Mild Catalytic Degradation of Crystalline Polyethylene Units in a Solid State Assisted by Carboxylic Acid Groups.

Crystalline polyethylenes bearing carboxylic acid groups in the main chain were successfully degraded with a Ce catalyst and visible light. The reaction proceeds in a crystalline solid state without swelling in acetonitrile or water at a reaction temperature as low as 60 or 80 °C, employing dioxygen in air as the only stoichiometric reactant with nearly quantitative recovery of carbon atoms. Heterogeneous features of the reaction allowed us to reveal a dynamic morphological change of polymer crystals during the degradation.

Synthesis of Novel Polymers with Biodegradability by Main-Chain Editing of Chiral Polyketones.

Although the use of biodegradable plastics is suitable for unrecoverable, single-use plastic, their high production cost and much lower variety compared to commodity plastics limit their application. In this study, we developed a new polymer with potential biodegradability, poly(ketone/ester), synthesized from propylene and carbon monoxide. Propylene and carbon monoxide are easily available at low costs from fossil resources, and they can also be derived from biomass. Using an atom insertion reaction to the main chain of the polymer, the main-chain editing of the polymer molecule proceeded with up to 89% selectivity for atom insertion over main-chain cleavage.

Synthesis of Long-Chain Polyamides via Main-Chain Modification of Polyethyleneketones.

Long-chain polyamides (polyethyleneamides) were prepared from polyethylenes bearing in-chain carbonyl groups (polyethyleneketones) by the oxime formation and successive Beckmann rearrangement. (Diethylamino)sulfur trifluoride (DAST) was utilized as a promoter, which allowed mild conversion of the oxime group in spite of low solubility of the polymers. The polyethyleneamide exhibited different tensile property compared to a commercial HDPE.

Effects of network junctions and defects on the crystallization of model poly(ethylene glycol) networks.

Polymer crystallization drastically changes the physical properties of polymeric materials. However, the crystallization in polymer networks has been little explored. This study investigated the crystallization behavior of a series of poly(ethylene glycol) (PEG) networks consisting of well-defined branched precursors. The PEG networks were prepared by drying gels synthesized at various conditions. The PEG networks showed slower crystallization with lower final crystallinity than uncrosslinked PEGs with amine end groups. Surprisingly, the effect of network formation was not as significant as that of the relatively bulky end-groups introduced in the uncrosslinked polymer. The molecular weight of the precursor PEG, or equivalently the chain length between neighboring junctions, was the primary parameter that affected the crystallization of the PEG networks. Shorter network chains led to lower crystallization rates and final crystallinity. This effect became less significant as the network chain length increased. On the other hand, the spatial and topological defects formed in the gel synthesis process did not affect the crystallization in the polymer networks at all. The crystallization in the polymer networks seems insensitive to these mesoscopic defects and can be solely controlled by the chain length between junctions.

Linking microscopic structural changes and macroscopic mechanical responses in a near-ideal bottlebrush elastomer under uniaxial deformation.

Bottlebrush (BB) elastomers, in which load-bearing network strands are densely grafted with side chains, are gaining much attention due to their unique mechanical properties. Herein, we used in situ small-angle X-ray scattering coupled with tensile tests to investigate the microscopic structural changes induced in a model BB elastomer with a controlled network structure under uniaxial deformation. The model BB elastomer was synthesized by end-linking a monodisperse star-shaped BB polymer, which ensured a controlled network structure. The BB elastomer exhibited both significant strain stiffening and backbone chain alignment under uniaxial loading, and these properties were not observed in an analogous side chain-free elastomer and gel. It was also found that the side chains in the BB elastomer did not show any sign of chain orientation even when the attached backbone chain was aligned in the stretching direction. These observations highlighted the roles of side chains: they were structurally disordered at the segment level but their steric repulsion made the backbone chain aligned and overstretched.

Quantifying the effects of cooperative hydrogen bonds between vicinal diols on polymer dynamics.

