Local Consolidation Therapy (LCT) After First Line Tyrosine Kinase Inhibitor (TKI) for Patients With EGFR Mutant Metastatic Non–small-cell Lung Cancer (NSCLC)

Introduction

Although most NSCLC patients with sensitizing epidermal growth factor receptor (EGFR) mutations have an impressive initial response, the vast majority has residual disease and develops acquired resistance after 9 to 14 months of EGFR tyrosine kinase (TKI) therapy. We recently reported a phase II trial showing that, for patients with molecularly unselected oligometastatic NSCLC who did not progress after first-line systemic therapy, local consolidation therapy (LCT) with surgery or radiation improved progression-free survival (PFS), compared with maintenance therapy alone. Herein, we report a retrospective analysis of LCT after TKI in patients with metastatic EGFR mutant NSCLC.

Formulation and characterization of amphotericin B-chitosan-dextran sulfate nanoparticles

A new nanoparticulate delivery system for amphotericin B (AmB) has been developed by means of the polyelectrolyte complexation technique. Two opposite charged polymers were used to form nanoparticles through electrostatic interaction, chitosan (CH) as a positively charged polymer and dextran sulfate (DS) as a polymer with a negative charge, together with zinc sulfate as a crosslinking and hardening agent. The AmB nanoparticles obtained possessed a mean particle size of 600-800 nm with a polydispersity index of 0.2, indicating a narrow size distribution. The measured zeta potential of the nanoparticle surface was approximately -32 mV indicating a strong negative charge at the particle's surface. Scanning electron microscopy revealed spherical particles with a smooth surface. Drug association efficacy of up to 65% was achieved. Dissolution studies demonstrated a fast release behavior suggesting that AmB exhibits only moderate interaction with the weakly crosslinked polymers of the nanoparticles. Although, electronic absorbance spectra showed that the aggregation state of AmB was modified within the nanoparticles, a reduction of nephrotoxicity was observed in an in vivo renal toxicity study.     

PD-L1 Expression,Tumor Mutational Burden,and Cancer Gene Mutations Are Stronger Predictors of Benefit from Immune Checkpoint Blockade than HLA Class I Genotype in Non–Small Cell Lung Cancer

IntroductionImmune checkpoint blockade (ICB) has revolutionized the treatment of NSCLC, but only approximately 15% of patients achieve durable benefit. Understanding mechanisms of resistance to ICB is pivotal in developing more effective treatment strategies. Recent studies showed that human leukocyte antigen (HLA) class I heterozygosity might be important in mediating benefit from ICB. We aimed to investigate the impact of HLA class I genotype on outcomes of patients with NSCLC treated with ICB.MethodsWe collected HLA typing, genomic, and clinical data from patients with advanced NSCLC treated with ICB at M. D. Anderson Cancer Center. We compared HLA class I–heterozygous and HLA class I–homozygous patients for progression-free survival (PFS) and overall survival (OS). HLA I supertype/alleles were also analyzed. To validate our findings, we also analyzed two previously published independent cohorts of patients with NSCLC (the CheckMate-012 and Chowell cohorts).ResultsNo significant correlations were observed for HLA class I zygosity and PFS or OS in the M. D. Anderson Cancer Center (n = 200), CheckMate-012 (n = 75), or Chowell (n = 371) cohorts. No HLA class I supertype/allele was consistently shown to be correlated with PFS or OS. Predictors of worse outcome across the three cohorts included presence of targetable driver mutation, serine/threonine kinase 11 gene (STK11) mutation, negative programmed death ligand 1 expression, and low tumor mutational burden.ConclusionsHLA class I genotype is not correlated with survival in advanced NSCLC treated with ICB. This suggests that the impact of HLA class I diversity may be disease specific and that tumor genomic and immune markers are more impactful in predicting benefit from ICB in NSCLC.     

Encapsulation of poorly water-soluble drugs into organic nanotubes for improving drug dissolution

