Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study.

BACKGROUND: The benefit of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma is unknown. We assess the antitumor activity of neoadjuvant and adjuvant pembrolizumab plus chemotherapy in patients with locally advanced resectable gastric or gastro-oesophageal adenocarcinoma. METHODS: The KEYNOTE-585 study is a multicentre, randomised, placebo-controlled, double-blind, phase 3 study done at 143 medical centres in 24 countries. Eligible patients were aged 18 years or older with untreated, locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma, and an Eastern Cooperative Oncology Group performance status 0-1. Patients were randomly assigned (1:1) by an interactive voice response system and integrated web response system to neoadjuvant pembrolizumab 200 mg intravenously or placebo (saline) plus cisplatin-based doublet chemotherapy (main cohort) every 3 weeks for 3 cycles, followed by surgery, adjuvant pembrolizumab or placebo plus chemotherapy for 3 cycles, then adjuvant pembrolizumab or placebo for 11 cycles. A small cohort was also randomly assigned (1:1) to pembrolizumab or placebo plus fluorouracil, docetaxel, and oxaliplatin (FLOT)-based chemotherapy (FLOT cohort) every 2 weeks for four cycles, followed by surgery, adjuvant pembrolizumab, or placebo plus FLOT for four cycles, then adjuvant pembrolizumab or placebo for 11 cycles. Patients were stratified by geographic region, tumour stage, and chemotherapy backbone. Primary endpoints were pathological complete response (reviewed centrally), event-free survival (reviewed by the investigator), and overall survival in the intention-to-treat population, and safety assessed in all patients who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT03221426, and is closed to accrual. FINDINGS: Between Oct 9, 2017, and Jan 25, 2021, of 1254 patients screened, 804 were randomly assigned to the main cohort, of whom 402 were assigned to the pembrolizumab plus cisplatin-based chemotherapy group and 402 to the placebo plus cisplatin-based chemotherapy group, and 203 to the FLOT cohort, of whom 100 were assigned to the pembrolizumab plus FLOT group and 103 to placebo plus FLOT group. In the main cohort of 804 participants, 575 (72%) were male and 229 (28%) were female. In the main cohort, after median follow-up of 47·7 months (IQR 38·0-54·8), pembrolizumab was superior to placebo for pathological complete response (52 [12·9%; 95% CI 9·8-16·6] of 402 vs eight [2·0%; 0·9-3·9] of 402; difference 10·9%, 95% CI 7·5 to 14·8; p<0·00001). Median event-free survival was longer with pembrolizumab versus placebo (44·4 months, 95% CI 33·0 to not reached vs 25·3 months, 20·6 to 33·9; hazard ratio [HR] 0·81, 95% CI 0·67 to 0·99; p=0·0198) but did not meet the threshold for statistical significance (p=0·0178). Median overall survival was 60·7 months (95% CI 51·5 to not reached) in the pembrolizumab group versus 58·0 months (41·5 to not reached) in the placebo group (HR 0·90, 95% CI 0·73 to 1·12; p=0·174). Grade 3 or worse adverse events of any cause occurred in 312 (78%) of 399 patients in the pembrolizumab group and 297 (74%) of 400 patients in the placebo group; the most common were nausea (240 [60%] vs 247 [62%]), anaemia (168 [42%] vs 158 [40%]), and decreased appetite (163 [41%] vs 172 [43%]). Treatment-related serious adverse events were reported in 102 (26%) and 97 (24%) patients. Treatment-related adverse events that led to death occurred in four (1%) patients in the pembrolizumab group (interstitial ischaemia, pneumonia, decreased appetite, and acute kidney injury [n=1 each]) and two (<1%) patients in the placebo group (neutropenic sepsis and neutropenic colitis [n=1 each]). INTERPRETATION: Although neoadjuvant and adjuvant pembrolizumab versus placebo improved the pathological complete response, it did not translate to significant improvement in event-free survival in patients with untreated, locally advanced resectable gastric or gastro-oesophageal cancer. FUNDING: Merck Sharp & Dohme.

Liquid-Crystal Ordering and Microphase Separation in the Lamellar Phase of Rod-Coil-Rod Triblock Copolymers. Molecular Theory and Computer Simulations.