Transient cross-links such as hydrogen bonds (H-bonds) are a central concept for creating polymers with mechanical functionalities, including toughness and self-healing properties. While conventional strong H-bonding groups are based on rigid and planar molecular motifs with multidentate intermolecular interactions, we recently discovered that a structurally simple and flexible vicinal diol (VDO) could serve as a robust yet dynamic cross-link with multiple intermolecular H-bonds between hydroxy groups. In this work, we investigated the effects of cooperativity of H-bonds in VDOs on polymer dynamics. We synthesized model polybutadienes with either VDO or monool (MO) side groups by a radical-mediated thiol-ene click reaction. The oscillatory shear rheology data were analyzed by using the sticky Rouse model. The characteristic time of a single modified segment (δτ0) was significantly longer for the VDO-modified polymers than for the MO-modified polymers, even when they had the same number density of hydroxy groups. The increase in δτ0 with increasing degree of modification was much more drastic for the VDO-modified polymers than for the MO-modified polymers. Moreover, the characteristic time of an unmodified Rouse segment (τ0) was found to increase upon increasing the number of VDOs in the chain, while it was unchanged against the number of MOs. These observations highlight the cooperative effects of placing two hydroxy groups in a close vicinal arrangement. The multiplicity of H-bonds and the structural flexibility of VDOs led to efficient retardation of the chain dynamics.

Restricted mean survival time as a summary measure of time-to-event outcome.

Many clinical research studies evaluate a time-to-event outcome, illustrate survival functions, and conventionally report estimated hazard ratios to express the magnitude of the treatment effect when comparing between groups. However, it may not be straightforward to interpret the hazard ratio clinically and statistically when the proportional hazards assumption is invalid. In some recent papers published in clinical journals, the use of restricted mean survival time (RMST) or τ-year mean survival time is discussed as one of the alternative summary measures for the time-to-event outcome. The RMST is defined as the expected value of time to event limited to a specific time point corresponding to the area under the survival curve up to the specific time point. This article summarizes the necessary information to conduct statistical analysis using the RMST, including the definition and statistical properties of the RMST, adjusted analysis methods, sample size calculation, information fraction for the RMST difference, and clinical and statistical meaning and interpretation. Additionally, we discuss how to set the specific time point to define the RMST from two main points of view. We also provide developed SAS codes to determine the sample size required to detect an expected RMST difference with appropriate power and reconstruct individual survival data to estimate an RMST reference value from a reported survival curve.

A Simple and Versatile Method for the Construction of Nearly Ideal Polymer Networks.

Polymer networks usually contain numerous inhomogeneities that deteriorate their physical properties and should be eliminated to create reliable, high-performance materials. A simple method is introduced for the production of nearly ideal networks from various vinyl polymers through controlled polymerization and subsequent crosslinking. Monodisperse star polymers with bromide end groups were synthesized by atom-transfer radical polymerization and end-linked with dithiol linkers using thiol-bromide chemistry. This simple procedure formed nearly ideal polymer networks, as revealed from elasticity of the formed gel and model conjugation reactions involving linear polymers. The versatility of this method was demonstrated by preparing networks of common vinyl polymers, including polyacrylates, polymethacrylate, and polystyrene. This method can be used to prepare multiple functional nearly ideal gels and elastomers and to explore fundamental aspects of polymer networks.

Subgroup analysis of Japanese patients in a Phase 3 study of atezolizumab in advanced triple-negative breast cancer (IMpassion130).

BACKGROUND: In the randomised Phase 3 IMpassion130 trial, atezolizumab combined with nab-paclitaxel (atezo + nab-P) in 902 patients with triple-negative breast cancer (TNBC) showed prolonged progression-free survival (PFS) in both the intention-to-treat (ITT) population and programmed death-ligand 1 (PD-L1)-positive subgroup compared with placebo plus nab-P (plac + nab-P). This study assessed the efficacy and safety of atezo + nab-P in the IMpassion130 Japanese subpopulation. METHODS: Eligible patients had unresectable locally advanced or metastatic TNBC previously untreated with chemotherapy for metastatic disease. Patients were randomised 1:1 to receive either atezo + nab-P or plac + nab-P. Co-primary endpoints were investigator-assessed PFS and overall survival (ITT population and PD-L1-positive subgroup). These were also assessed in the Japanese subpopulation. RESULTS: There were 65 Japanese patients (34 atezo + nab-P; 31 plac + nab-P). The PD-L1-positive subgroup included 25 patients (12 atezo + nab-P; 13 plac + nab-P). Median PFS was 7.4 months (atezo + nab-P) versus 4.6 months (plac + nab-P; hazard ratio [HR], 0.47; 95% CI, 0.25-0.90). In the PD-L1-positive subgroup, median PFS was 10.8 months (atezo + nab-P) versus 3.8 months (plac + nab-P; HR, 0.04; 95% CI, <0.01-0.35). Safety results in the Japanese subgroup were consistent with those in the overall population. The Japanese subgroup had a lower incidence of adverse events leading to treatment withdrawal than the overall population. More patients in the atezo + nab-P arm had neutrophil count decreases and stomatitis than patients in the plac + nab-P arm. CONCLUSIONS: Atezo + nab-P efficacy in Japanese patients was consistent with the overall IMpassion130 population. No new safety signals were observed, and tolerability was consistent with that of the overall population.

