Salvage therapy for BCG failure with intravesical sequential gemcitabine and docetaxel in patients with recurrent NMIBC.

INTRODUCTION: Bacillus Calmette-Guérin (BCG) failure occurs in approximately 40% of patients with non-muscle-invasive bladder cancer (NMIBC) within two years. We describe our institutional experience with sequential intravesical gemcitabine and docetaxel (gem/doce) as salvage therapy post-BCG failure in patients who were not candidates for or declined radical cystectomy (RC). METHODS: We retrospectively reviewed NMIBC patients with BCG failure who received gem/doce from April 2019 through October 2022 at the CHU de Québec-Université Laval. Patients received at least five weekly intravesical instillations according to published protocols. Patients who responded to gem/doce had maintenance instillations monthly for up to two years. Primary outcome was progression-free survival (PFS). Secondary outcomes included recurrence-free survival (RFS), cystectomy-free survival (CFS), cancer-specific survival (CSS), overall survival (OS), and treatment adverse events. Survival probabilities were estimated using the Kaplan-Meier method from the first gem/doce instillation. RESULTS: Thirty-five patients with a median age of 78 years old were included in the study. The median followup time was 21 months (interquartile range 10-29). More than 25% of patients received two or more prior BCG induction treatments. Overall and MIBC PFS estimates at one year were 85% and 88%, and at two years, 60% and 70%, respectively. Adverse events occurred in 37% of the patients, but only two patients didn't complete the treatment due to intolerance. Three patients underwent RC due to cancer progression. OS was 94% at two years. CONCLUSIONS: With 60% of PFS at two years, gem/doce appears to be a safe and well-tolerated option for BCG failure patients. Further studies are needed to justify widespread use.

Descriptive Analysis of First-Line Non-Small Cell Lung Cancer Treatment with Pembrolizumab in Tumors Expressing PD-L1 ≥ 50% in Patients Treated in Quebec's University Teaching Hospitals (DALP-First Study).

Since July 2017, pembrolizumab has been approved as a first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients with a PD-L1 score ≥ 50% in Quebec. Study objectives were to describe and assess the real-world use of pembrolizumab; report progression-free survival (PFS), overall survival (OS), and immune-related adverse events (IRAEs); and compare outcomes between a fixed dose (FD) and a weight-based capped dose (WCD). Medical records of patients treated in one of Quebec's four adult university teaching hospitals who received pembrolizumab between 1 November 2017 and 31 October 2019 were reviewed and followed until 29 February 2020. Two hundred and seventy-nine patients were included. The median real-world PFS and OS were 9.4 (95% CI, 6.6 to 11.2) and 17.3 months (95% CI, 12.9 to not reached), respectively. IRAEs causing delays or treatment interruptions were seen in 34.4% of patients. Initiating treatment with a FD (49 patients) or using a WCD (230 patients) does not appear to affect PFS, OS, or the occurrence of IRAEs. The use of a WCD strategy allowed approximately CAD 5.8 million in savings during the course of our study. These findings support the effectiveness and safety of pembrolizumab in a real-world setting. The use of a WCD does not appear to have a negative impact on patient outcomes.

Original synthesis and spectroscopic study of thiophene triazine derivatives with enhanced luminescence properties.

A straightforward access to π-conjugated oligothiophenes bearing amino-rich groups was developed. Palladium-catalyzed C-H arylation applied in the main step of the synthesis allowed to couple 2-thiophenecarbonitriles and aryl bromides with moderate to excellent yields (35-93%). Then, to improve their basic fluorescence properties, these compounds were transformed into their 2,4-diamino-1,3,5-triazine derivatives, also with good to excellent yields (74-98%). UV-Visible absorption and fluorescence studies identified a strongly emissive molecule (fluorescence quantum yield: ΦF = 0.78 ±â€¯0.05), which could find use in sensors for applications in biology and in material chemistry. We observed an antagonistic effect in the spectroscopic properties of oligothiophenes bearing 2,4-diamino-1,3,5-triazine, resulting in improved absorptive and emissive properties for more constrained structures having shorter oligothiophenes chains.

pH-mediated control over the mesostructure of ordered mesoporous materials templated by polyion complex micelles.

