightweight concrete for structural applications. This process leads to a significant improvement in the precise control of the fresh and hardened properties, which was unachievable with the normal practice used with lightweight concrete.The utilization of manufactured lightweight aggregates adds another dimension to the cost of the preparation of self-compacting concrete (SCC). The common practice of adding absorption water to the lightweight aggregates before concreting leads to inaccurate calculations of the water-to-cement ratio. Moreover, the absorption of water weakens this interfacial bond between aggregates and the cementitious matrix. A particular type of black volcanic rock with a vesicular texture known as scoria rocks (SR) is utilized. With an adapted sequence of additions, the occurrence of water absorption can be minimized to overcome the issue of calculating the true water content. In this study, the approach of preparing the cementitious paste first with adjusted rheology followed by the addition of fine and coarse SR aggregates enabled us to circumvent the need for adding absorption water to the aggregates. This step has improved the overall strength due to the enhanced bond between the aggregate and the cementitious matrix, rendering a lightweight SCC mix with a target compressive strength of 40 MPa at 28 days, which makes it appropriate for structural applications. Different mixes were prepared and optimized for the best cementitious system that achieved the goal of this study. The optimized quaternary cementitious system included silica fume, class F fly ash, and limestone dust as essential ingredients for low-carbon footprint concrete. The rheological properties and parameters of the optimized mix were tested, evaluated, and compared to a control mix prepared using normal-weight aggregates. The results showed that the optimized quaternary mix satisfied both fresh and hardened properties. Slump flow, T50, J-ring flow, and average V-funnel flow time were in the ranges of 790–800 mm, 3.78–5.67 s, 750–780 mm, and 9.17 s, respectively. Moreover, the equilibrium density was in the range of 1770–1800 kg/m Manuf00 kg/m3 . The mec00 kg/m3 ,9. The oo 60 MPa ,11. Simio 60 MPa . There ao 60 MPa . The redo 60 MPa . In addio 60 MPa ,18,19,20o 60 MPa ,22,23,240 MPa [2 . Scoria 0 MPa [2 . Scoria Different types of cementitious materials were used as the main binder for the preparation of SCC mixes. The cementitious materials and fine powders were ordinary Portland cement (PC), silica fume (SF), class F fly ash, and limestone dust obtained from local aggregate crushers . Limestone dust (LSD) powder was procured from stone crushers in the Rumah area, northeast of Riyadh. PC meets the ASTM C 150 specification , whereasIn this study, different SRs of nominal sizes 4 and 10 mm were used to obtain low-density concrete. Moreover, the use of dune sand (DS) as fine aggregates was investigated in this study in the optimization tests to evaluate its effect on the density of concrete. The sieve analysis and physical properties of SR and DS aggregates are given in Mercury intrusion porosimetry (MIP) analysis of SR grains is shown in For trial concrete mixes, a blend of SR4 and natural dune sand (DS) complying with ASTM C33 ,31 was aThe testing program is divided into various parts that discuss different parameters and issues that hinder the delivery of the final mix. The effect of the water content, if the scoria aggregates have different moisture contents, on the concrete properties is covered in this study. The parameters affecting the unit weight and the quality of the desired flowability, including the influence of superplasticizer, are the main goals of the study to reach the final mix with an accurate water-to-binder ratio, SCC flowability, and target hardened properties. The final mix obtained is under investigation for structural applications in reinforced concrete beams.The effect of the water content of SR aggregates is very critical in defining the water-to-binder ratio accurately. In this study, different water contents of 0, 25, 65, and 100% of SR aggregates were investigated for the flowability of concrete mix using a modified mini-slump test. The optimum content was defined according to this test.The unit weight was the primary criterion for considering the concrete mix for further investigation in this section of the study. The use of dune sand along with SR4 and SR10 was assessed first, followed by 100% utilization of various blends of SR4 and SR10.The optimal combination of SR4 and SR10 was investigated in various combinations with different SR10 weight ratios to total aggregates (SR10/(SR4+SR10)). These ratios varied from 0.125 to 0.2.The optimization of superplasticizer dosage is critical as it affects the rheological properties as well as the stability of the concrete mix. The effect of different dosages on flowability and surface stability was investigated to determine the optimum superplasticizer dosage.After optimizing the parameters defining the mix composition of the final mix, the rheological properties of the cementitious paste composing the concrete mix and final concrete mix were investigated. The temperature profiles of the cementitious and concrete phases were determined in this part of the study.