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Aim: Atezolizumab plus bevacizumab combination therapy (Atezo + Beva) is used as the first‐line therapy for unresectable hepatocellular carcinoma (u‐HCC). Serious adverse events (AEs), including rupture of esophagogastric varices, have been seen during treatment. Therefore, the relationships of efficacy, safety, and portal hypertension (PH) were analyzed. Methods: A total of 146 patients with u‐HCC and Child‐Pugh Scores of 5–7 received Atezo + Beva. Prophylactic treatment for varices was performed for patients with the risk of rupture of varices before the start of Atezo + Beva. A propensity score‐matched cohort was created to minimize the risk of potential confounders. Efficacy was assessed in 41 propensity score‐matched pairs. AEs were assessed between patients without PH (n = 80) and with PH (n = 66). Results: In patients without PH and with PH, median overall survival was 18.4 months and 18.8 months (p = 0.71), and median progression‐free survival was 8.6 months and 5.8 months (p = 0.92), respectively. On the best radiological response evaluation for Response Evaluation Criteria in Solid Tumors, the objective response rate was 31.7% and 26.8% (p = 0.81), respectively. Variceal rupture occurred in three patients with PH, but there were no significant differences in the occurrence of variceal rupture (p = 0.090) and Grade 3–4 AEs between patients without and with PH. Conclusions: No significant differences in efficacy and safety were observed with PH. Prophylactic treatment for varices before the start of Atezo + Beva would allow treatment to continue relatively safely. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitor therapy has been rapidly developed for the treatment of unresectable hepatocellular carcinoma (HCC). In the IMbrave150 trial, atezolizumab plus bevacizumab was seen as the first-line systemic drug therapy for unresectable HCC because overall survival and progression-free survival were significantly prolonged compared with sorafenib. However, an effective regimen after atezolizumab plus bevacizumab failure has not yet been established. Lenvatinib, on the other hand, also demonstrated good outcomes in unresectable HCC in the REFLECT trial as first-line therapy and is currently positioned as one of the second-line therapies after atezolizumab plus bevacizumab. The aim of this retrospective study was to evaluate the efficacy and safety of lenvatinib after atezolizumab plus bevacizumab for unresectable HCC. A total of 137 HCC patients treated with atezolizumab plus bevacizumab from October 2020 to September 2022 were enrolled. The median overall survival (OS) and progression-free survival (PFS) from the beginning of atezolizumab plus bevacizumab were 21.1 months (range, 18.8 months–not reached) and 10.5 months (range, 8.2–12.1 months), respectively. Fifty patients were diagnosed with progressive disease after atezolizumab plus bevacizumab. Of this group, 24 patients were administered lenvatinib, and the median OS and PFS from the beginning of lenvatinib were 15.3 months (range, 10.5 months–not reached) and 4.0 months (range, 2.5–6.4 months), respectively. The objective response rates based on the response evaluation criteria in solid tumors (RECISTs) criteria version 1.1 and modified RECISTs were 33.3% and 54.2%, respectively. There was no significant difference in the median serum alpha-fetoprotein level between before and after lenvatinib. In the multivariate analysis, Child–Pugh class A (hazard ratio 0.02, 95% confidence interval (CI) 0.02–0.76, p = 0.02) and intrahepatic tumor occupancy rate < 50% (hazard ratio < 0.01, 95% CI 0.003–0.35, p < 0.01) were the significant factors for OS. There were some frequent adverse events (AEs) in patients treated with lenvatinib such as hypertension, fatigue, anorexia, proteinuria, and so on, but none directly caused death. In conclusion, lenvatinib after atezolizumab plus bevacizumab for unresectable HCC should be considered an effective treatment option. [ABSTRACT FROM AUTHOR]