A molecular model of the orientationally ordered lamellar phase exhibited by asymmetric rod-coil-rod triblock copolymers has been developed using the density-functional approach and generalizing the molecular-statistical theory of rod-coil diblock copolymers. An approximate expression for the free energy of the lamellar phase has been obtained in terms of the direct correlation functions of the system, the Flory-Huggins parameter and the Maier-Saupe orientational interaction potential between rods. A detailed derivation of several rod-rod and rod-coil density-density correlation functions required to evaluate the free energy is presented. The orientational and translational order parameters of rod and coil segments depending on the temperature and triblock asymmetry have been calculated numerically by direct minimization of the free energy. Different structure and ordering of the lamellar phase at high and low values of the triblock asymmetry is revealed and analyzed in detail. Asymmetric rod-coil-rod triblock copolymers have been simulated using the method of dissipative particle dynamics in the broad range of the Flory-Huggins parameter and for several values of the triblock asymmetry. It has been found that the lamellar phase appears to be the most stable one at strong segregation. The density distribution of the coil segments and the segments of the two different rods have been determined for different values of the segregation strength. The simulations confirm the existence of a weakly ordered lamellar phase predicted by the density-functional theory, in which the short rods separate from the long ones and are characterized by weak positional ordering.

Liquid Crystal Ordering in the Hexagonal Phase of Rod-Coil Diblock Copolymers.

Density functional theory of rod-coil diblock copolymers, developed recently by the authors, has been generalised and used to study the liquid crystal ordering and microphase separation effects in the hexagonal, lamellar and nematic phases. The translational order parameters of rod and coil monomers and the orientational order parameters of rod-like fragments of the copolymer chains have been determined numerically by direct minimization of the free energy. The phase diagram has been derived containing the isotropic, the lamellar and the hexagonal phases which is consistent with typical experimental data. The order parameter profiles as functions of temperature and the copolymer composition have also been determined in different anisotropic phases. Finally, the spatial distributions of the density of rigid rod fragments and of the corresponding orientational order parameter in the hexagonal phase have been calculated.

Enchancement of Toremifene Anti-Tumor Action by Metformin and Unusual Side Effect of Toremifene in Male Transgenic Mice with HER2-Positive Breast Tumor.

HER2-positive breast tumors are found in 25-30% of patients with breast cancer and are characterized by aggressive course and reduced sensitivity to both chemotherapy and hormone therapy. The aim of the work was to study the possibilities of enhancing the therapeutic effect of anti-estrogen drug toremifene by combining it with biguanide, metformin, on the HER2-positive breast cancer model in FVB/N HER-2/neu transgenic mouse. Male FBV/N mice with intramuscularly transplanted HER2-positive mammary gland tumor from a female mouse of the same strain have been given toremifene (30 mg/kg, orally daily) or metformin (100 mg/kg, orally daily) that had a moderate antitumor effect (decrease the area under the kinetic curve of tumor growth by 1.6 and 1.5 times, respectively, when compared with intact control). Co-administration of these drugs in the same doses had a more pronounced effect (the area under the kinetic curve of tumor growth decreased by 3.1 times compared to intact control; p<0.05). After 10 days, in group receiving toremifene all 10 mice developed inguinal-scrotal hernias, and in group that received toremifene plus metformin - only 5 of 10 (p=0.0325). By the 15th day after the start of treatment, the hernias was also determined in all mice treated with the combination of toremifene and metformin, but the size of the hernial sac was significantly smaller than in those receiving only toremifene - 537 ± 96 mm3 and 1309 ± 120 mm3, respectively (p=0.0001). A possible explanation is the manifestation of collagen-degrading effect of toremifene.

Unexpected electric-field-induced antiferroelectric liquid crystal phase in the SmC_{α}

The unique nanometer-sized helical structure in SmC_{α}^{*} may sometimes evolve continuously to the micrometer-sized one in SmC^{*}; conceivably ferroelectric SmC_{α}^{*} is to be unwound by an applied electric field. By drawing electric-field-induced birefringence contours in the field-temperature phase diagram and by studying the superlattice structure of the field-induced subphase with resonant x-ray scattering, we established that an applied field unexpectedly stabilizes the well-known antiferroelectric four-layer biaxial subphase as well as the other prototypal ferrielectric three-layer one in the SmC_{α}^{*} temperature range; the effective long-range interlayer interaction due to the discrete flexoelectric effect actually plays an important role in stabilizing not only the biaxial subphases but also the optically uniaxial SmC_{α}^{*} subphase, contrary to the notion that the competition between the direct interactions of the nearest-neighbor layers and those of the next-nearest-neighbor layers should be required for the nanometer-sized helical structure.