−1 and speed accuracy of 0.001 RPM. The temperature profile of the same paste mix was determined.Different paste mixes composing the concrete mix shown in The low-carbon optimum mix composition of the quaternary cementitious matrix contained 55% cement, 18.5% FA, 7% SF, and 19.6% LSD, while the aggregate volume of the total volume was about 45%. The fine SR aggregate made up about 87.2% of the total aggregate weight. The optimum dosage of superplasticizer is defined in this part of the study. Different concrete mixes with the mix composition shown in -Homogenize the cementitious binder  for 5 min of dry mixing;-Add water with chemical admixture and mix for 6 min;-Add fine aggregates and mix for another 4 min until flowable, followed by a 1-min pause to add coarse aggregate and mix for another 6 min or more, will guarantee the desired apparent flowability characteristic of the SCC mix.Based on the physical properties of aggregates and the adopted concept of mixing, the specific sequence of adding materials becomes as follows:The fresh mix was then tested for unit weight, rheological properties, and the temperature profile, and then the mix was cast into a 2-inch cube and two sizes of molds (40 × 40 × 160 mm and 150 × 150 × 600 mm) for compressive and flexural properties using the test setups. The whole process is visualized in Typical test setups for fresh properties are shown in A sub-version of the Rheomixer, the ConTec Rheometer-4SCC with Rotary Vane, was used in this study to investigate the LWSCC final mix with the measuring sequence shown in The test setups for the compressive and flexural properties are shown in The effect of the degree of absorptivity of lightweight aggregates to mixing water, as indicated by an increase in strength with increasing lightweight aggregate content , was inv3, as demonstrated in Different trial mixes containing different contents of DS varied from 3.7 to 25% of the total volume of aggregates, compared to the mixes with 100% SR, and were prepared and tested for unit weight as the main criterion to test the fresh and hardened mix properties. All mixes with DS have surpassed a unit weight of 1900 kg/mIn this part of the study, the effect of different coarse aggregate-to-total aggregate ratios (R = SR10/(SR4 + SR10)) of 0.125, 0.14, 0.16, and 0.2 under constant superplasticizer dosage on flowability was evaluated, as shown in Different dosages of superplasticizer  were used to assess their effect on the regular flowability and segregation of LWSCC mixes. This test was conducted on a mini-scale first and verified on a normal scale, as shown in Based on the optimized parameters from previous sections of this study, the following final mix composition could be obtained, as shown in The rheology of the paste phase with and without the fine powder from SR4 and SR10 below 75 µm was determined as shown in The temperature profiles of the two paste mixes without and with fine powder from SR aggregates are shown in 3. Owing to the reported values of the equilibrium density, which fall within the ACI 318 range of 1441.7 to 2162.5 kg/m3, the current concrete mix has been classified. Various density values as per the measuring conditions of the test mixes could be calculated. The range of fresh densities varied between 1790 and 1842 kg/m3. The saturated density varied between 1905 and 1928 kg/m3. Meanwhile, the air-dry density at a relative humidity of 20% and the saturated density at a relative humidity of 50% were in the ranges of 1757–1792, and 1770–1800 kg/m3, respectively. The oven-dry density obtained the lowest values in the range of 1707–1750 kg/m3, as lightweight concrete [3. The saturated density varied between 1905 and 1928 kg/m3. Meanwhile, the air-dry density at a relative humidity of 20% and the saturated density at a relative humidity of 50% were in the ranges of 1757–1792, and 1770–1800 kg/m3, respectively. The oven-dry density obtained the lowest values in the range of 1707–1750 kg/m3. It is reported that the accepted variation in the fresh density to the target value would be in the typical range of ±65 kg/m3 [The typical fresh properties of the final mix with the composition shown in concrete . Various65 kg/m3 ,41.The rheological properties of the mix, represented by the shear rate versus shear stress, are shown in Oven-dry unit weight3, while that at 600 h has reached 1694 kg/m3. If the water is entrapped inside the vesicles, the time needed should be much less than this reported long period of time. The unit weight value at 24 h is higher than that reported due to the prolonged curing time in water, which provided enough hydration time to make it difficult for the free water to escape during the early hours of oven treatment. However, the early reduction was attributed to the large pores. Once the finer pores are emptied, the stability of the unit weight shows a substantial reduction until 600 h, followed by stability for a longer time.It is shown that scoria rock grains are formed of vesicles bridged together in such a way that light reflection inside these vesicles can be easily monitored, as presented in bCompressive and flexural properties.The development of the compressive and flexural strengths of the optimized mix specimens with an R ratio of about 0.12 is shown in The effect of the degree of absorptivity of lightweight aggregates on mixing water becomes critical in the case of using 100% scoria aggregates. For this reason, a special mixing sequence of adding lightweight aggregates to already-prepared cement paste to increase viscosity and prevent water absorption from the mix was initiated and investigated.3.The presence of DS increases the compactness of the mix due to the spherical nature of its grains and consequently increases the unit weight to pass over 1900 kg/mThe effect of different coarse aggregate-to-total aggregate ratios (R = SR10/(SR4 + SR10)) was shown to be critical, with an optimum ratio of 0.125 that delivered a successful LWSCC mix.The final LWSCC mix could be categorized as low-cement concrete with acceptable fresh, rheological, and hardened properties both in the paste and concrete phases.The modulus of rupture of 6.2 MPa encourages proceeding with investigating and testing the developed LWSCC for structural applications.Finally, structural LWSCC can be obtained using 100% scoria aggregates.From the results of this study, the following can be concluded:The insertion of different types and contents of manufactured and recycled fibers is recommended for further investigation in these types of LWSCC mixes for advanced structural application.