Introduction: Measurements of body composition, such as the skeletal muscle index (SMI), are useful for predicting prognosis in hepatocellular carcinoma (HCC). This study aimed to analyze the relationship between skeletal muscle changes during therapy with atezolizumab plus bevacizumab (Atezo + Beva) or lenvatinib (Len) and the association between SMI and prognosis. Methods: Patients with advanced HCC and Child-Pugh A status received Atezo + Beva or Len as first-line systemic chemotherapy. We assessed prognosis and body composition obtained by bioelectrical impedance analysis. Results: A total of 109 patients received treatment (Atezo + Beva, n = 47; Len, n = 62). During treatment, the arm SMI was reduced in the Len group and maintained in the Atezo + Beva group. The extracellular water to total body water ratio (ECW/TBW) increased significantly in both groups during treatment. In the Atezo + Beva group, no factor was associated with prognosis. Multivariate analysis showed that in the Len group, the arm SMI (hazard ratio [HR], 0.5; 95% CI: 0.26–0.89; p = 0.02), ECW/TBW (HR: 2.7; 95% CI: 1.21–6.01; p = 0.01), and Child-Pugh score (HR: 2.3; 95% CI: 1.31–6.13; p = 0.004) were associated with progression-free survival. Conclusion: Assessing body composition with BIA before Atezo + Beva and Len treatment may be useful. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is reportedly the fifth most common malignancy in the world. Atezolizumab plus bevacizumab combination therapy (Atezo + Beva) was approved in 2020 as the first immune-combined therapy and the standard of care for first-line systemic treatment of unresectable HCC. Alpha-fetoprotein (AFP) is the most widely used serum biomarker in HCC. Although some studies have shown the benefit and safety of Atezo + Beva, there are no reports on when to switch from Atezo + Beva to the next treatment, and this is not yet clear. This study investigated the relationship between radiological response and prognosis in patients assessed as having stable disease (SD) in whom it is necessary to decide whether to continue Atezo + Beva. The results showed that a decreased AFP level may reflect early efficacy, and AFP trends could help determine whether to continue Atezo + Beva in patients assessed as having SD. Atezolizumab plus bevacizumab combination therapy (Atezo + Beva) is currently positioned as the first-line therapy for unresectable hepatocellular carcinoma (u-HCC). It may be difficult to decide whether to continue this treatment if radiological response is assessed as stable disease (SD). Therefore, the relationship between radiological response and prognosis was analyzed. A total of 109 patients with u-HCC and Child–Pugh Score of 5–7 received this treatment. Radiological response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST at the first and second evaluations. Of SD patients (n = 71) at the first RECIST evaluation, partial response, SD, and progressive disease (PD) were seen in 10, 55, and 6 patients, respectively, at the second evaluation. On multivariate analysis, in patients with SD at the first RECIST evaluation, a 25% or greater increase in the alpha-fetoprotein (AFP) value from initiation of treatment (odds ratio, 7.38; p = 0.037) was the independent factor for PD at the second evaluation. In patients with SD (n = 59) at the second RECIST evaluation, decreased AFP from initiation of treatment (hazard ratio, 0.46; p = 0.022) was the independent factor related to progression-free survival on multivariate analysis. AFP trends could help decide the Atezo + Beva treatment strategy. [ABSTRACT FROM AUTHOR]