Ordered mesoporous silica materials were prepared under different pH conditions by using a silicon alkoxide as a silica source and polyion complex (PIC) micelles as the structure-directing agents. PIC micelles were formed by complexation between a weak polyacid-containing double-hydrophilic block copolymer, poly(ethylene oxide)-b-poly(acrylic acid) (PEO-b-PAA), and a weak polybase, oligochitosan-type polyamine. As both the micellization process and the rate of silica condensation are highly dependent on pH, the properties of silica mesostructures can be modulated by changing the pH of the reaction medium. Varying the materials synthesis pH from 4.5 to 7.9 led to 2D-hexagonal, wormlike or lamellar mesostructures, with a varying degree of order. The chemical composition of the as-synthesized hybrid organic/inorganic materials was also found to vary with pH. The structure variations were discussed based on the extent of electrostatic complexing bonds between acrylate and amino functions and on the silica condensation rate as a function of pH.

Supramolecular Chemistry-Driven Preparation of Nanostructured, Transformable, and Biologically Active Chitosan-Clustered Single, Binary, and Ternary Metal Oxide Bioplastics.

Aside from their economical cost and resource depletion, petroleum-based plastics generate annually a substantial amount of waste with a negative and extremely alarming impact on the environment and public health. Consequently, rising interest was devoted to search for biobased materials to find sustainable alternatives. Herein, we report a new and straightforward method to incorporate endogenous nano-objects (exemplified herein by metal oxide clusters) within polysaccharide-based films. Supramolecular chemistry based on polysaccharide self-assembly associated with the sol-gel polymerization allowed converting soluble chitosan and metal alkoxide precursors to nanostructured chitosan-clustered metal oxide films. A broad range of discrete single, binary, and ternary mixed metal oxides was successfully incorporated in the resulting bioplastics. The multifaceted use of these films was demonstrated by transforming them under gentle thermal treatment to partially oxidized chitosan-metal oxide materials or by disintegrating them in aqueous conditions to yield stable, water-dispersed chitosan-coated-metal oxide nanoparticles. The utility of these functional films was demonstrated through their use as antimicrobial agents, where significant improvement for inhibiting growth of positive and negative bacteria was observed compared to native, nonmodified chitosan films.

Interfacial complexation driven three-dimensional assembly of cationic phosphorus dendrimers and graphene oxide sheets.

High content nitrogen, sulfur and phosphorus heteroatoms assembled in tree-like dendrimers (DG n ) are confined within the galleries of two-dimensional graphene oxide (GO). The presence of the ternary diethyl-N-ethyl-ammonium groups on the dendrimer peripheries ensures the exfoliation of graphene sheets thereby affording interfacially bridged, three-dimensional heteroatom-enriched graphene-based hybrid nanostructures (DG n -GO). Dendrimer generation (from 1 to 4) that reflects the bulkiness of these conceived nano-trees impacts increasingly the degree of dispersion-exfoliation and sheet desordering. The long-term stability of these aqueous suspensions associated with their handling flexibility allows uniform accommodation of the resulting hybrid materials as flame-retardants in bioplastics.

Large-Pore Periodic Mesoporous Organosilicas as Advanced Bactericide Platforms.

Despite the versatility of periodic mesoporous organosilicas (PMOs), the bactericide capacity of these hybrid platforms has seldom been explored. Herein, we describe the synthesis of large-pore phenylene-bridged PMOs, mesostructured by polyion complex (PIC) micelles (PICPMOs) incorporating an antibiotic, neomycin B. A key feature of this approach is that the bioactive molecules are directly encapsulated within the PICPMOs during their formation. The engineered PICPMOs exhibit a well-ordered hexagonal mesophase with a molecular-scale crystallinity and large mesopores (8 nm), which facilitates pH-triggered delivery of the drug. The results obtained with a pathogenic Escherichia coli strain clearly demonstrate the potential of such PICPMOs for antibacterial applications.

