Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma.

BACKGROUND: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug. METHODS: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred. CONCLUSIONS: This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

Donor-Acceptor Dyads and Triads Employing Core-Substituted Naphthalene Diimides: A Synthetic and Spectro (Electrochemical) Study.

Donor-acceptor dyads and triads comprising core-substituted naphthalene diimide (NDI) chromophores and either phenothiazine or phenoxazine donors are described. Synthesis combined with electrochemical and spectroelectrochemical investigations facilitates characterisation of the various redox states of these molecules, confirming the ability to combine arrays of electron donating and accepting moieties into single species that retain the redox properties of these individual moieties.

Artificial Graphene Nanoribbons: A Test Bed for Topology and Low-Dimensional Dirac Physics.

We synthesize artificial graphene nanoribbons by positioning carbon monoxide molecules on a copper surface to confine its surface state electrons into artificial atoms positioned to emulate the low-energy electronic structure of graphene derivatives. We demonstrate that the dimensionality of artificial graphene can be reduced to one dimension with proper "edge" passivation, with the emergence of an effectively gapped one-dimensional nanoribbon structure. These one-dimensional structures show evidence of topological effects analogous to graphene nanoribbons. Guided by first-principles calculations, we spatially explore robust, zero-dimensional topological states by altering the topological invariants of quasi-one-dimensional artificial graphene nanostructures. The robustness and flexibility of our platform allow us to toggle the topological invariants between trivial and nontrivial on the same nanostructure. Ultimately, we spatially manipulate the states to understand fundamental coupling between adjacent topological states that are finely engineered and simulate complex Hamiltonians.

Immunotargeted therapy in melanoma: patient, provider preferences, and willingness to pay at an academic cancer center.

New melanoma therapies have shifted the expectations of patients and providers. Evaluating the impact of treatment characteristics may enhance shared decision making. A survey, including a discrete choice experiment, was utilized to evaluate perceived trade-offs of different melanoma treatments and to estimate out-of-pocket (OOP) willingness-to-pay (WTP) thresholds (January 2016 to March 2016). Participants included patients with melanoma at Huntsman Cancer Institute and their cancer care providers. Stakeholder focus groups were conducted to identify treatment attributes. Descriptive and comparative statistics and multinomial logit model were used to evaluate responses. Response rates were 41.9% (N = 220) for patients and 37.7% (N = 20) for providers. Immunotherapy and targeted therapy attributes considered important by participants were overall survival, immunotherapy-related side effects, and skin toxicities. Patients and providers had significantly different views of quality-of-life expectations, anxiety toward melanoma, trust to make treatment decisions, sharing concerns about treatment, time to discuss treatment, understanding OOP costs, and willingness to undergo/recommend treatment (half of the patients would undergo treatment if it was effective for > 24 months). Among patients, the average monthly OOP WTP for combination immunotherapy with nivolumab + ipilimumab was $ 2357 and for BRAF/MEK inhibitor was $1648. Among providers, these estimates were $ 2484 and $1350, respectively. Discordance existed between patients' and providers' perceptions about quality of life expectations, degree of anxiety, sharing of opinions, and progression-free survival. Our study suggests that patients and providers exhibit a higher OOP WTP for combination immunotherapy treatment compared with BRAF/MEK inhibitors, influenced predominately by overall survival expectations.

Restricting shuttling in bis(imidazolium) pillar[5]arene rotaxanes using metal coordination.

Metal coordination to a series of bis (imidazolium)…pillar[5]arene [2]rotaxanes through the formation of metal-carbene bonds facilitates a new strategy to restrict the shuttling motion in [2]rotaxanes. Whereas the pillar[5]arene macrocycle rapidly shuttles along the full length of the bis (imidazolium) rod for the parent [2]rotaxane, Ag(i) coordination to the imidazolium groups through the formation of N-heterocyclic carbenes leads to restricted motion, effectively confining the shuttling motion of the [2]rotaxane. The Ag(i) coordinated [2]rotaxanes can be reacted further, either removing the Ag-carbene species to recreate the parent [2]rotaxane, or reaction with more bulky Pd(ii) species to further restrict the shuttling motion through steric inhibition.