Real-World Pharmacokinetics, Effectiveness, and Safety of Atezolizumab in Patients With Unresectable Advanced or Recurrent NSCLC: An Exploratory Study of J-TAIL.

Introduction: This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen. Methods: A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (Cmax) calculated using the existing PopPK model and AEs of special interest (AESIs). Results: Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated Cmax at cycle 1 increased. Conclusions: In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated Cmax at cycle 1 may be associated with an increased frequency of AESIs.

Module-Assembled Elastomer Showing Large Strain Stiffening Capability and High Stretchability.

Elastomers are indispensable materials due to their flexible, stretchable, and elastic nature. However, the polymer network structure constituting an elastomer is generally inhomogeneous, limiting the performance of the material. Here, a highly stretchable elastomer with unprecedented strain-stiffening capability is developed based on a highly homogeneous network structure enabled by a module assembly strategy. The elastomer is synthesized by efficient end-linking of a star-shaped aliphatic polyester precursor with a narrow molecular-weight distribution. The resulting product shows high strength (≈26 MPa) and remarkable stretchability (stretch ratio at break ≈1900%), as well as good fatigue resistance and notch insensitivity. Moreover, it shows extraordinary strain-stiffening capability (>2000-fold increase in the apparent stiffness) that exceeds the performance of any existing soft material. These unique properties are due to strain-induced ordering of the polymer chains in a uniformly stretched network, as revealed by in situ X-ray scattering analyses. The utility of this great strain-stiffening capability is demonstrated by realizing a simple variable stiffness actuator for soft robotics.

Effects of Alkyl Ester Chain Length on the Toughness of PolyAcrylate-Based Network Materials.

Polyacrylate-based network materials are widely used in various products owing to their facile synthesis via radical polymerization reactions. In this study, the effects of alkyl ester chains on the toughness of polyacrylate-based network materials were investigated. Polymer networks were fabricated via the radical polymerization of methyl acrylate (MA), ethyl acrylate (EA), and butyl acrylate (BA) in the presence of 1,4-butanediol diacrylate as a crosslinker. Differential scanning calorimetry and rheological measurements revealed that the toughness of MA-based networks drastically increased compared with that of EA- and BA-based networks; the fracture energy of the MA-based network was approximately 10 and 100 times greater than that of EA and BA, respectively. The high fracture energy was attributed to the glass transition temperature of the MA-based network (close to room temperature), resulting in large energy dissipation via viscosity. Our results set a new basis for expanding the applications of polyacrylate-based networks as functional materials.

Effectiveness and Safety of Atezolizumab Monotherapy in Previously Treated Japanese Patients With Unresectable Advanced or Recurrent NSCLC: A Multicenter, Prospective, Observational Study (J-TAIL).

Introduction: The efficacy and safety of atezolizumab in previously treated patients with NSCLC have been established in the registrational phase 3 OAK trial. In this study, we evaluated the effectiveness and safety of atezolizumab monotherapy in a large real-world cohort to confirm the reproducibility of the results of the registrational trial. Methods: This was a multicenter, prospective, single-arm observational study. Consecutive patients with previously treated NSCLC scheduled to receive atezolizumab monotherapy were enrolled. The primary end point was the 18-month overall survival (OS) rate. The incidence of adverse events (AEs) and immune-related AEs was evaluated. Results: Overall, 1002 patients were included in the safety analysis set and 1000 in the full analysis set. Median follow-up was 11.5 months. Of the full analysis set, 62% were ineligible for the OAK trial (OAK-unlike subpopulation). The 18-month OS rate was 41.1%, with a median OS of 13.0 months (95% confidence interval: 12.2-15.1). The 18-month OS rate was 49.4% and 36.1% in OAK-like and OAK-unlike subpopulations, respectively; that in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2 was 14.3%. The incidence of AEs overall, in the OAK-like, and OAK-unlike subpopulations was 43.9%, 46.2%, and 42.5%; that of immune-related AEs was 19.0%, 20.1%, and 18.3%, respectively. Conclusions: The findings suggest that atezolizumab may be effective and safe for previously treated patients with NSCLC in real-world settings; however, atezolizumab administration should be considered carefully regarding the benefit-risk balance for the OAK-unlike subpopulation, especially in patients with Eastern Cooperative Oncology Group performance status greater than or equal to 2.