Research has shown that neoadjuvant immunotherapy may provide more significant clinical benefits to cancer patients undergoing surgery than adjuvant therapy. This study examines the development of neoadjuvant immunotherapy research using bibliometric analysis. As of 12 February 2023, articles on neoadjuvant immunotherapy in the Web of Science Core Collection were collected. Co-authorship and keyword co-occurrence analyses and visualizations were performed using VOSviewer, while CiteSpace was used to identify bursting keywords and references. The study analyzed a total of 1222 neoadjuvant immunotherapy publications. The top contributors to this field were the United States, China, and Italy, and the journal with the most publications was Frontiers in Oncology. Francesco Montorsi had the highest H-index. The most common keywords were ‘immunotherapy’ and ‘neoadjuvant therapy’. The study conducted a bibliometric analysis of over 20 years of neoadjuvant immunotherapy research, identifying the countries, institutions, authors, journals, and publications involved in this field. The findings provide a comprehensive overview of neoadjuvant immunotherapy research. HighlightsThis study presents the first bibliometric analysis in the field of neoadjuvant immunotherapy.Burst detection revealed that applying neoadjuvant immunotherapy for urothelial carcinoma and radical cystectomy had become a hot topic.The United States is the leading country in articles, researchers, and institutions researching neoadjuvant immunotherapy, with China following closely behind.1 and breast cancer2. It involves administering immunotherapeutic agents before surgical resection to enhance the host immune response and reduce the primary tumor size3. The use of neoadjuvant immunotherapy in cancer treatment has gained significant attention in recent years, and there is a growing body of literature on the subject. An in-depth bibliometric study of publications, countries, institutions, journals, authors, and keywords is still required.Neoadjuvant immunotherapy has emerged as a promising approach for treating various types of cancer, including melanoma4. Bibliometrics has several advantages, including the ability to identify and quantify the impact of research, provide evidence-based assessments of scientific productivity, and track the dissemination and influence of study over time. Bibliometrics can also support the identification of research trends, emerging fields, and collaborations and inform strategic planning and resource allocation in research organizations5. With the growing volume of scientific literature and the increasing importance of research impact, bibliometrics will continue to play a significant role in evaluating and assessing research.Bibliometrics is a field of study that uses quantitative and statistical methods to analyze the production and dissemination of research literature. It involves collecting, organizing, and analyzing bibliographic data, such as the number of citations, co-authorship patterns, and publication venuesThis bibliometric study aims to provide a comprehensive overview of the current knowledge and understanding of neoadjuvant immunotherapy. This study addresses the following research question: What is the current knowledge and experience of neoadjuvant immunotherapy in cancer treatment? A thorough bibliometric analysis was conducted to assess the trends, findings, and gaps in the existing research on neoadjuvant immunotherapy. This research revealed that neoadjuvant immunotherapy had shown promising results in preclinical and clinical trials, with some studies demonstrating improved outcomes compared to standard adjuvant therapies. However, the literature also highlights the need for further research to fully understand the mechanisms underlying neoadjuvant immunotherapy’s efficacy and optimize treatment protocols. This study will fill the gap in the existing literature by synthesizing the present findings and trends in the field, providing a comprehensive overview of the current state of knowledge and understanding about neoadjuvant immunotherapy for researchers, clinicians, and policymakers.6. The relevant articles in the Web of Science Core Collection (WoSCC) were searched and exported on 12 February 2023, using all database versions. All authors agreed on the search strategy following consultations with senior literature search experts, with the following criteria: (TS = (Neoadjuvant) AND (TS = (Immunotherapy) OR (TS = (Immunotherapies)). To facilitate further analysis of literature content, only regular articles written in English were included. A complete record and cited references were then extracted from relevant publications, saved in plain text format, for further research. To further compare the development patterns and frontier topics of neoadjuvant immunotherapy in different cancer types, we conducted an additional investigation on 25 April 2023, examining the publication status of neoadjuvant immunotherapy articles for the top 5 cancer types by frequency. The keyword frequency, search strategy, and the number of articles are displayed in Table S2, Supplemental Digital Content 1, http://links.lww.com/JS9/A537. The remaining limitations are consistent with the primary search strategy mentioned above.Web of Science was selected as the primary database for this study due to its comprehensive coverage of over 12 000 academic journals and its frequent usage by researchers. When compared to other databases such as Scopus, Medline, and PubMed, Web of Science provides the most comprehensive and reliable bibliometric analysis7, VOSviewer8, and CiteSpace9 as the software tools for performing bibliometric analysis. We calculated the frequency of collaboration between countries using the Bibliometrix R package version 4.0.010. The number of publications, citations, and keyword frequency were calculated using VOSviewer. With the software’s embedded clustering algorithm, co-occurrence networks of essential keywords from scientific literature were constructed and visualized11. The co-authorship and co-occurrence analysis was the primary focus of this study. This tool was used to analyze country, institution, and author collaborations.This study used R version 4.0.1To identify highly cited references and keywords that experienced significant citation increases during a specific period, CiteSpace was used.https://bibliometric.com/), we were able to visualize international collaborations between countries. The number of publications was analyzed using an exponential growth function in Excel12.Through the online bibliometrics website (2=0.966). This strong correlation suggests that neoadjuvant