Ordering of anisotropic nanoparticles in diblock copolymer lamellae: Simulations with dissipative particle dynamics and a molecular theory.

Local distribution and orientation of anisotropic nanoparticles in microphase-separated symmetric diblock copolymers has been simulated using dissipative particle dynamics and analyzed with a molecular theory. It has been demonstrated that nanoparticles are characterized by a non-trivial orientational ordering in the lamellar phase due to their anisotropic interactions with isotropic monomer units. In the simulations, the maximum concentration and degree of ordering are attained for non-selective nanorods near the domain boundary. In this case, the nanorods have a certain tendency to align parallel to the interface in the boundary region and perpendicular to it inside the domains. Similar orientation ordering of nanoparticles located at the lamellar interface is predicted by the molecular theory which takes into account that the nanoparticles interact with monomer units via both isotropic and anisotropic potentials. Computer simulations enable one to study the effects of the nanorod concentration, length, stiffness, and selectivity of their interactions with the copolymer components on the phase stability and orientational order of nanoparticles. If the volume fraction of the nanorods is lower than 0.1, they have no effect on the copolymer transition from the disordered state into a lamellar microstructure. Increasing nanorod concentration or nanorod length results in clustering of the nanorods and eventually leads to a macrophase separation, whereas the copolymer preserves its lamellar morphology. Segregated nanorods of length close to the width of the diblock copolymer domains are stacked side by side into smectic layers that fill the domain space. Thus, spontaneous organization and orientation of nanorods leads to a spatial modulation of anisotropic composite properties which may be important for various applications.

Spatial distribution and nematic ordering of anisotropic nanoparticles in lamellae and hexagonal phases of block copolymers.

Orientational and translational ordering of anisotropic nanoparticles in the lamellae and hexagonal phases of diblock copolymers have been considered theoretically in the case of strong segregation taking into account the anisotropic interaction between the nanoparticles and the monomers in different blocks. It has been shown that anisotropic nanoparticles are orientationally ordered in the boundary region between the blocks and the nematic order parameter possesses opposite signs in different blocks: the nanoparticles align parallel to the boundary in one block and perpendicular to it in the other. In the hexagonal phase, a weak biaxial ordering of nanoparticles is also induced in the boundary region. Explicit analytical results have been obtained for the distribution of nanoparticles in the lamellae phase. The results are compared with the existing experimental data.

Orientational distribution functions and order parameters in "de Vries"-type smectics: A simulation study.

Simple smectic A liquid crystal phases with different types of prescribed orientational distribution functions have been simulated and compared in order to study the possibility to distinguish between the Maier-Saupe type and cone-like orientational distributions using the popular method of Davidson et al. [J. Phys. II 5, 113 (1995)]. This method has been used to extract the orientational distribution functions from simulated diffraction patterns, and the results have been compared with actual distribution functions which have been prescribed during simulations. It has been shown that it is indeed possible to distinguish between these two qualitatively different types of orientational distribution already from the shape of the 2D diffraction pattern. Moreover, typical experimental diffraction patterns for "de Vries"-type smectic liquid crystals appear to be close to the ones which have been simulated using the prescribed Maier-Saupe orientational distribution function.

Short-range smectic fluctuations and the flexoelectric model of modulated nematic liquid crystals.

We show that the flexoelectric model of chiral and achiral modulated nematics predicts the compression modulus that is by orders of magnitude lower than the measured values. The discrepancy is much larger in the chiral modulated nematic phase, in which the measured value of the compression modulus is of the same order of magnitude as in achiral modulated nematics, even though the heliconical pitch is by an order of magnitude larger. The relaxation of a one-constant approximation in the biaxial elastic model used for chiral modulated nematics does not solve the problem. Therefore, we propose a structural model of the modulated nematic phase, which is consistent with the current experimental evidence and can also explain large compression modulus: the structure consists of short-range smectic clusters with a fourfold symmetry and periodicity of two molecular distances. In chiral systems, chiral interactions lead to a helicoidal structure of such clusters.