Drug-Polymer Electrostatic Complexes as New Structuring Agents for the Formation of Drug-Loaded Ordered Mesoporous Silica.

Using aminoglycoside antibiotics as drug models, it was shown that electrostatic complexes between hydrophilic drugs and oppositely charged double-hydrophilic block copolymers can form ordered mesophases. This phase behavior was evidenced by using poly(acrylic acid)-block-poly(ethylene oxide) block copolymers in the presence of silica precursors, and this allowed preparing drug-loaded mesoporous silica directly from the drug-polymer complexes. The novel synthetic strategy of the hybrid materials is highly efficient, avoiding waste and multistep processes; it also ensures optimal drug loading and provides pH-dependence of the drug release from the materials.

Two-photon excitation of porphyrin-functionalized porous silicon nanoparticles for photodynamic therapy.

Porous silicon nanoparticles (pSiNPs) act as a sensitizer for the 2-photon excitation of a pendant porphyrin using NIR laser light, for imaging and photodynamic therapy. Mannose-functionalized pSiNPs can be vectorized to MCF-7 human breast cancer cells through a mannose receptor-mediated endocytosis mechanism to provide a 3-fold enhancement of the 2-photon PDT effect.

Self-templating amphiphilic polysiloxanes to design nanostructured silica-based architectures.

The self-assembly and sol-gel polymerisation of novel alkoxysilane-functionalized polymethylsiloxanes provide versatile access to nano-assembled containers, silica-based micro- and nano-architectures and dispersed mixed metal oxide hybrid materials.

Mesostructured fatty acid-tethered silicas: sustaining the order by co-templating with bulky precursors.

The co-condensation of functional alkoxysilanes with tetraethoxysilane in the presence of a structure directing agent under sol-gel process chemistry is a common way to access functional organosilica with an ordered mesostructure. In this report, bulky silylated fatty acid methyl esters were used both as co-templating bio-molecules and functionalizing agents in the process of supra-molecular silica mineralization. The highest structural regularity in terms of pore size distribution and channel size homogeneity was observed for carboxy-tethered silica possessing SBA-15-type architecture due to an enhanced fatty acid precursor-surfactant interaction. The carboxylic surface embedded within the hydrophobic environment of the fatty compounds confers to these materials interesting reactive-surface properties with promising applications as drug-delivery systems and bio-catalytic nanoreactors.

Efficient mesoporous silica-titania catalysts from colloidal self-assembly.

Mesoporous silica-titania materials of tunable composition and texture, which present a high catalytic activity in the mild oxidation of sulfur compounds, have been obtained by combining the spray-drying process with the colloidal self-assembly of α-chitin nanorods (biopolymer acting as a template) and organometallic oligomers.

Synthesis of stable free base secochlorins and their corresponding metal complexes from meso-tetraarylporphyrin derivatives.

Cleavage reactions of 2,3-diamino-meso-tetraarylporphyrins and meso-tetraarylporphyrins fused to imidazole rings afforded secochlorins including stable free base derivatives.

Azoic dye hosted in layered double hydroxide: physicochemical characterization of the intercalated materials.