immunotherapy has experienced significant growth and development, particularly in the era of ICIs.As shown in Figure National publication counts were analyzed to investigate the countries/regions contributing the most in this field. In Figure http://links.lww.com/JS9/A538. According to the results, the US leads the way in neoadjuvant immunotherapy research. The most frequent collaborations are between the US and China and between the US and Italy (with a frequency of 47). The following are the most frequent collaborators are: Germany (frequency=43), France (frequency=35), and the UK (frequency=34). The collaborators from these countries are all from the US. Thirty-four countries have published five or more articles (34/56). We conducted a co-authorship analysis of all publications from the 34 countries above  to investigate the collaboration between countries. The size of the circles in the clustering network and the time-overlapping network represent the number of publications. The color of the circles indicates the collaboration strength of the research groups in the clustering network. The colors of the circles represent the average publication year for each country in a specific area of research in the time-overlapping network. As shown in Figure S2A, Supplemental Digital Content 2, http://links.lww.com/JS9/A538, the 34 countries formed five clusters. The blue cluster, which includes most countries, has seven countries. In Figure S2B, Supplemental Digital Content 2, http://links.lww.com/JS9/A538, the US was an early pioneer in neoadjuvant immunotherapy, while Chinese researchers’ studies in this field are relatively recent.As part of our investigation, we visualized the collaborations among countries/regions in Figure S1, Supplemental Digital Content 2, To explore institutions’ contributions to neoadjuvant immunotherapy, the number of publications from various institutions was analyzed. Neoadjuvant immunotherapy research was conducted at approximately 2296 institutions worldwide. As shown in Figure http://links.lww.com/JS9/A538 shows that 68 institutions published at least 10 papers. These 68 institutions formed five clusters, with the red cluster being the largest, consisting of 21 institutions, mainly from China. Several American research institutions, led by Johns Hopkins University, contributed significantly to neoadjuvant immunotherapy’s early development. In contrast, multiple Chinese research institutions became more involved in neoadjuvant immunotherapy research after 2020.To further investigate collaboration between institutions, we performed a co-authorship analysis of all publications. Supplementary Figure 3A, Supplemental Digital Content 2, 13. Seven top 10 journals were in the first quartile (Q1) of the Journal Citation Reports (JCR). There are three publishers from the US, UK, and Switzerland, but only one publisher from China.The study included 1222 articles published in 405 journals. Table A total of 10 825 authors participated in research on neoadjuvant immunotherapy. Table http://links.lww.com/JS9/A538. Circle size represents the number of publications, and color represents cluster. One hundred twenty-two authors with five or more articles were grouped into 14 clusters. Six clusters were located outside the more prominent community consisting of eight clusters. There was no collaboration between these six scattered clusters and the larger clusters, indicating that collaboration between research teams/laboratories conducting research related to neoadjuvant immunotherapy needs to be strengthened. The time-overlapping network of clustering results is shown in Supplementary Figure 4B, Supplemental Digital Content 2, http://links.lww.com/JS9/A538. We observed that researchers from China are forming a new research network on neoadjuvant immunotherapy. National and institutional collaborations are one of the future directions due to the inadequate collaboration between different research groups.Researchers’ collaborative relationships are illustrated in Supplementary Figure 4A, Supplemental Digital Content 2, http://links.lww.com/JS9/A545, we list the top 10 most cited publications, with all articles cited over 300 times. There was one article published in 2018 that has received the most citations: ‘Neoadjuvant PD-1 Blockade in Resectable Lung Cancer’14. The study reported that neoadjuvant therapy with nivolumab had few side effects, did not delay surgery, and induced complete pathological responses in 45% of resected tumors. The New England Journal of Medicine also published the second most cited publication. Schmid et al. found that in early triple-negative breast cancer (TNBC) patients, patients who received pembrolizumab plus neoadjuvant chemotherapy had a significantly higher rate of complete pathological response than who received placebo plus neoadjuvant chemotherapy15. These two studies provide strong evidence for the clinical application of neoadjuvant immunotherapy.It is possible to evaluate the most cited articles based on the frequency of citations in that field. In Supplementary Table 1, Supplemental Digital Content 9, http://links.lww.com/JS9/A538. A burst is when a publication receives a significantly higher number of citations than usual, lasting at least two years9. The blue line represents the observation period from 1990 to 2022, while the red line indicates the burst time. The article ‘Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer’, published in the New England Journal of Medicine, has the highest citation burst value (citation burst=14.08) between 1990 and 202216. Additionally, 11 articles are still experiencing citation bursts, including ‘Durvalumab after Chemoradiotherapy in Stage III NonSmall-Cell Lung Cancer’, which has the highest burst value of 11.24. This article was published in the New England Journal of Medicine in 2017 and reports on the safety and efficacy of using Durvalumab after chemotherapy in stage III nonsmall-cell lung cancer17. The results show that the progression-free survival is significantly longer with Durvalumab than with a placebo, and the safety between the two groups is similar. Necchi et al. reported that neoadjuvant pembrolizumab