Simple Summary: Many treatment options are available for hepatocellular carcinoma. Radiation therapy is one of the local options, along with surgery and radiofrequency ablation. Stereotactic body radiation therapy is an effective therapy for hepatocellular carcinoma that provides good outcomes with tolerable toxicities and has been recognized as a local therapy for patients who are ineligible for surgery or radiofrequency ablation. Hepatocellular carcinoma tends to recur, so stereotactic body radiation therapy is also used for recurrent cases. However, few reports have summarized local tumor control, transition of liver function, and side effects in cases of repeated stereotactic body radiation therapy. This study retrospectively evaluated the efficacy of stereotactic body radiation therapy, including repeated radiation therapy, for hepatocellular carcinoma. The present study retrospectively evaluated the efficacy of stereotactic body radiation therapy (SBRT), including repeated SBRT, for hepatocellular carcinoma. Participants comprised 220 HCC patients treated with SBRT in Hiroshima University Hospital between December 2008 and December 2021. Median overall survival (OS) and disease-free survival were 52 months (range, 45–64 months) and 17 months (range, 14–23 months), respectively. The 5-year local tumor recurrence rate was 3.4% (95% confidence interval (CI), 1.3–6.9%). Fifty-three patients underwent repeated SBRT (twice, 53 cases; three times, 10 cases; four times, 4 cases; five times, 1 case). Median interval between first and second SBRT was 20 months. Median OS from first SBRT was 76 months (95% CI, 50–102 months). Among patients with repeated SBRT, only one case showed local recurrence after second SBRT. Albumin–bilirubin score increased significantly from 6 to 12 months after repeated SBRT, both in the same segment and in remote segments, but the increase was not significant in the same segment. Only one case of grade 3 bile duct stricture was observed in patients who were treated with repeated SBRT. In conclusion, repeated SBRT provides good local control and a low risk of side effects. [ABSTRACT FROM AUTHOR]

The catalytic enantioselective allenylation of ketimines derived from isatins is described. Products with high regio‐ and enantioselectivities were obtained in the presence of a bis(imidazoline)‐palladium catalyst. The obtained products were then converted into various chiral amines. The stereoselectivity origin was revealed by DFT calculations of the transition state. [ABSTRACT FROM AUTHOR]

Simple Summary: With the emergence of the concepts of transarterial chemoembolization (TACE) refractoriness and unsuitability and recent advances in systemic therapy, treatment options for intermediate-stage, unresectable hepatocellular carcinoma (u-HCC) are increasing. However, the efficacy of lenvatinib and its combination with TACE in clinical practice has not yet been adequately investigated. This study investigated the efficacy of lenvatinib and its combination with TACE after lenvatinib in patients with intermediate-stage u-HCC who were mainly judged to be TACE-refractory or -unsuitable. The results demonstrated the efficacy of lenvatinib and confirmed that further improvements in prognosis could be obtained with TACE after lenvatinib induction. In the intermediate-stage u-HCC, the results suggest it may be important to consider not only the use of lenvatinib but also its combination with TACE to improve patients' prognosis further, even if they are deemed TACE-refractory or -unsuitable. Transarterial chemoembolization (TACE) has been the standard treatment for intermediate-stage, unresectable hepatocellular carcinoma (u-HCC). However, with recent advances in systemic therapy and the emergence of the concept of TACE-refractory or -unsuitable, the effectiveness of systemic therapy, as well as TACE, has been demonstrated for patients judged to be TACE-refractory or -unsuitable. In this study, the efficacy of lenvatinib and its combination with TACE after lenvatinib was investigated in 140 patients with intermediate-stage u-HCC treated with lenvatinib mainly because of being judged to be TACE-refractory or -unsuitable. Median overall survival (OS) and progression-free survival (PFS) were 24.4 and 9.0 months, respectively, indicating a good response rate. In multivariate analysis, modified albumin–bilirubin (mALBI) grade and up to seven criteria were identified as independent factors for OS, and mALBI grade and tumor morphology were identified as independent factors for PFS. While 95% of all patients were TACE-refractory or -unsuitable, the further prognosis was prolonged by the combination with TACE after lenvatinib initiation. These findings suggest that systemic therapy should be considered for intermediate-stage u-HCC, even in patients judged to be TACE-refractory or -unsuitable. The use of TACE after the start of systemic therapy may further improve prognosis. [ABSTRACT FROM AUTHOR]

This paper presents a novel design methodology for optimum structural design of magnetic actuators using a level set based topology optimization method where the level set method can represent the precise boundary shape of a structure and also deal with complex topological changes during the optimization process. The distribution of ferromagnetic material is represented by introducing a level set function into the definition of the magnetic reluctivity. The optimization problem is defined to obtain optimal configurations that maximize the magnetic energy of actuators under a minimum bound of total volume. The movement of the implicit moving boundaries of the structure is driven by a transformation of design sensitivities of the objective and the constraints into speed functions that govern the level set propagation. The proposed method is applied to the structural design of magnetic actuators, and is confirmed to be useful for achieving optimal configurations that deliver higher performance and lighter weight designs. Index Terms--Level set method, magnetic actuator, structural boundary design, topology optimization.