Intercalation compounds were obtained by introduction of guest methyl orange (MO) into the interlayer space of host Mg/Al and Ni/Al layered double hydroxides (LDHs). Three synthesis methods of organic anion-LDH intercalation compounds, i.e., coprecipitation, reconstruction of the MII(Al)O mixed oxides, and anion exchange of LDH, were compared. The former method gives rise to a highly organized MO-intercalated Mg/Al LDH with an interlayer spacing of 2.43 nm and up to seven (00l) reflection orders. Reconstruction of the mixed oxide by intercalation with MO in the restored LDH was only achieved with Mg(Al)O. In this case, a competitive adsorption of MO on the external surface of the crystals was also seen. On the other hand, intercalation compounds exhibiting interlayer spacing of 2.43 nm were obtained with both Mg- and Ni-containing LDH using the anionic exchange method. The equilibrium and kinetic adsorption properties of the compounds were analyzed by UV-visible spectroscopy in anionic exchange experiments. According to the pseudo-second-order adsorption model, the amounts of adsorbed MO reach 3.82 and 2.83 mequiv/g for Mg- and Ni-containing LDHs, respectively, which are close to their respective anionic exchange capacity. The adsorption rates are on the same order of magnitude for the two LDHs (0.10-0.44 g mmol(-1) min(-1)), the equilibrium being reached in less than 60 min. The decomposition of MO by combustion of the organic moieties under an oxidizing atmosphere is delayed in Mg-containing MO-LDH hybrids when compared to the free MO molecule, showing that the thermal stability of MO species is enhanced after intercalation. In Ni-containing LDH, the main decomposition step of MO occurs 300 degrees C below that of Mg-containing LDH. This was rationalized in terms of a catalysis by the Ni-containing oxides formed during the thermal treatment. So these materials exhibit several advantages useful for the development of eco-friendly processes for the removal of dyes from effluents of textile, plastic, and paper industries.

Single-step dispersion of functionalities on a silica surface.

A new process for coating a mesoporous silica gel with a mixture of the grafting reagents para-aminophenyltrimethoxysilane and phenyltrimethoxysilane is thoroughly analyzed. The dilution of para-aminophenylsilane with phenylsilane at different ratios allows the density of the functional amino groups present on the silica surface to be controlled, while keeping constant the overall number of grafts. Furthermore, the choice of a rigid linker prevents undesirable interactions between the active function and the inorganic support that could alter the function reactivity. This simple and new method, which results in the improvement of the dispersion of a functionality in a one-pot synthesis, could be particularly interesting in the field of supported catalysis and molecular recognition. The dispersion of the functional groups of the synthesized hybrid solids is investigated using a pyrene derivative covalently linked to the free amino groups of the para-aminophenylsilanes by analyzing the excimer and monomer fluorescence properties of the probe.

Carboxy SNARF-4F as a fluorescent pH probe for ensemble and fluorescence correlation spectroscopies.

The optical spectroscopic properties of 1,4(and 5)-benzenedicarboxylic acid, 2-[10-(dimethylamino)-4-fluoro-3-oxo-3H-benzo[c]xanthen-7-yl] (carboxy SNARF-4F), a commercial promising fluorescent pH probe, are investigated in buffered aqueous solutions in the 5.6-8.2 pH range by steady-state and time-resolved spectroscopy. A multiexponential global analysis of the picosecond time-resolved data is performed. The nonprotonated A species decays monoexponentially (0.73 ns), while the protonated species AH decays following a biexponential law with time constants of 0.40 and 1.87 ns. A kinetic scheme is proposed to explain the observations, which involves AH in equilibrium with a species denoted Y. The nature of Y is discussed in terms of a possible structural change in the molecule producing the lactone form, although the formation of a hydrogen-bonded complex to the solvent cannot be ruled out. Finally, the ability of the dye to probe pH at the single-molecule level is explored using fluorescence correlation spectroscopy.

Designing the selectivity of the fluorescent detection of amino acids: a chemosensing ensemble for histidine.

The imidazole group of histidine deprotonates and bridges the two CuII centers of a dimetallic polyamine macrocyclic complex, displacing the previously bound and quenched fluorescent indicator I. Thus, histidine recognition is signaled by the revival of the fluorescence of I. Selectivity with respect to other natural amino acids is achieved by choosing an indicator of tuned affinity toward the dicopper(II) receptor.