therapy resulted in a pT0 status in 42% of patients and was safe in patients with muscle-invasive urothelial bladder carcinoma (MIBC). This study suggests that pembrolizumab may be a reliable neoadjuvant therapy for MIBC when restricted to patients with PD-L1-positive or high tumor mutation burden tumors18. In the future, such research topics may continue to be popular and become a potential frontier area of neoadjuvant immunotherapy research.The top 25 most cited references are illustrated in Supplementary Figure 5, Supplemental Digital Content 2, 8. In order to reflect the critical themes in neoadjuvant immunotherapy research, the 54 keywords were grouped into six clusters. Closely related keywords were clustered together. Group 1, represented in red, focused on the application of neoadjuvant chemotherapy in different cancers, such as ‘breast cancer’, ‘colorectal cancer’, and ‘ovarian cancer’. Group 2, represented in green, focused on various treatment methods for bladder and urothelial carcinoma, with keywords such as ‘cisplatin’, ‘cystectomy’, ‘immunotherapy’, and ‘PD-1’. Some terms, such as ‘survival’, were also included in Group 2. Group 3, represented in blue, focused on the clinical application of neoadjuvant immunotherapy, with keywords such as ‘neoadjuvant immunotherapy’, ‘lung cancer’, ‘muscle-invasive bladder cancer’, and common ICIs. The yellow Group 4 focused on the clinical application of neoadjuvant chemoradiotherapy combined with immunotherapy, mainly involving ‘pancreatic cancer’, ‘prostate cancer’, ‘esophageal squamous cell carcinoma’, and ‘rectal cancer’. The purple Group 5 mainly included adjuvant and neoadjuvant therapy for renal cell carcinoma. The sixth light blue cluster mainly included ‘esophageal cancer’, ‘gastric cancer’, ‘chemotherapy’, ‘surgery’, and ‘radiotherapy’, which seemed to be related to traditional treatment methods. Figure N=195) and ‘immune checkpoint inhibitors’ (N=96). ‘Neoadjuvant immunotherapy’ appeared 55 times, ranking ninth. Among the top 20 keywords, cancer types that appeared included ‘non-small cell lung cancer (NSCLC)’ (N=93), ‘breast cancer’ (N=66), ‘bladder cancer’ (N=41), ‘melanoma’ (N=38) and ‘triple-negative breast cancer’ (N=38).Among 2027 keywords, 54 met the threshold of 10 occurrences, and were analyzed. If these keywords had similar meanings, they were merged. Figure http://links.lww.com/JS9/A539 presents the top 10 countries, institutions, journals, and authors regarding publication volume for each cancer type. The United States is leading in neoadjuvant immunotherapy for breast, bladder, melanoma, and TNBC. China ranks first with 91 published articles on neoadjuvant immunotherapy for NSCLC. The University of Texas System has the highest number of publications in neoadjuvant immunotherapy research for NSCLC, breast cancer, and melanoma, consistent with the overall research findings. The journals with the most publications in NSCLC, breast cancer, bladder cancer, melanoma, and TNBC are Frontiers in Oncology, Clinical Cancer Research, Urologic Oncology: Seminars and Original Investigations, Journal of Translational Medicine, and Clinical Cancer Research, respectively. In NSCLC, the most active author is Boris Sepesi, with six published articles. Lajos Pusztai has published 11 articles on neoadjuvant immunotherapy for breast cancer and six on neoadjuvant immunotherapy for TNBC, making him the most active author in both fields. Andrea Necchi is the most active author in bladder cancer neoadjuvant immunotherapy research, with 15 articles published. In melanoma research, Paolo A. Ascierto leads the field with 11 articles.To compare the progress of neoadjuvant immunotherapy development across different cancer types, we conducted a bibliometric analysis of the top five cancer types by keyword frequency. In summary, bibliometric analysis indicates that the research popularity of neoadjuvant immunotherapy varies among cancer types, with melanoma and NSCLC demonstrating the most significant growth in publications and citations. In comparison, bladder cancer, breast cancer, and TNBC have experienced relatively slower progress. This information is valuable for oncologists and researchers to identify areas of opportunity and focus their efforts on advancing neoadjuvant immunotherapy research across all cancer types. Table S3, Supplemental Digital Content 3, http://links.lww.com/JS9/A540, Supplemental Digital Content 5, http://links.lww.com/JS9/A541, Supplemental Digital Content 6, http://links.lww.com/JS9/A542, Supplemental Digital Content 7, http://links.lww.com/JS9/A543, Supplemental Digital Content 8, http://links.lww.com/JS9/A544 present the top 10 most cited articles in neoadjuvant therapy research for NSCLC, breast cancer, bladder cancer, melanoma, and TNBC.To further understand the application of neoadjuvant immunotherapy across different cancer types, we analyzed the citation frequency of the included articles. Tables S4 through S8, Supplemental Digital Content 4, In Figure 19. Therefore, research institutions have continued to increase their support for neoadjuvant immunotherapy-related research, and research funding has continued to increase, promoting the rapid development of this field.Bibliometric methods were used to analyze the growth pattern of neoadjuvant immunotherapy-related research from 1990 to 2022. There are two stages of neoadjuvant immunotherapy-related research growth based on whether the number of publications exceeds 10 per year for two consecutive years. Before 2011, there was a slow growth stage, except for 12 publications in 2007. The number of publications in other years was at most 10. Since 2016, neoadjuvant immunotherapy-related research has entered a rapid growth stage, with more than 10 publications per year. By 2022, the annual publication volume has reached 1222, indicating that neoadjuvant immunotherapy-related research has entered a phase of rapid development. The potential reason may be that with the popularity of ICIs in cancer treatment, people began to realize that moving ICIs treatment forward may favor patientsA total of 1026 articles were published by the top 10 countries, accounting for 83.96% of all articles. The