Influence of Hydrogen-Bonding Interactions on Nuclearity and Structure of Palladium Tiara-like Complexes.

The role of intramolecular hydrogen-bonding interactions upon the nuclearity of palladium tiara-like complexes is reported herein. The synthesis of three palladium tiaras is described with three related thiolate ligands that vary in their hydrogen-bonding capability, amide vs ester for N-acetylcysteamine (tiara 1) vs 2-mercaptoethyl acetate (tiara 2) or ethyl thioglycolate (tiara 3), and in the relative position of the ester group, 2-mercaptoethyl acetate (2) or ethyl thioglycolate (3). Mass spectrometry indicates that, in the absence of protic solvents, N-acetylcysteamine reacts to form exclusively a six-membered tiara, [Pd(SCH2CH2NHCOCH3)2]6, 1, whereas the ester containing analogues form both six- and eight-membered tiaras. Single-crystal X-ray diffraction studies indicate the significance of intramolecular N-H···O hydrogen bonds in determining the nuclearity of the amide-containing tiara 1. NMR studies indicate that 1 is not in equilibrium with larger tiaras in solution, and that the smaller size of the aggregate inhibits the fluxional behavior of the pendant thiolate ligands, typically observed for larger tiaras. Electrochemical investigations of 1 reveal reductive processes that exhibit an increase in current upon addition of acid, along with the formation of palladium nanoparticles.

Thionated naphthalene diimides: tuneable chromophores for applications in photoactive dyads.

Varying the degree of thionation of a series of naphthalene diimide (NDI) and naphthalic imide (NI) phenothiazine dyad systems affords a systematic approach for tuning the system's donor-acceptor energy gap. Each dyad was compared to model NDI/NI systems and fully characterised through single crystal X-ray diffraction, NMR, cyclic voltammetry, electron paramagnetic resonance (EPR), transient absorption spectroscopy (TA), time-resolved infra-red spectroscopy (TRIR) and DFT. The measurements reveal that thionation increases both electron affinity of the NDI/NI acceptor dyad component and accessibility of the singly or doubly reduced states. Furthermore, FTIR and TA measurements show that excited state behaviour is greatly affected by thionation of the NDI and induces a decrease in the lifetime of the excited states formed upon the creation of charge-separated states.

Complexity of two-dimensional self-assembled arrays at surfaces.

The self-assembly of supramolecular arrays at solid surfaces is discussed with an emphasis on the degree of complexity that can be generated in such structures. The preparation of multi-component arrays is reviewed illustrating the approaches to generating many-component networks and the challenges that are encountered. The complexity of quasicrystalline and fractal molecular structures is also demonstrated along with recent developments in the synthesis of complexity perpendicular to the solid substrate through the formation of bilayer structures. Overall the importance of characterisation by scanning probe microscopy is evident in determining the complexity of structures at the molecular level.

Core-Substituted Naphthalene Diimides: Influence of Substituent Conformation on Strong Visible Absorption.

Functionalization of the aromatic core of naphthalene diimide (NDI) chromophores with morpholine substituents leads to molecules with strong absorbance in the visible spectrum. The shift of absorption maxima to lower energy is determined not only by the degree of substitution but also by the relative conformation and orientation of the tertiary amine with respect to the plane of the NDI.

Thionated perylene diimides with intense absorbance in the near-IR.

A synthetic strategy involving a combination of tetra-thionation and amine substitution in the bay region of a perylene diimide (PDI) leads to remarkable examples of neutral PDIs with intense absorption maxima in the near infrared. Generation of the corresponding monoanions red shifts the absorption profile to give short-wavelength infrared bands.