Treatment with immune checkpoint inhibitors (ICPi) has greatly improved survival for patients with advanced melanoma in recent years. Anti-CTLA-4 and anti-PD1 antibodies have been approved following ...large Phase III trials. Immune-related neurological toxicity of varying severity has been reported in the literature. The cumulative incidence of neurotoxicity among ipilimumab, nivolumab and pembrolizumab is reported as <1% in published clinical trials. We aimed to identify the incidence of neurotoxicity in our institution across anti-CTLA4 and anti-PD-1 antibodies, including the combination of ipilimumab with nivolumab. We also review the existing literature and propose an investigation and management algorithm.
All patients with advanced melanoma treated with ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab (ipi + nivo), managed at the Royal Marsden Hospital between September 2010 and December 2015, including patients on (published) clinical trials were included. Medical records for each patient were reviewed and information on neurotoxicity recorded. A systematic search strategy was performed to collate existing reports of neurological toxicity.
In total, 413 immunotherapy treatment episodes in 352 patients were included, with median follow-up of 26.7 months. Ten cases of neurotoxicity were recorded, affecting 2.8% of patients overall, ranging from grade 1 to 4, affecting both central and peripheral nervous systems. A rate of 14% was noted with ipi + nivo. Three of five patients commenced on corticosteroids responded to these. Six patients had made a full recovery at the time of reporting. A favorable radiological response was found in 7 of the 10 cases. Unusual presentations are described in detail.
Neurological toxicity is not uncommon, and may be more frequent in patients treated with combination ipi + nivo. Patterns of presentation and response to treatment are varied. A prompt and considered approach is required to optimize outcomes in this group of patients.
A vast impact on molecular nanoscience can be achieved using simple transition metal complexes as dynamic chemical systems to perform specific and selective tasks under the control of an external ...stimulus that switches "ON" and "OFF" their electronic properties. While the interest in single-ion magnets (SIMs) lies in their potential applications in information storage and quantum computing, the switching of their slow magnetic relaxation associated with host-guest processes is insufficiently explored. Herein, we report a unique example of a mononuclear cobalt(ii) complex in which geometrical constraints are the cause of easy and reversible water coordination and its release. As a result, a reversible and selective colour and SIM behaviour switch occurs between a "slow-relaxing" deep red anhydrous material (compound
) and its "fast-relaxing" orange hydrated form (compound
). The combination of this optical and magnetic switching in this new class of vapochromic and thermochromic SIMs offers fascinating possibilities for designing multifunctional molecular materials.
Abstract Background In the last decade, mTOR inhibitors (mTOR-is) have become the cornerstone of the calcineurin inhibitor (CNI)-reduced/free regimens aimed to the preservation of post-transplant ...renal function. We compared utility and safety of the total replacement of calcineurin inhibitors with a mTOR-i with a strategy based on calcineurin inhibitor minimization and concomitant use of m-TOR-i. Methods In a retrospective multi-center cohort of 394 maintenance cardiac recipients with renal failure (GFR < 60 mL/min/1.73 m2 ), we compared 235 patients in whom CNI was replaced with a mTOR-i (sirolimus or everolimus) with 159 patients in whom mTOR-is were used to minimize CNIs. A propensity score analysis was carried out to balance between group differences. Results Overall, after a median time of 2 years from mTOR-i initiation, between group differences for the evolution of renal function were not observed. In a multivariate adjusted model, improvement of renal function was limited to patients with mTOR-i usage within 5 years after transplantation, particularly with the conversion strategy, and in those patients who could maintain mTOR-i therapy. Significant differences between strategies were not found for mortality, infection and mTOR-i withdrawal due to drug-related adverse events. However, conversion group tended to have a higher acute rejection incidence than the minimization group (p = 0.07). Conclusion In terms of renal benefits, our results support an earlier use of mTOR-is, irrespective of the strategy. The selection of either a conversion or a CNI minimization protocol should be based on the clinical characteristics of the patients, particularly their rejection risk.