US and China dominate the number of publications among the 10 countries. Furthermore, US-centered international cooperation occupies eight positions in the 10 countries with the highest frequency of cooperation. The above findings confirm the US’s critical contributions and leading position in neoadjuvant immunotherapy research, which may result from the United States’ national economic conditions and high medical investment levels. This field will benefit from extensive international cooperation, which will improve the overall standard of research.Fourteen of the top 20 institutions are in the US, similar to the distribution of publication numbers by country. Despite China’s second-place ranking in publication numbers, only four institutions make the top 20. Italy ranked third in the number of publications and has only one institution in the top 20, ranking 17th. In contrast, a Netherlands institution ranks sixth with 29 papers. These studies are mainly based on international cooperation, indicating that seeking extensive cooperation between institutions may be crucial to improving research competitiveness under economic or resource limitations.A peer-reviewed journal is essential to academic publishing. Core journals often publish the necessary research in the field. Researchers can identify potential journals to submit their manuscripts to based on the number of journal publications in the neoadjuvant immunotherapy field. Frontiers in Oncology has the most publications, with 54. The journal with the highest impact factor is Clinical Cancer Research (IF 13.801), followed by The Journal for ImmunoTherapy of Cancer (IF 12.469). Impact factor and JCR are commonly used indicators to evaluate the influence of journals. JCR divides all journals into four quartiles (Q1–Q4) based on their IF. In the top 10 journals by paper count, Q1 journals account for 70%. Moreover, despite China’s significant contributions to neoadjuvant immunotherapy research, Asian publishers are underrepresented in the top 10 journals. There is a need to establish and develop internationally influential journals in Asia.20. Highly cited publications often represent the fundamental themes in a research field. Research hotspots can be identified by calculating citation counts and identifying highly cited publications. In this study, the 10 most frequently cited publications were published between 2013 and 2020 and mainly focused on neoadjuvant immunotherapy’s mechanism and clinical application.This study aims to answer a question regarding the research hotspots that were widely studied by researchers over a certain period of time. Citation count can serve as one of the indicators of the academic influence of a publicationet al. suggested that low-dose irradiation of human pancreatic cancer with new adjuvant local gamma rays can normalize abnormal blood vessels and effectively recruit tumor-specific T cells in the tumor area. The authors further verified T-cell-mediated antitumor immune response and extended survival in otherwise immune refractory spontaneous and xenotransplant mouse tumor models21. Although this study does not directly confirm that neoadjuvant immunotherapy provides a survival benefit for pancreatic cancer patients, it provides an essential theoretical basis for neoadjuvant immunotherapy and boosts the investigators’ confidence.In 2013, Klug et al. analyzed tumor-infiltrating lymphocytes (TILs)’ clinical and molecular characteristics in residual lesions of TNBC after neoadjuvant chemotherapy. Their research aimed to develop a better understanding of the complex interactions between TILs and TNBC in order to improve treatment strategies. They explored a treatment strategy combining MEK inhibitors and PD-1/PD-L1 targeted immunotherapy in a mouse model. The authors pointed out that activating the Ras-MAPK pathway could promote immune escape in TNBC. Their findings suggest that a combined approach targeting MEK and PD-L1 might effectively counteract this immune escape, potentially leading to improved outcomes for TNBC patients22. In addition, Liu et al. used a mouse model of spontaneous metastatic breast cancer to demonstrate that neoadjuvant therapy was significantly more effective than adjuvant therapy23. These studies highlight the potential of neoadjuvant immunotherapy as a promising treatment strategy for TNBC patients, particularly when combined with targeted therapies such as MEK inhibitors. By building on these foundational findings, future research can continue to refine and optimize treatment approaches for TNBC, ultimately improving patient outcomes and quality of life.In 2016, Loi et al. published an article titled ‘Neoadjuvant PD-1 Blockade in Resectable Lung Cancer’ in the New England Journal of Medicine, which had the highest number of citations in this research. In this study, the authors administered PD-1 inhibitor nivolumab to adults with previously untreated, operable early  NSCLC. The results showed that the side effects of neoadjuvant therapy with nivolumab were acceptable and unrelated to the delay of surgery. Nine of the 20 resected tumors showed a complete pathological response (45%)14. As higher complete response rates are associated with a better prognosis, this study’s results further increase the researchers’ confidence to conduct clinical studies on neoadjuvant immunotherapy. Subsequently, researchers have achieved breakthroughs in patients with glioma24, TNBC15, and colon cancer25, confirming the safety and effectiveness of neoadjuvant immunotherapy from multiple perspectives and cancer types. However, a clinical study conducted by Blank et al. suggests that although neoadjuvant immunotherapy seems promising, the current regimen  induced high toxicity in resectable stage III melanoma patients, with 9/10 patients experiencing one or more grade 3/4 adverse events. Therefore, further research is needed to maintain efficacy while reducing toxicity26. Overall, while the results from numerous studies demonstrate the potential of neoadjuvant immunotherapy in treating different cancers, continued research is necessary to refine treatment regimens and ensure the best possible outcomes for patients.In 2018, Forde