Osteonecrosis development in a novel rat model characterized by a single application of oxidative stress.

OBJECTIVE: To investigate the relationship between transient oxidative stress and the development of osteonecrosis in a rat model. METHODS: A total of 160 male Wistar rats (24 weeks old) were injected only once with the pro-oxidant DL-buthionine-(S,R)-sulfoximine (BSO) (500 mg/kg given intraperitoneally) and were killed 12 hours (group A), 1 day (group B), 3 days (group C), 4 days (group D), 5 days (group E), 7 days (group F), or 14 days (group G) after administration (n = 20 per group). Twenty untreated rats were used as a control group (group N). Femurs were examined histopathologically for the presence of osteonecrosis, and reduced glutathione (GSH) in liver tissue was measured as an index of oxidative stress. RESULTS: GSH decreased rapidly after BSO administration. Significant decreases were noted in groups A and B as compared to group N (P < 0.0001 and P = 0.0007, respectively), confirming the development of transient extreme oxidative stress soon after BSO administration. The histopathologic study revealed osteonecrosis in 10% of the rats in group E, 35% of the rats in group F, and 40% of the rats in group G. CONCLUSION: Transient extreme oxidative stress was confirmed to induce osteonecrosis in this model. Since preparation of this model is extremely simple and because rats are well suited to genetic studies, this model may be of use in elucidating the pathophysiology of femoral head osteonecrosis in future studies.

Synthesis of a Bottlebrush Polymer Gel with a Uniform and Controlled Network Structure.

A structurally controlled polymer gel was synthesized by end-linking a monodisperse star polymer in which each arm was a bottlebrush (BB) polymer densely grafted with side chains. The combination of atom transfer radical polymerization and postpolymerization modification yielded a four-arm star-shaped BB polymer with a controlled polymerization degree of the backbone and side chains. The reactive end groups introduced at the end of each arm reacted with small bifunctional linkers in solution, leading to the formation of a BB polymer gel. The elasticity study on the BB polymer gel suggested its uniform network structure. Our method enables precise and uniform tuning of essential structural parameters across the entire BB polymer network, which will be beneficial for developing soft materials with desired mechanical responses.

Impact of Tumor Assessment Frequency on Statistical Power in Randomized Cancer Clinical Trials Evaluating Progression-Free Survival.

BACKGROUND: Progression-free survival (PFS) is frequently used as a primary endpoint in late-phase clinical trials for anti-metastatic cancer agents. Previous studies have indicated that the frequency of tumor assessment affects the statistical power for PFS because progression dates are inaccurate; however, this finding may be difficult to generalize because of its unrealistic assumptions. Therefore, we re-examined this issue under realistic assumptions and various scenarios that approximate actual clinical trials. METHODS: Randomized clinical trials comparing two interventions against a solid tumor were simulated under conditions where progressive disease (PD)-dominant PFS or a non-negligible number of deaths (death-competitive PFS) contributed to PFS events, which are conditions that resemble clinical trials of first-line therapy and later-line therapy, respectively. We assessed the impact of tumor assessment frequency on the statistical power. RESULTS: Under the PD-dominant PFS condition, even in extreme scenarios, statistical power loss was only approximately 3%. Under the death-competitive PFS condition, tumor assessment frequency affected the statistical power of PFS if the effect of the treatment on overall survival was lower than that on time to progression. In this case, loss of statistical power was often more than 10% in some realistic scenarios. CONCLUSION: In trials investigating first-line treatments (PD-dominant PFS), tumor assessment frequency has a negligible impact on statistical power, whereas in trials investigating late-line therapies (death-competitive PFS), the potential impact of tumor assessment frequency on statistical power should be carefully evaluated at the design stage.

Fabrication of nacre-like polymer/clay nanocomposites with water-resistant and self-adhesion properties.