Three, mononuclear complexes of the formula Co(bmim)2(SCN)2 (1), Co(bmim)2(NCO)2 (2) and Co(bmim)2(N3)2 (3) bmim = 1-benzyl-2-methylimidazole were prepared and structurally analyzed by single-crystal ...X-ray crystallography. The cobalt(ii) ions in 1-3 are tetrahedrally coordinated with two bmim molecules and two pseudohalide anions. The angular distortion parameter δ was calculated and the SHAPE program (based on the CShM concept) was used for 1-3 to estimate the angular distortion from an ideal tetrahedron. The molecules of 1-3 are effectively separated, and the values of the shortest distance of cobalt-cobalt are 8.442(6) and 6.774(8) Å for 1, 10.349(8) and 10.716(8) Å for 2 and 6.778(1) and 9.232(1) Å for 3. Direct current (dc) magnetic susceptibility measurements on the crushed crystals of 1-3 were carried out in the temperature range 1.9-295 K. The variable-temperature magnetic data of 1-3 mainly obey the zero-field splitting effect (D) of the 4A2 ground term of the tetrahedral cobalt(ii) complexes (2D being the energy gap between the |±1/2 and |±3/2 levels of the spin). The analysis of their magnetic data through the Hamiltonian H = DS2z - S(S + 1)/3 + E(Sx2 - Sy2) + gβHS led to the following best-fit parameters: g = 2.29, D = -7.5 cm-1 and E/D = 0.106 (1), g = 2.28, D = + 6.3 cm-1 and E/D = 0.007 (2) and g = 2.36, D = + 6.7 cm-1 and E/D = 0.090 (3). The signs of D for 1-3 were confirmed by Q-band EPR spectra on powdered samples in the temperature range 4.0-20 K. Field-induced SIM behaviour was observed for 1-3 below 4.0 K, and the frequency-dependent maxima of χ''M were observed for 1 and only incipient signals of χ''M occurred for 2 and 3. The values of the exponential factor (τ0) and activation energy (Ea) for 1-3 which were obtained from the Arrhenius plot suggest a single relaxation process characteristic of an Orbach mechanism.
A nanoscopic {Fe
} coordination cage (approximately 3 nm) was prepared by the self assembly of a partially blocked tricyanidoferrate(iii) complex and tris(alkoxo)-based iron(iii) coordination motifs. ...This cage is a rare example of a mixed cyanido/alkoxo-bridged high nuclearity complex and it exemplifies the great potential of this new synthetic route to generate uncommon molecular architectures using cyanometallates as metalloligands versus alkoxo-based polynuclear entities.
An oxamato‐bridged CoIICuII chain compound has been obtained via the self‐assembly of mononuclear bis‐bidentate copper(II) anionic building blocks and cobalt(II) cations. It is the first example of a ...heterobimetallic ferrimagnetic chain that incorporates slow magnetic relaxation behavior (see Figure).
The coordinating properties of
N,
N′-bis(coordinating group substituted)oxamides have been thoroughly investigated both in aqueous solution and in the solid state. The easy
cis–
trans isomerization ...equilibria that they exhibit together with the great variety of
N,
N′-substituents which can be used to play on the overall charge, complexing ability and polarity, make them very suitable ligands in designing homo- and heterometallic species. The knowledge of their complex formation in aqueous solution by potentiometry and using the hydrogen ion concentration as a probe, allowed us to settle the basis of a rational design of oxamidate-containing polynuclear species whose nuclearity can be easily tuned. Concerning their electronic properties, the strong basicity of the deprotonated amide–nitrogen atoms stabilizes high oxidation states of late first-row transition metal ions. Finally, one of the most appealing aspects of this type of ligands is the remarkable efficiency they exhibit to mediate strong antiferromagnetic interactions between paramagnetic centres when acting as bridges but in order to maintain the present work within a rational length, we have omitted this last point which deserves a further review.
A one-pot strategy for the direct growth of continuous and regular thin films of a neutral oxamato-bridged heterobimetallic chain, synthesized from Co2+ nitrate and the tetramethylammonium salt of ...the anionic copper(II) complex (Me4N)2Cu(2,6-Et2pa)2·6H2O (1) (2,6-Etpa = N-2,6-diethylphenyloxamate) over Si(111) surfaces functionalized with carboxylic acid terminating groups has been developed. Variation of the growth conditions can provide important differences in the morphology of the obtained films when working in H2O at 20 °C. An anisotropic growth of 1-D fibers is observed under stoichiometric conditions (Co2+/1 = 1:1), while an isotropic growth of 3-D particles occurs for an excess of Co2+, as demonstrated by AFM. The dc magnetic measurements performed over the fiber- (3d) or particle-based films (3e) show a characteristic behavior of a 1-D ferrimagnetic chain compound. They are comparable to the ones of the bulk material of formula CoCu(2,6-Et2pa)2(H2O)2 (2) prepared in H2O at 20 °C which possesses slow magnetic relaxation effects typical of a SCM.