et al. found that B-cell biomarkers were differentially expressed in tumors of immune responders and nonresponders, indicating that B cells and their products may play a critical role in the antitumor immune response27. By integrating B-cell biomarkers and further exploring the roles and interactions of various immune cells within the tumor microenvironment, researchers may enhance the overall efficacy of cancer immunotherapy and contribute to developing more effective, personalized treatment strategies.In 2020, Helmink reported a critical study emphasizing the importance of focusing on immune cells and structures beyond T cells to develop new biomarkers and immune-enhancing strategies. Helmink 30. However, research on biomarkers related to neoadjuvant immunotherapy is rare. Since some patients may experience disease progression after neoadjuvant immunotherapy or lose the opportunity for surgery due to immune-related adverse events, screening for patient groups with potential benefits for neoadjuvant immunotherapy is critical32. Exploring biomarkers related to the efficacy of neoadjuvant immunotherapy through various methods can be an effective tool for maximizing individual treatment outcomes. In conclusion, co-occurrence analysis of high-frequency keywords in research studies can highlight focus areas, such as neoadjuvant immunotherapy and biomarkers. Expanding our understanding of biomarkers related to the efficacy of neoadjuvant immunotherapy is essential for optimizing treatment outcomes. Further research in this area can significantly enhance the effectiveness of personalized cancer treatments.Since keywords reflect the core content of a study, co-occurrence analysis can identify high-frequency keywords that appear in different studies, thus helping researchers to quickly grasp research hotspots. In this study, the most frequent keywords were ‘immunotherapy’ and ‘neoadjuvant therapy’. The frequency of ‘neoadjuvant immunotherapy’ was 55 times. Furthermore, ‘biomarkers’ were another frequently appearing keyword. Studies have shown that biomarkers can predict the efficacy of ICIs, disease progression, and recurrencesTo further investigate the differences in neoadjuvant immunotherapy among various cancer types to guide clinical practice better. We analyzed the five cancer types with the highest frequency of keywords. The development of neoadjuvant immunotherapy for NSCLC, breast cancer, bladder cancer, melanoma, and TNBC was compared. The different levels of development of neoadjuvant immunotherapy research in these cancer types are discussed, as well as the reasons for these differences.33. Combined therapies, such as nivolumab and ipilimumab, have also been explored in resectable NSCLC, with positive outcomes34. Furthermore, compartmental analysis of T-cell clonal dynamics has helped identify pathologic responses to neoadjuvant PD-1 blockade, providing insights into treatment efficacy and resistance35. Despite these advancements, further research is needed to optimize treatment strategies and improve patient outcomes.Neoadjuvant immunotherapy in NSCLC has shown promising results. For instance, PD-1 blockade has successfully improved patient outcomes, with studies such as the SAKK 16/14 trial investigating the addition of durvalumab to neoadjuvant chemotherapy in stage IIIA (N2) NSCLC patients23. Combining ICIs, such as pembrolizumab and durvalumab, with standard anthracycline-taxane-based chemotherapy has shown clinical promise36. Research also reveals correlations between immune biomarkers, such as PD-L1 expression, TILs, and response to neoadjuvant therapy37. These findings highlight the therapeutic potential of neoadjuvant immunotherapy and emphasize the need for further research to optimize treatment strategies.Neoadjuvant immunotherapy for breast cancer has emerged as a promising approach, particularly in aggressive subtypes like TNBC. Studies have shown that neoadjuvant immunotherapy can improve outcomes compared to adjuvant therapy, which helps eradicate metastatic disease38. At the same time, the NABUCCO trial investigated the preoperative combination of ipilimumab and nivolumab in locoregionally advanced urothelial cancer39. Although the FDA has approved atezolizumab for treating progressive advanced urothelial carcinoma, more research is needed to explore the full potential of neoadjuvant immunotherapy in this cancer type.Developing neoadjuvant immunotherapy in bladder cancer has centered around using ICIs, such as pembrolizumab and atezolizumab. The PURE-01 study demonstrated the preliminary activity of neoadjuvant pembrolizumab in patients with muscle-invasive bladder carcinoma1. Additionally, immune circulation and tumor microenvironment monitoring has been investigated in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab40. While these studies provide valuable insights into treatment efficacy and patient stratification, further research is necessary to refine neoadjuvant immunotherapy approaches in melanoma.Neoadjuvant immunotherapy has shown significant promise in melanoma, particularly in combination therapies such as ipilimumab and nivolumab. The OpACIN-neo and OpACIN trials analyzed survival and biomarker data from neoadjuvant immunotherapy in stage III melanoma patients36. Another area of interest has been the relationship between RAS/MAPK activation and TILs and the therapeutic cooperation between MEK inhibitors and PD-1/PD-L1 ICIs22. The role of PD-L1 expression and TILs in TNBC prognosis has also been investigated, highlighting the importance of understanding the tumor microenvironment in developing effective immunotherapies41.TNBC, a particularly aggressive breast cancer subtype, has seen significant research into neoadjuvant immunotherapy. Studies such as the GeparNuevo trial have investigated the use of durvalumab in addition to anthracycline-taxane-based neoadjuvant therapy, with promising results42. Furthermore, neoadjuvant interferons are critical for effective PD-1-based immunotherapy in TNBC43. Lastly, the therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor, and anti-PD-L1 antibodies has been examined for TNBC treatment44.Innovative approaches, such as