Elucidation of the mechanism by which the shape of bones is formed is essential for understanding vertebrate development. Bones support the body of vertebrates by withstanding external loads, such as those imposed by gravity and muscle tension. Many studies have reported that bone formation varies in response to external loads. An increased external load induces bone synthesis, whereas a decreased external load induces bone resorption. This relationship led to the hypothesis that bone shape adapts to external load. In fact, by simulating this relationship through topology optimization, the internal trabecular structure of bones can be successfully reproduced, thereby facilitating the study of bone diseases. In contrast, there have been few attempts to simulate the external structure of bones, which determines vertebrate morphology. However, the external shape of bones may be reproduced through topology optimization because cells of the same type form both the internal and external structures of bones. Here, we constructed a three-dimensional topology optimization model to attempt the reproduction of the external shape of teleost vertebrae. In teleosts, the internal structure of the vertebral bodies is invariable, exhibiting an hourglass shape, whereas the lateral structure supporting the internal structure differs among species. Based on the anatomical observations, we applied different external loads to the hourglass-shaped part. The simulations produced a variety of three-dimensional structures, some of which exhibited several structural features similar to those of actual teleost vertebrae. In addition, by adjusting the geometric parameters, such as the width of the hourglass shape, we reproduced the variation in the teleost vertebrae shapes. These results suggest that a simulation using topology optimization can successfully reproduce the external shapes of teleost vertebrae. By applying our topology optimization model to various bones of vertebrates, we can understand how the external shape of bones adapts to external loads. Author summary: In this paper, we developed a computational method to investigate the relationship between three-dimensional bone shape and external loads imposed on bones. Many studies report that bone formation varies in response to external loads. An increased external load induces bone synthesis, whereas a decreased external load induces bone resorption. This relationship led to the hypothesis that the shape of bones adapts to external load. However, it remains unclear whether this hypothesis can explain the shape of bones. Here, we constructed a three-dimensional mathematical model that imitates the cellular activities of bone formation to attempt the reproduction of the shape of teleost vertebrae. In teleosts, the shape of the vertebrae differs among the species. We set the multiple types of external load conditions in the simulations and compared the simulation results with different teleost vertebrae. The produced structures that can resist the deformation of the surrounding tissues exhibited multiple structural features similar to the vertebrae of several teleost species. This result shows that the formation of bone shape can be explained by the adaptation to external load. [ABSTRACT FROM AUTHOR]

This paper proposes an optimization method with a high degree of freedom for the doping profile optimization of power devices. In this method, which is based on topology optimization, the design domain is divided into many elements, and the doping or dose densities of all of the elements are taken as the design variables to be optimized. An optimal structure is obtained by repeatedly modifying a given structure using mathematical programming. The proposed optimization method was applied to two design problems. First, the tradeoff between the breakdown voltage and ON-resistance was optimized for a p-n diode by using a function of the electric field strength as the objective function under a constraint to the ON-resistance. Second, for a junction termination extension structure, a robust optimization method considering the ion implantation process was applied to prevent the concentration of the electric field by dose fluctuation. The numerical results from these two problems demonstrate that the proposed method can be effectively used to derive an improved doping profile for power devices. [ABSTRACT FROM AUTHOR]