Smectic layer instabilities in liquid crystals.

Scientists aspire to understand the underlying physics behind the formation of instabilities in soft matter and how to manipulate them for diverse investigations, while engineers aim to design materials that inhibit or impede the nucleation and growth of these instabilities in critical applications. The present paper reviews the field-induced rotational instabilities which may occur in chiral smectic liquid-crystalline layers when subjected to an asymmetric electric field. Such instabilities destroy the so-named bookshelf geometry (in which the smectic layers are normal to the cell surfaces) and have a detrimental effect on all applications of ferroelectric liquid crystals as optical materials. The transformation of the bookshelf geometry into horizontal chevron structures (in which each layer is in a V-shaped structure), and the reorientation dynamics of these chevrons, are discussed in details with respect to the electric field conditions, the material properties and the boundary conditions. Particular attention is given to the polymer-stabilisation of smectic phases as a way to forbid the occurrence of instabilities and the decline of related electro-optical performances. It is also shown which benefit may be gained from layer instabilities to enhance the alignment of the liquid-crystalline geometry in practical devices, such as optical recording by ferroelectric liquid crystals. Finally, the theoretical background of layer instabilities is given and discussed in relation to the experimental data.

Flexoelectricity in chiral nematic liquid crystals as a driving mechanism for the twist-bend and splay-bend modulated phases.

We present a continuum theoretical model describing the impact of chirality on nematic systems with large flexoelectricity. As opposed to achiral materials, where only one type of the modulated structure can exist in a given material, the model predicts that chirality can stabilize several modulated phases, which have already been observed experimentally [A. Zep et al., J. Mater. Chem. C 1, 46 (2013)].

Sign inversion of the spontaneous polarization in a "de Vries"-type ferroelectric liquid crystal.

In contrast to common ferroelectric smectic C* liquid crystals, the siloxane-terminated smectic mesogen E6 is characterized by an unusual temperature variation of the spontaneous polarization. The polarization starts to grow from nearly zero despite the first-order SmA*-SmC* transition, and increases faster than linearly over a large temperature interval while the tilt angle rapidly saturates. To study this behavior in more detail, binary mixtures of different concentrations of E6 in the achiral SmC material C8Cl, which has a similar chemical structure, were investigated. Surprisingly, all mixtures show a temperature dependent polarization sign inversion, which shifts towards the SmC*-SmA* transition with increasing E6 concentration. For the pure E6 the inversion temperature meets the SmA*-SmC* phase transition temperature. In a second binary mixture with E6 and a conventional material C9-2PhP we found out, that the dependence of the inversion temperature on the concentration of E6 changes qualitatively when the nanosegregation is partially destroyed. A molecular theory of the polarization sign inversion in smectics C* with strong polar intermolecular interactions is developed which enables one to explain the concentration dependence of the inversion temperature in both mixtures.

Molecular theory of phase separation in nematic liquid crystals doped with spherical nanoparticles.

A molecular-statistical theory is developed, which enables one to describe the nematic-isotropic phase transition in liquid crystals doped with spherical nanoparticles taking into account the effects of phase separation. It has been shown that in the case of strong interaction between nanoparticles and mesogenic molecules the nematic nanocomposite possesses a number of unexpected properties. In particular, the nematic-isotropic co-existence region appears to be very broad, and the system either undergoes a direct transition from the isotropic phase into the phase-separated state, or undergoes the transition into the homogeneous nematic phase first and then phase-separates at a lower temperature. Phase separation does not occur at all if the concentration of the nanoparticles is sufficiently low, and in some cases it takes place only within a finite region of nanoparticle concentration. A number of temperature-concentration phase diagrams is presented and the molar fractions of nanoparticles in the co-existing isotropic and nematic phases are calculated numerically as functions of temperature.

Molecular theory of the tilting transition in smectic liquid crystals with weak layer contraction and diffused cone orientational distribution.

