Phase I/II study to evaluate consolidative hypofractionated radiation therapy for boosting the residual primary disease in combination with durvalumab after definitive chemoradiation therapy for stage III non-small cell lung cancer (NSCLC): study protocol for a prospective trial.

Background: Recent advancements in the management of non-small cell lung cancer (NSCLC) have confirmed the utility of adding adjuvant immunotherapy to concurrent chemoradiotherapy in stage III disease but intrathoracic progression remains at high rate. Additional studies have sought to investigate the synergistic relationship of immunotherapy and radiation therapy (RT). The goal of this study is to evaluate the safety and efficacy of combining consolidative hypofractionated radiation therapy (hfRT) using stereotactic body radiotherapy (SBRT) technique for boosting the residual primary lung cancer with adjuvant anti-programmed death-ligand 1 (PD-L1) therapy concurrently after completion of definitive chemoradiation therapy (dCRT) in the rates of tumor control locoregionally and distantly. Methods: Eligible subjects with stage III NSCLC must have gross residual tumor that is smaller than 5.0 cm in maximal dimension following dCRT. Consolidative hfRT will be delivered 1 to 2 months after finishing dCRT and concurrently with adjuvant anti-PD-L1 therapy using durvalumab. Consolidative hfRT will start from 6.5 Gy ×2 fractions and dose escalate to 10 Gy ×2 fractions in a 3+3 design. At the final determined consolidative hfRT dose level, a total of 32 subjects with pathologically documented stage III NSCLC treated with two or more cycles of platinum-based doublet chemotherapy concurrently with RT will be enrolled for data analyses. Discussion: We hypothesize that the use of consolidative hfRT directed to the residual primary lung tumor in combination with adjuvant anti-PD-L1 therapy will provide additional immunostimulation and therefore improved locoregional and distant control when compared to either modality used independently. Registration: Clinicaltrials.gov: NCT04748419.

Positive margins matter regardless of subsequent resection findings.

OBJECTIVES: In the resection of oral cavity squamous cell carcinoma (OCSCC), an intraoperative positive surgical margin (SM) communicated to the head and neck surgeon necessitates further resection of the area of identified involvement to achieve a final negative SM. The prognostic implication of initial positive SM when the final SM is negative is understudied. MATERIALS AND METHODS: We retrospectively reviewed 249 patients with non-metastatic (stage I-IVB) OCSCC who underwent a resection from 2010 to 2019 to assess the prognostic impact of an initial positive SM. Chi-squared analysis was used to evaluate the association between an initial positive SM and clinicopathologic parameters. A Kaplan-Meier analysis was performed to estimate patient outcomes with Cox regression analysis used to determine absolute hazards. RESULTS: At a median follow-up of 28.4 months, the 2-year freedom from local recurrence (FFLR), disease-free survival (DFS), and overall survival (OS) rates were 82.1%, 63.5%, and 78.5%, respectively. Fifty patients (20.1%) had an initial positive SM which was revised to a negative SM on frozen and permanent sections by resecting further tissue while 12 patients (4.8%) had a final positive SM. An initial positive SM was independently associated with a worse FFLR (HR: 2.696, p = 0.004), DFS (HR: 1.57, p = 0.044), and OS (HR: 1.72, p = 0.029). CONCLUSION: An initial positive SM is independently associated with worse disease control and patient survival. A positive SM may be a surrogate for diffusely infiltrative disease as further malignancy identified on the re-resection specimen was associated with worse outcomes.

A New Mode of Chemical Reactivity for Metal-Free Hydrogen Activation by Lewis Acidic Boranes.

We herein explore whether tris(aryl)borane Lewis acids are capable of cleaving H2 outside of the usual Lewis acid/base chemistry described by the concept of frustrated Lewis pairs (FLPs). Instead of a Lewis base we use a chemical reductant to generate stable radical anions of two highly hindered boranes: tris(3,5-dinitromesityl)borane and tris(mesityl)borane. NMR spectroscopic characterization reveals that the corresponding borane radical anions activate (cleave) dihydrogen, whilst EPR spectroscopic characterization, supported by computational analysis, reveals the intermediates along the hydrogen activation pathway. This radical-based, redox pathway involves the homolytic cleavage of H2 , in contrast to conventional models of FLP chemistry, which invoke a heterolytic cleavage pathway. This represents a new mode of chemical reactivity for hydrogen activation by borane Lewis acids.

"Janus" Calixarenes: Double-Sided Molecular Linkers for Facile, Multianchor Point, Multifunctional, Surface Modification.

We herein report the synthesis of novel "Janus" calix[4]arenes bearing four "molecular tethering" functional groups on either the upper or lower rims of the calixarene. These enable facile multipoint covalent attachment to electrode surfaces with monolayer coverage. The other rim of the calixarenes bear either four azide or four ethynyl functional groups, which are easily modified by the copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC), either pre- or postsurface modification, enabling these conical, nanocavity reactor sites to be decorated with a wide range of substrates to impart desired chemical properties. Redox active species decorating the peripheral rim are shown to be electrically connected by the calixarene to the electrode surface in either "up" or "down" orientations of the calixarene.