transformable nanoparticle-enabled immunotherapy and anti-folate receptor alpha-directed antibody therapies, have been explored to enhance TNBC treatmentThe development of neoadjuvant immunotherapy varies across cancer types, with melanoma and NSCLC demonstrating more advanced progress than bladder, breast, and TNBC. These disparities may include differences in tumor biology, the immune microenvironment, and the prevalence of specific cancer subtypes that respond well to immunotherapies.45. NSCLC also exhibits significant progress in neoadjuvant immunotherapy development, partly because of its high incidence and the presence of actionable molecular targets, such as PD-L146.Melanoma, in particular, has shown a high response rate to immunotherapies due to its high mutational burden and immunogenicityIn contrast, bladder cancer, breast cancer, and TNBC have experienced a slower pace of development in neoadjuvant immunotherapy. The complex tumor biology and heterogeneity of breast cancer, including varying responses to treatment across subtypes, may partly explain this disparity. TNBC, a highly aggressive subtype of breast cancer, has shown promise in neoadjuvant immunotherapy research, but challenges remain in understanding and overcoming immune evasion mechanisms. Lastly, bladder cancer has a lower incidence than NSCLC and breast cancer, which may contribute to the slower progress in neoadjuvant immunotherapy research.Neoadjuvant immunotherapy has demonstrated the potential to improve patient outcomes across various cancer types, including NSCLC, breast cancer, bladder cancer, melanoma, and TNBC. While melanoma and NSCLC have made significant progress, bladder cancer, breast cancer, and TNBC still require further investigation to optimize treatment strategies. Understanding the underlying reasons for disparities in neoadjuvant immunotherapy development can help guide future research, with the ultimate goal of providing personalized and effective treatment options for patients.9. Researchers can use keywords and cited references with burst features to explore hotspots of research. In this study, ‘urothelial carcinoma’, ‘ipilimumab’, and ‘radical cystectomy’ were keywords that continued to burst as of 2022. This suggests that neoadjuvant immunotherapy for urological system cancer may be a potential research hotspot in the future49. In addition, seven cited references continued to burst in 2022. Of these, three studies focused on the application of ICIs in neoadjuvant immunotherapy23, and two discussed the application of ICIs in adjuvant therapy51. One study by Necchi et al. is worth noting. This study showed that pembrolizumab could be a reliable neoadjuvant therapy for MIBC, limited to patients with PD-L1 positivity or high tumor mutation burden. This is consistent with the results of the burst detection of keywords18. In addition, Ayers et al. reported an IFN-γ-related mRNA profile that can predict the efficacy of ICIs52. Reck et al.53 pointed out that in advanced NSCLC patients, pembrolizumab significantly prolonged progression-free survival and overall survival with fewer adverse events compared to platinum-based chemotherapy when PD-L1 was expressed in at least 50% of tumor cells. In light of the burst detection results mentioned above, clinical trials of neoadjuvant immunotherapy and predictive biomarkers for therapeutic efficacy in different types of cancer may be research directions worth paying attention to soon.CiteSpace’s ‘burst detection’ method identifies keywords or cited references with significant changes over timeThere are some limitations to this study. First, it only includes articles written in English and recorded in the WoSCC database. Since WoSCC covers the vast majority of high-quality studies, this does not affect the overall trend of the results. Second, recently published high-quality studies may not have received the attention they deserved due to citation delays and need to be updated in subsequent studies. Nevertheless, this study will significantly assist relevant researchers in understanding the development, hotspots, trends, and frontiers of neoadjuvant immunotherapy and identifying areas that still require further research.In recent years, there has been increasing attention paid to research related to neoadjuvant immunotherapy. The substantial increase in publications each year indicates the growing importance of this research field. This study identifies the top researchers and institutions worldwide involved in neoadjuvant immunotherapy research. Frontiers in Oncology is the most active journal, and Francesco Montorsi is the most influential author. Immunotherapy as a neoadjuvant treatment for urological cancer and the development of efficacy predictive biomarkers are hot topics. The long-term prognosis of patients receiving neoadjuvant immunotherapy may be a critical area for future research. Therefore, a comprehensive overview of the evolution and frontiers of the field is available to researchers and policymakers who are new to the area.No ethical approval and patient consent were required for all analyses were based on literature research.This research was partly supported by the National High Level Hospital Clinical Research Funding (2022-PUMCH-C-049).X.L., Y.X., and X.S.: conceived and designed the study; S.J.: wrote the manuscript and participated in the design of the study; S.J., H.Z., and Y.L.: were responsible for analysis and network construction; L.Z.: and performed the data analysis and data interpretation. All authors contributed to the article and reviewed the submitted version.The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.Not required.xuyiyao@pumch.cn.Yiyao Xu, Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Dongcheng, Beijing 100730, China. E-mail: luxin@pumch.cn.Xin Lu, Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, PUMC & Chinese Academy of Medical Sciences, Dongcheng, Beijing 100730, China. E-mail: The data in this study is not sensitive in nature and is accessible in the public domain. The data is therefore available and not of a confidential nature. All the data used in the study have been included in the article/Supplementary Material.