This paper presents topology optimization for the design of flow fields in vanadium redox flow batteries (VRFBs), which are large-scale storage systems for renewable energy resources such as solar and wind power. It is widely known that, in recent VRFB systems, one of the key factors in boosting charging or discharging efficiency is the design of the flow field around carbon fiber electrodes and in flow channels. In this study, topology optimization is applied in order to achieve optimized flow field designs. The optimization problem is formulated as a maximization problem for the generation rate of the vanadium species governed by a simplified electrochemical reaction model. A typical porous model is incorporated into the optimization problem for expressing the carbon fiber electrode; furthermore, a mass transfer coefficient that depends on local velocity is introduced. We investigate the dependencies of the optimized configuration with respect to the porosity of the porous electrode and the pressure loss. Results indicate that patterns of interdigitated flow fields are valid designs for VRFBs. [ABSTRACT FROM AUTHOR]

In this paper, we propose a three-dimensional (3D) grayscale-free topology optimization method using a conforming mesh to the structural boundary, which is represented by the level-set method. The conforming mesh is generated in an r-refinement manner; that is, it is generated by moving the nodes of the Eulerian mesh that maintains the level-set function. Although the r-refinement approach for the conforming mesh generation has many benefits from an implementation aspect, it has been considered as a difficult task to stably generate 3D conforming meshes in the r-refinement manner. To resolve this task, we propose a new level-set based r-refinement method. Its main novelty is a procedure for minimizing the number of the collapsed elements whose nodes are moved to the structural boundary in the conforming mesh; in addition, we propose a new procedure for improving the quality of the conforming mesh, which is inspired by Laplacian smoothing. Because of these novelties, the proposed r-refinement method can generate 3D conforming meshes at a satisfactory level, and 3D grayscale-free topology optimization is realized. The usefulness of the proposed 3D grayscale-free topology optimization method is confirmed through several numerical examples. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We examined whether AN69ST (acrylonitrile and methallyl sulfonate copolymer) membranes adsorb nafamostat mesilate. This study retrospectively analyzed 87 continuous hemodiafiltration sessions in vivo. We divided the continuous hemodiafiltration sessions into AN69ST and non-AN69ST groups using the nafamostat mesilate dose and activated clotting time as indicators of nafamostat mesilate adsorption onto the membrane. Furthermore, we studied the in vitro adsorption of nafamostat mesilate from nafamostat mesilate solutions onto four different hemodialysis membranes. This in vivo study shows that nafamostat mesilate doses were significantly higher, but activated clotting times were shorter ( P < 0.001) in the AN69ST group than in the non-AN69ST group. These results suggest that AN69ST adsorbs nafamostat mesilate. Further, the in vitro experiments show that nafamostat mesilate adsorbs AN69ST on membranes significantly more than the other membranes tested. These in vitro and clinical findings provide evidence that AN69ST may adsorb nafamostat mesilate. [ABSTRACT FROM AUTHOR]

In this paper, we report design and characteristics of a compact and low-loss multicast switch (MCS) based on a high Δ planar lightwave circuit (PLC) which consists of ZrO2 doped silica glass. Chip size of an 8 × 8 MCS consists of an eight-arrayed 1 × 8 splitter and an eight-arrayed 8 × 1 switch is reduced to 30 mm × 9 mm by using the ZrO2-SiO2 PLC with 5.5%-Δ. Eight-input and eight-output ports of the MCS are arrayed at the one side of the chip, and coupled to optical fibers with a 16-fiber V-groove array. A high Δ fiber is used to reduce coupling loss to the ZrO2-SiO2 PLC, and the high Δ fiber is spliced to a single-mode fiber (SMF) by using low-loss splicing technique. Coupling loss between the ZrO2-SiO2 PLC and the SMF is reduced to 0.4 dB/facet. Average insertion loss of the fabricated MCS is 12.8 dB including coupling loss to the SMF. Extinction ratio and polarization dependent loss of the MCS are over 50 dB and less than 0.5 dB in L-band, respectively. [ABSTRACT FROM PUBLISHER]