HYPOTHESIS: Nacre-like polymer/clay nanocomposites are a fascinating material thanks to its superior mechanical property. However, it has been a great challenge to incorporate hydrophobic polymer components due to highly hydrophilic nature of clay, which limits further improvement of water-resistance and addition of various functionalities. To overcome this problem, we developed a method to form regular nacre-like layered structure from a hydrophobic polymer and hydrophilic clay by a combination of surface modification of clay and selective click reaction between the polymer and clay surfaces. EXPERIMENTS: Natural clay, montmorillonite, was modified with a hydrophobic surfactant bearing an ethenyl group and subsequently reacted in situ with a thiol-functionalized hydrophobic polysiloxane. The layered structure, as well as its formation process, mechanical property, physical stability in water, and self-adhesion property of the nanocomposites were investigated. FINDINGS: In situ thiol-ene click reaction between surface-modified clay and polymer led to self-alignment of clay platelets into a regular layered structure. The resultant nacre-like nanocomposites not only showed the good mechanical property but also had excellent stability in water and self-adhesion ability, both of which originated from the characteristics of the polymer used. These findings widen the possibility of functional nacre-like nanocomposites by expanding the range of applicable polymers to hydrophobic ones.

Efficacy of trastuzumab emtansine in Japanese patients with previously treated HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: A subgroup analysis of the GATSBY study.

AIM: The phase II/III GATSBY study (NCT01641939) showed that trastuzumab emtansine did not have an efficacy benefit over taxane in patients with previously treated, human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic gastric or gastroesophageal junction cancer. We evaluated patients from Japanese centers within GATSBY. METHODS: In stage one, patients (randomized 2:2:1) received trastuzumab emtansine 3.6 mg/kg every 3 weeks, trastuzumab emtansine 2.4 mg/kg weekly, or physician's choice of taxane (docetaxel 75 mg/m² every 3 weeks or paclitaxel 80 mg/m² weekly). In stage two, patients (randomized 2:1) received trastuzumab emtansine 2.4 mg/kg weekly or taxane. Eligible patients had centrally assessed HER2-positive disease and progression during or after first-line therapy. Primary endpoint was overall survival. We present the 2.4 mg/kg weekly data. RESULTS: Eighty-two patients were randomized (intention-to-treat: 48 to trastuzumab emtansine 2.4 mg/kg weekly, 23 to taxane; September 2012-August 2014) at 19 sites. Median overall survival was 11.8 months (95% confidence interval [CI], 9.3-16.3) with trastuzumab emtansine 2.4 mg/kg weekly and 10.0 months (95% CI, 7.1-18.2) with taxane (unstratified hazard ratio = 0.94, 95% CI, 0.52-1.72). Trastuzumab emtansine 2.4 mg/kg weekly, versus taxane, was associated with fewer grade ≥3 adverse events (AEs; 52.1% vs 68.2%) and serious AEs (14.6% vs 18.2%). There were no fatal AEs. CONCLUSIONS: Efficacy in Japanese patients within GATSBY was consistent with the overall population; overall survival was not prolonged with trastuzumab emtansine 2.4 mg/kg weekly versus taxane. The safety profile of trastuzumab emtansine was similar to the overall population.

Phase I study of ipatasertib as a single agent and in combination with abiraterone plus prednisolone in Japanese patients with advanced solid tumors.

PURPOSE: Ipatasertib is a selective inhibitor of Akt, a frequently activated protein kinase in human cancers. The current study assessed the safety, tolerability, and pharmacokinetics of ipatasertib in Japanese patients with solid tumors. METHODS: This was a phase I, open-label, 3 + 3 dose-escalation study conducted in two stages. In stage I, Japanese patients with solid tumors were administered ipatasertib 200, 400, or 600 mg/day for 21 days of a 28-day cycle. In stage II, Japanese patients with castration-resistant prostate cancer were administered ipatasertib 200 or 400 mg/day in combination with abiraterone and prednisolone in 28-day cycles. Dose-limiting toxicity (DLT) was assessed at each dose before enrolling patients at a higher dose; DLT was used to determine the maximum tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic parameters were assessed after a single dose and at steady state. RESULTS: Fifteen patients were enrolled in Stage I and six in Stage II. The ipatasertib MTD was 600 mg as monotherapy and MAD was 400 mg in combination with abiraterone and prednisolone. Ipatasertib plasma exposure was dose proportional across the dose range, and was not markedly affected by concurrent administration of abiraterone plus prednisolone. Stable disease (SD) was observed in eight patients treated with ipatasertib monotherapy (53.3%); four patients had SD and one had complete response with ipatasertib plus abiraterone and prednisolone. CONCLUSIONS: Ipatasertib, at the monotherapy MTD of 600 mg/day and MAD of 400 mg/day in combination with abiraterone and prednisolone, was safe and tolerable in Japanese patients with solid tumors.