A molecular field theory of the smectic-A-smectic-C transition has been developed for smectics with a diffused cone orientational distribution of molecules (volcano-like distribution function) in the smectic-A phase and anomalously weak layer contraction in the smectic-C phase. Orientational order parameters and smectic layer spacing have been calculated numerically as functions of temperature and compared with the results obtained using a model with a standard Maier-Saupe-type distribution function that has been considered before. A molecular theory of the electroclinic effect in chiral smectics has also been developed using the recently proposed simple biaxial interaction potential. A comparison has been made between the absolute values and temperature variations of the electroclinic coefficient obtained using the volcano model, the model with Maier-Saupe-type distribution, and the orthodox cone model proposed by de Vries. It has been shown that the model with a conventional "sugar loaf" type orientational distribution function in the smectic-A phase is sufficient to describe the main properties of smectics with anomalously weak layer contraction.

Influence of dipole-dipole correlations on the stability of the biaxial nematic phase in the model bent-core liquid crystal.

A molecular theory of biaxial nematic ordering in the system of bent-core molecules has been developed in the two-particle cluster approximation which enables one to take into account short-range polar correlations determined by both electrostatic dipole-dipole interaction and polar molecular shape. All orientational order parameters and short-range correlation functions are calculated numerically as functions of temperature in the uniaxial and in the biaxial nematic phases, and the results are compared with the ones obtained in the mean-field approximation and in the cluster approximation but without taking into consideration the dipole-dipole interaction. It is shown that short-range polar correlations and, in particular, the dipole-dipole correlations dramatically increase the temperature of the transition into the biaxial nematic phase and enhancing its stability range. The results are also very sensitive to the value of the opening angle of a model bent-core molecule.

Electrolyte effects on the chiral induction and on its temperature dependence in a chiral nematic lyotropic liquid crystal.

We present a study on the effect of added CsCl and of temperature variation on the chiral induction in a chiral nematic lyotropic liquid crystal (LC) composed of the surfactant cesium perfluorooctanoate (CsPFO), water, and the chiral dopant d-Leucine (d-Leu). The chiral induction was measured as the helical pitch P. The role of the additives CsCl and d-Leu on the phase behavior is investigated and discussed. The thermal stabilization effect of CsCl is shown to lead to an apparent salt effect on the pitch when the pitch is compared at a constant temperature. This apparent effect is removed by comparing the pitch measured for different salt concentrations at a temperature relative to the phase-transition temperatures; thus, the real salt effect on the pitch is described. High salt concentrations are shown to increase the pitch, that is, hinder the chiral induction. The effect is discussed in terms of a decreased solubilization of the amphiphilic chiral solute d-Leu in the micelles due to the salt-induced screening of the surfactant head groups and the consequential denser packing of the surfactants. The temperature variation of the pitch is investigated for all CsCl concentrations and is found to be essentially independent of the salt concentration. The temperature variation is analyzed and discussed in the context of a theoretical model taking into account specific properties of lyotropic liquid crystals. A hyperbolic decrease of the pitch is found with increasing temperature, which is known, from thermotropic liquid crystals, to stem from pretransitional critical fluctuations close to the lamellar phase. However, the experimental data confirmed the theoretical prediction that, at high temperature, that is, far away from the transition into the lamellar phase, the pitch is characterized by a linear temperature dependence which is determined by a combination of steric and dispersion chiral interactions. The parameters of the theoretical expression for the pitch have been determined by fitting the experimental data. The analysis of the salt concentration dependence of these parameters indicates that the chiral induction mechanism of d-Leu is dominated by chiral steric interactions.

Orientational order parameters in liquid crystals: a comparative study of x-ray diffraction and polarized Raman spectroscopy results.

The orientational order parameters and in the nematic liquid crystal 4-pentyl-4'-cyanobipheny (5CB) have been determined by means of the two completely different techniques: polarized Raman spectroscopy and x-ray scattering. In particular, the values of and obtained using two different Raman methods, proposed by Jen [J. Chem. Phys 66, 4635 (1977)] and Jones [J. Mol. Struct. 708, 145 (2004)], respectively, are compared with the results of x-ray measurements. A good agreement between the experimental values of and and the results of the Humphries-James-Luckhurst mean field theory has been found whenever they were determined using either x-ray measurement or following the Jen method. In addition, a study of the influence of the intensity of the exiting laser source on the apparent values of the order parameters has been performed. Therefore, it was found that the discrepancies of the value of determined following Jen and Jones could be determined by nonlinear effects.