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Dostopno za:
BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Two new Re(iv) compounds of formulae H2tppzReCl6 (1) and Cu(bpzm)2(μ-Cl)ReCl3(μ-ox)Cu(bpzm)2(μ-ox)ReCl3(μ-Cl)n (2) tppz = 2,3,5,6-tetrakis(2-pyridyl)pyrazine and bpzm = bis(pyrazolyl-1-yl)methane ...have been prepared and their crystal structures determined by X-ray diffraction on single crystals. Compound 1 is a mononuclear species whose structure consists of octahedral hexachlororhenate(iv) anions and diprotonated H2tppz(2+) cations which are arranged in the unit cell as alternating anionic and cationic layers, held together by electrostatic forces. The structure of 2 is made up of alternating Cu(1)(bpzm)2(2+) and (ox)ReCl3(μ-Cl)Cu(2)(bpzm)2(μ-Cl)ReCl3(ox)(2-) entities interlinked by oxalate bridges to afford a neutral heterobimetallic chain. The oxalate group adopts the didentate (at Re)/monodentate (at Cu) bridging mode. The magnetic behavior of 1 and 2 has been investigated over the temperature range 1.9-295 K. 1 is a magnetically diluted Re(iv) complex, the relatively large value of the zero-field splitting of the ground level D = -15.8(2) cm(-1) accounting for the variation of χMT in the low temperature range. Weak intrachain ferromagnetic interactions between Re(iv) and Cu(ii) through oxalate (J1 = +0.15 cm(-1)) and single chloro (J2 = +4.9 cm(-1)) bridges occur in 2 which are obscured by the large zero-field splitting of the Re(iv) ion (DRe = 42 cm(-1)). In addition, interchain antiferromagnetic interactions are also involved in 2 which are responsible for the metamagnetic behavior observed, the value of the critical dc magnetic field (Hc) being 20 kOe.
The preparation, crystal structures and magnetic properties of the copper(II) complexes of formula Cu(pyim)(tcm)(2)(n) (1), Cu(bpy)(tcm)(2)(n) (2), Cu(4)(bpz)(4)(tcm)(8) (3), {Cu(terpy)(tcm).tcm}(n) ...(4) and {Cu(2)(tppz)(tcm)(4).3/2H(2)O}(n) (5) pyim = 2-(2-pyridyl)imidazole, tcm = tricyanomethanide, bpy = 2,2'-bipyridine, bpz = 2,2'-bipyrazine, terpy = 2,2':6',2''-terpyridine and tppz = 2,3,5,6-tetrakis(2-pyridyl)pyrazine are reported. Complexes, 1, 2 and 4 are uniform copper(II) chains with single- (1 and 4) and double-(2) micro-1,5-tcm bridges with values of the intrachain copper-copper separation of 7.489(1) (1), 7.520(1) and 7.758(1) (2) and 7.469(1) A (4). Each copper atom in 1, 2 and 4 is five-coordinate with bidentate pyim (1)/bpy (2) and tridentate terpy (4) ligands and nitrile-nitrogen atoms from bridging (1,2 and 4) and terminal (1) tcm groups building a distorted square pyramidal surrounding. The structure of 3 is made up of neutral centrosymmetric rectangles of (2,2'-bipyrazine)copper(II) units at the corners, the edges being built by single- and double-micro-1,5-tcm bridges with copper-copper separations of 7.969(1) and 7.270(1) A, respectively. Five- and six-coordinated copper atoms with distorted square pyramidal and elongated octahedral environments occur in . Compound 5 is a neutral copper(II) chain with regular alternating bis-tridentate tppz and double micro-1,5-tcm bridges, the intrachain copper-copper distances being 6.549(7) and 7.668(1) A, respectively. The two crystallographically independent copper atoms in 5 have an elongated octahedral geometry with three tppz nitrogen atoms and a nitrile-nitrogen atom from a bridging tcm group in the equatorial positions, and two nitrile nitrogen atoms from a terminal and a bridging tcm ligand occupying the axial sites. The investigation of the magnetic properies of 1-5 in the temperature range 1.9-295 K has shown the occurrence of weak ferro- J = +0.11(1) cm(-1) (2) and antiferromagnetic interactions J = -0.093(1) (1), -0.083(1) (4), -0.04(1) and 1.21(1) cm(-1) (3) across the micro-1,5-tcm bridges and intermediate antiferromagnetic coupling -J = 37.4(1) cm(-1) (5) through bis-tridentate tppz. The values of the magnetic interactions are analyzed through simple orbital symmetry considerations and compared with those previously reported for related systems.