This paper proposes a level-set based topology optimization method incorporating a boundary tracking mesh generating method and nonlinear programming. Because the boundary tracking mesh is always conformed to the structural boundary, good approximation to the boundary is maintained during optimization; therefore, structural design problems are solved completely without grayscale material. Previously, we introduced the boundary tracking mesh generating method into level-set based topology optimization and updated the design variables by solving the level-set equation. In order to adapt our previous method to general structural optimization frameworks, the incorporation of the method with nonlinear programming is investigated in this paper. To successfully incorporate nonlinear programming, the optimization problem is regularized using a double-well potential. Furthermore, the sensitivities with respect to the design variables are strictly derived to maintain consistency in mathematical programming. We expect the investigation to open up a new class of grayscale-free topology optimization. The usefulness of the proposed method is demonstrated using several numerical examples targeting two-dimensional compliant mechanism and metallic waveguide design problems. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A general topology optimization method, which is capable of simultaneous design of density and orientation of anisotropic material, is proposed by introducing orientation design variables in addition to the density design variable. In this work, the Cartesian components of the orientation vector are utilized as the orientation design variables. The proposed method supports continuous orientation design, which is out of the scope of discrete material optimization approaches, as well as design using discrete angle sets. The advantage of this approach is that vector element representation is less likely to fail into local optima because it depends less on designs of former steps, especially compared with using the angle as a design variable (Continuous Fiber Angle Optimization) by providing a flexible path from one angle to another with relaxation of orientation design space. An additional advantage is that it is compatible with various projection or filtering methods such as sensitivity filters and density filters because it is free from unphysical bound or discontinuity such as the one at θ = 2 π and θ = 0 seen with direct angle representation. One complication of Cartesian component representation is the point-wise quadratic bound of the design variables; that is, each pair of element values has to reside in a given circular bound. To overcome this issue, we propose an isoparametric projection method, which transforms box bounds into circular bounds by a coordinate transformation with isoparametric shape functions without having the singular point that is seen at the origin with polar coordinate representation. A new topology optimization method is built by taking advantage of the aforementioned features and modern topology optimization techniques. Several numerical examples are provided to demonstrate its capability. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In this paper, we report design and characteristics of a compact coherent mixer based on high Δ planar lightwave circuit (PLC) which consists of ZrO2-doped silica glass. The PLC with 5% or more Δ is realized by employing ZrO2 as a dopant. Propagation loss of the fabricated 5.5%-Δ ZrO2-SiO2 PLC is reduced to 0.02 dB/cm by an optimized fabrication process. A coherent mixer is designed and fabricated by using ZrO2-SiO2 PLC and size of the mixer chip is reduced to 4 mm × 2 mm. Coupling loss between standard single-mode fiber and ZrO2-SiO2 PLC is reduced to less than 0.31 dB/facet by an optimized spot-size converter. [ABSTRACT FROM PUBLISHER]

SUMMARY In this paper, we propose a new BEM for level-set based topology optimization. In the proposed BEM, the nodal coordinates of the boundary element are replaced with the nodal level-set function and the nodal coordinates of the Eulerian mesh that maintains the level-set function. Because this replacement causes the nodal coordinates of the boundary element to disappear, the boundary element mesh appears to be immersed in the Eulerian mesh. Therefore, we call the proposed BEM an immersed BEM. The relationship between the nodal coordinates of the boundary element and the nodal level-set function of the Eulerian mesh is clearly represented, and therefore, the sensitivities with respect to the nodal level-set function are strictly derived in the immersed BEM. Furthermore, the immersed BEM completely eliminates grayscale elements that are known to cause numerical difficulties in topology optimization. By using the immersed BEM, we construct a concrete topology optimization method for solving the minimum compliance problem. We provide some numerical examples and discuss the usefulness of the constructed optimization method on the basis of the obtained results. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]