Unconventional ferroelectric behavior in nanosegregating liquid crystals with de Vries-like behavior.

Two nanosegregating siloxane-terminated mesogens with chiral (S,S)-2,3-epoxyoctyloxy side chains (E6, E11) have been synthesized. These compounds form chiral SmA∗ and SmC∗ phases and show an untypical behavior of the spontaneous polarization which increases with decreasing temperature in a convex manner while the tilt angle saturates. We compare these results with results obtained for two similar mesogens with chiral (R,R)-2,3-difluorooctyloxy side chains (F6, F11), which both show a typical concave curvature with decreasing temperature. A theoretical explanation is given for the unexpected temperature dependency of the spontaneous polarization. The materials also exhibited first-order SmC∗-SmA∗ phase transitions and hence, very high values of the tilt angle. All substances show increased de Vries character in the range of 50%, which is substantially higher than 20% for the nonsiloxane analogs. Furthermore, for the latter materials, second-order phase transitions are common, while the siloxane materials exhibit first-order SmA∗-SmC∗ phase transitions. These results clearly suggest that the achievement of nanosegregation is a powerful tool to induce de Vries behavior and to promote first-order SmA∗-SmC∗ phase transitions.

Ferroelectricity in low-symmetry biaxial nematic liquid crystals.

Order parameters and phenomenological theory for both high- and low-symmetry biaxial nematic phases are presented and it is predicted that the chiral low-symmetry biaxial phase must be ferroelectric. This conclusion is based on general symmetry arguments and on the results of the Landau-de Gennes theory. The microscopic mechanism of the ferroelectric ordering in this chiral biaxial phase is illustrated using a simple molecular model based on dispersion interactions between biaxial molecules of low symmetry. Similar to the chiral smectic C* phase, the ferroelectricity in the chiral biaxial nematic phase is improper, i.e., polarization is not a primary order parameter and is not determined by dipolar interactions. Ferroelectric ordering in biaxial nematics may be found, in principle, in materials composed of chiral analogues of the tetrapod molecules which are known to exhibit biaxial phases.

Stabilization of the smectic-Calpha* phase in mixtures with chiral dopants.

A series of mixtures comprising an antiferroelectric liquid-crystal host and a chiral dopant is described in which the layer spacing variation at the orthogonal smectic-A* (SmA*) to tilted smectic-C* or smectic-Calpha* (SmC* or SmCalpha*) phase transition changes from the usual strong contraction in the pure system to one in which there is almost no layer spacing change observed across the transition for dopant concentrations of 7%. The nature of the orthogonal to tilted phase transition is examined using Raman spectroscopy, to determine the order parameters and in the SmA* phase, and via a generalized Landau expansion to reveal the details of the phase transition itself. The results show that the value of at the orthogonal to tilted transition increases from around 0.6 to 0.7 as the dopant concentration increases, while remains constant at approximately 0.4 irrespective of dopant concentration. Further, the generalized Landau potential measurements prove that the transition is purely second order, while electro-optic measurements confirm that the tilt angle at the transition becomes smaller with increasing dopant concentration. The combined data show that the high-temperature tilted phase regime corresponds to a SmCalpha* phase rather than the mechanism suggested by de Vries that is inferred by the layer spacing data alone. We demonstrate that the lower-temperature SmCalpha*-SmC* phase transition is of first order. Further, the temperature range of the SmCalpha* phase increases dramatically with concentration, from around 2 K in the pure system to around 21 K in the 8% doped mixture, showing that the chiral dopant plays a role in stabilizing this phase. Indeed, we particularly note that for the 8% doped mixture all other SmC*-like phases disappear and that the only tilted phase remaining is SmCalpha*. This implies that we are reporting a liquid-crystalline phase sequence, namely, cryst.-SmCalpha*-SmA*-iso., i.e., a direct transition between the SmCalpha* phase and the crystalline phase.