Novel B(Ar')2(Ar'') hetero-tri(aryl)boranes: a systematic study of Lewis acidity.

A series of homo- and hetero-tri(aryl)boranes incorporating pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, and pentachlorophenyl groups, four of which are novel species, have been studied as the acidic component of frustrated Lewis pairs for the heterolytic cleavage of H2. Under mild conditions eight of these will cleave H2; the rate of cleavage depending on both the electrophilicity of the borane and the steric bulk around the boron atom. Electrochemical studies allow comparisons of the electrophilicity with spectroscopic measurements of Lewis acidity for different series of boranes. Discrepancies in the correlation between these two types of measurements, combined with structural characterisation of each borane, reveal that the twist of the aryl rings with respect to the boron-centred trigonal plane is significant from both a steric and electronic perspective, and is an important consideration in the design of tri(aryl)boranes as Lewis acids.

Exploring structural and electronic effects in three isomers of tris{bis(trifluoromethyl)phenyl}borane: towards the combined electrochemical-frustrated Lewis pair activation of H2.

Three structural isomers of tris{bis(trifluoromethyl)phenyl}borane have been studied as the acidic component of frustrated Lewis pairs. While the 3,5-substituted isomer is already known to heterolytically cleave H2 to generate a bridging-hydride; ortho-substituents in the 2,4- and 2,5-isomers quench such reactivity through electron donation into the vacant boron pz orbital and steric blocking of the boron centre; as shown by electrochemical, structural and computational studies. Electrochemical studies of the corresponding borohydrides identify that the two-electron oxidation of terminal-hydrides occurs at more positive potentials than observed for [HB(C6F5)3](-), while the bridging-hydride oxidizes at a higher potential still, comparable to that of free H2.

Metal-free electrocatalytic hydrogen oxidation using frustrated Lewis pairs and carbon-based Lewis acids.

Whilst hydrogen is a potentially clean fuel for energy storage and utilisation technologies, its conversion to electricity comes at a high energetic cost. This demands the use of rare and expensive precious metal electrocatalysts. Electrochemical-frustrated Lewis pairs offer a metal-free, CO tolerant pathway to the electrocatalysis of hydrogen oxidation. They function by combining the hydrogen-activating ability of frustrated Lewis pairs (FLPs) with electrochemical oxidation of the resultant hydride. Here we present an electrochemical-FLP approach that utilises two different Lewis acids - a carbon-based N-methylacridinium cation that possesses excellent electrochemical attributes, and a borane that exhibits fast hydrogen cleavage kinetics and functions as a "hydride shuttle". This synergistic interaction provides a system that is electrocatalytic with respect to the carbon-based Lewis acid, decreases the required potential for hydrogen oxidation by 1 V, and can be recycled multiple times.

Facile Protocol for Water-Tolerant "Frustrated Lewis Pair"-Catalyzed Hydrogenation.

Despite rapid advances in the field of metal-free, "frustrated Lewis pair" (FLP)-catalyzed hydrogenation, the need for strictly anhydrous reaction conditions has hampered wide-scale uptake of this methodology. Herein, we report that, despite the generally perceived moisture sensitivity of FLPs, 1,4-dioxane solutions of B(C6F5)3 actually show appreciable moisture tolerance and can catalyze hydrogenation of a range of weakly basic substrates without the need for rigorously inert conditions. In particular, reactions can be performed directly in commercially available nonanhydrous solvents without subsequent drying or use of internal desiccants.

Synthesis, Photochemical, and Redox Properties of Gold(I) and Gold(III) Pincer Complexes Incorporating a 2,2':6',2"-Terpyridine Ligand Framework.

Reaction of [Au(C6F5)(tht)] (tht = tetrahydrothiophene) with 2,2':6',2"-terpyridine (terpy) leads to complex [Au(C6F5)(η(1)-terpy)] (1). The chemical oxidation of complex (1) with 2 equiv of [N(C6H4Br-4)3](PF6) or using electrosynthetic techniques affords the Au(III) complex [Au(C6F5)(η(3)-terpy)](PF6)2 (2). The X-ray diffraction study of complex 2 reveals that the terpyridine acts as tridentate chelate ligand, which leads to a slightly distorted square-planar geometry. Complex 1 displays fluorescence in the solid state at 77 K due to a metal (gold) to ligand (terpy) charge transfer transition, whereas complex 2 displays fluorescence in acetonitrile due to excimer or exciplex formation. Time-dependent density functional theory calculations match the experimental absorption spectra of the synthesized complexes. In order to further probe the frontier orbitals of both complexes and study their redox behavior, each compound was separately characterized using cyclic voltammetry. The bulk electrolysis of a solution of complex 1 was analyzed by spectroscopic methods confirming the electrochemical synthesis of complex 2.

A combined "electrochemical-frustrated lewis pair" approach to hydrogen activation: surface catalytic effects at platinum electrodes.

Herein, we extend our "combined electrochemical-frustrated Lewis pair" approach to include Pt electrode surfaces for the first time. We found that the voltammetric response of an electrochemical-frustrated Lewis pair (FLP) system involving the B(C6 F5 )3 /[HB(C6 F5 )3 ](-) redox couple exhibits a strong surface electrocatalytic effect at Pt electrodes. Using a combination of kinetic competition studies in the presence of a H atom scavenger, 6-bromohexene, and by changing the steric bulk of the Lewis acid borane catalyst from B(C6 F5 )3 to B(C6 Cl5 )3 , the mechanism of electrochemical-FLP reactions on Pt surfaces was shown to be dominated by hydrogen-atom transfer (HAT) between Pt, [PtH] adatoms and transient [HB(C6 F5 )3 ](⋅) electrooxidation intermediates. These findings provide further insight into this new area of combining electrochemical and FLP reactions, and proffers additional avenues for exploration beyond energy generation, such as in electrosynthesis.

Metal-free dihydrogen oxidation by a borenium cation: a combined electrochemical/frustrated Lewis pair approach.

In order to use H2 as a clean source of electricity, prohibitively rare and expensive precious metal electrocatalysts, such as Pt, are often used to overcome the large oxidative voltage required to convert H2 into 2 H(+) and 2 e(-). Herein, we report a metal-free approach to catalyze the oxidation of H2 by combining the ability of frustrated Lewis pairs (FLPs) to heterolytically cleave H2 with the in situ electrochemical oxidation of the resulting borohydride. The use of the NHC-stabilized borenium cation [(IiPr2)(BC8H14)](+) (IiPr2=C3H2(NiPr)2, NHC=N-heterocyclic carbene) as the Lewis acidic component of the FLP is shown to decrease the voltage required for H2 oxidation by 910 mV at inexpensive carbon electrodes, a significant energy saving equivalent to 175.6 kJ mol(-1). The NHC-borenium Lewis acid also offers improved catalyst recyclability and chemical stability compared to B(C6F5)3, the paradigm Lewis acid originally used to pioneer our combined electrochemical/frustrated Lewis pair approach.

An electrochemical study of frustrated Lewis pairs: a metal-free route to hydrogen oxidation.

Frustrated Lewis pairs have found many applications in the heterolytic activation of H2 and subsequent hydrogenation of small molecules through delivery of the resulting proton and hydride equivalents. Herein, we describe how H2 can be preactivated using classical frustrated Lewis pair chemistry and combined with in situ nonaqueous electrochemical oxidation of the resulting borohydride. Our approach allows hydrogen to be cleanly converted into two protons and two electrons in situ, and reduces the potential (the required energetic driving force) for nonaqueous H2 oxidation by 610 mV (117.7 kJ mol(-1)). This significant energy reduction opens routes to the development of nonaqueous hydrogen energy technology.

Exploring the fate of the tris(pentafluorophenyl)borane radical anion in weakly coordinating solvents.

We report a kinetic and mechanistic study into the one-electron reduction of the archetypal Lewis acid tris(pentafluorophenyl)borane, B(C(6)F(5))(3), in dichloromethane and 1,2-difluorobenzene. Electrochemical experiments, combined with digital simulations, DFT computational studies and multinuclear NMR analysis allow us to obtain thermodynamic, kinetic and mechanistic information relating to the redox activity of B(C(6)F(5))(3). We show that tris(pentafluorophenyl)borane undergoes a quasi-reversible one-electron reduction followed by rapid chemical decomposition of the B(C(6)F(5))(3)˙(-) radical anion intermediate via a solvolytic radical pathway. The reaction products form various four-coordinate borates of which [B(C(6)F(5))(4)](-) is a very minor product. The rate of the follow-up chemical step has a pseudo-first order rate constant of the order of 6 s(-1). This value is three orders of magnitude larger than that found in previous studies performed in the donor solvent, tetrahydrofuran. The standard reduction potential of B(C(6)F(5))(3) is reported for the first time as -1.79 ± 0.1 V and -1.65 ± 0.1 V vs. ferrocene/ferrocenium in dichloromethane and 1,2-difluorobenzene respectively.

Evaluation of semiautomated multiplex PCR assay for determination of Streptococcus pneumoniae serotypes and serogroups.

A semiautomated method for the determination of five serotypes and three serogroups in Streptococcus pneumoniae was developed. Primers specific for serotypes 1, 3, 14, 19F, and 23F and serogroups 6, 19, and 23 were combined in three multiplex PCRs. Products were separated by capillary electrophoresis with a 7-min run time, and a serotype or serogroup was assigned on the basis of fragment size. The method was used to test 93 clinical isolates, and all isolates of the serotypes concerned were correctly detected. The strategy would allow the detection of multiple serotypes in a single sample. Detection of additional serotypes could be included as capsule locus sequences become available.