Hydrocortisone (HC), a poorly water-soluble drug, was encapsulated within organic nanotubes (ONTs), which were formed via the self-assembly of N-{12-[(2-α,β-d-glucopyranosyl) carbamoyl]dodecanyl}-glycylglycylglycine acid. The stability of the ONTs was evaluated in ten organic solvents, of differing polarities, by field emission transmission electron microscopy. The ONTs maintained their stable tubular structure in the highly polar solvents, such as ethanol and acetone. Furthermore, solution-state ¹H-NMR spectroscopy confirmed that they were practically insoluble in acetone at 25 °C (0.015 mg/mL). HC-loaded ONTs were prepared by solvent evaporation using acetone. A sample with a 3/7 weight ratio of HC/ONT was analyzed by powder X-ray diffraction, which confirmed the presence of a halo pattern and the absence of any crystalline HC peak. HC peak broadening, observed by solid-state ¹³C-NMR measurements of the evaporated sample, indicated the absence of HC crystals. These results indicated that HC was successfully encapsulated in ONT as an amorphous state. Improvements of the HC dissolution rate were clearly observed in aqueous media at both pH 1.2 and 6.8, probably due to HC amorphization in the ONTs. Phenytoin, another poorly water-soluble drug, also showed significant dissolution improvement upon ONT encapsulation. Therefore, ONTs can serve as an alternative pharmaceutical excipient to enhance the bioavailability of poorly water-soluble drugs.     

Molecular-level characterization of probucol nanocrystal in water by in situ solid-state NMR spectroscopy

The molecular state of colloidal probucol nanoparticles with additives was evaluated by ¹³C in situ solid-state NMR spectroscopy. The nanoparticles were obtained by dispersing a ternary co-ground mixture of probucol/polyvinylpyrrolidon (PVP)/sodium dodecyl sulfate (SDS) in water. Their mean particle size was found to be approximately 150 nm by dynamic light scattering and cryogenic-scanning electron microscopy measurements. The results of the ¹³C in situ solid-state NMR spectroscopy showed that probucol existed in the crystalline state (form I) in water. ¹³C liquid-state NMR results indicated that PVP and SDS interacted with probucol in water. Their broad signals suggested that the surface interaction of the probucol nanocrystal with PVP and SDS stabilized the suspension. In addition, a freeze-dried sample of the suspension was studied by ¹³C solid-state NMR and powder X-ray diffraction experiments, which confirmed the presence of the probucol nanocrystals. The combination of the in situ solid-state, solid-state, and liquid-state NMR measurement results provided molecular-level insights about the role of intermolecular interactions in the design of nanoformulations.     

The public’s viewpoint on the right to hastened death in Alberta,Canada: findings from a population survey study

A research study was conducted to determine public opinion in Alberta, a Canadian province, on the controversial topic of death hastening. Questions on the right to hastened death, end‐of‐life plans and end‐of‐life experiences were included in the Population Research Laboratory’s annual 2010 health‐care telephone survey, with 1203 adults providing results relatively representative of Albertans. Of all 1203, 72.6% said yes to the question: ‘Should dying adults be able to request and get help from others to end their life early, in other words, this is a request for assisted suicide’? Among all who provided an answer, 36.8% indicated ‘yes, every competent adult should have this right’ and 40.6% indicated ‘yes, but it should be allowed only in certain cases or situations’. Over 50% of respondents in all but one socio‐demographic population sub‐group (Religious‐other) were supportive of the right to hastened death. However, multinomial regression analysis revealed that the experiences of deciding to euthanise a pet/animal and developing or planning to develop an advance directive predicted support, while self‐reported religiosity predicted non‐support. Finding majority public support for death hastening suggests that legalisation could potentially occur in the future; but with this policy first requiring a careful consideration of the model of assisted suicide or euthanasia that best protects people who are highly vulnerable to despair and suffering near the end of life.     

Guest molecular size-dependent inclusion complexation of parabens with cholic acid by cogrinding

Effects of p-hydroxybenzoate (paraben) ester chain length on the stoichiometry and structure of grinding-induced inclusion complexes with cholic acid (CA) were investigated. Physicochemical properties of the ground mixture were evaluated by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, and solid-state nuclear magnetic resonance (NMR) measurements. Ethyl-, n-propyl-, and isopropyl-parabens formed equimolar inclusion complexes with CA, and the complex structures were of the β-trans bilayer type. In contrast, the stoichiometry of the CA-paraben complex was 2:1, and the structure was of the α-gauche bilayer type when isobutylparaben was used as a guest molecule. Although the stoichiometries and structures of the complexes differed, solid-state NMR showed that the molecular states of parabens in the complexes were similar and independent of the ester chain length. Complexes between CA and parabens with longer substituent groups (C >4) were not observed. Steric effects induced by increasing the guest size are likely to influence the overall structure of inclusion complexes. Mechanical forces and thermal activation by grinding were important factors in the mechanism of CA-paraben complex formation.     

Yellow coloration phenomena of incorporated indomethacin into folded sheet mesoporous materials

Solid-state (13)C nuclear magnetic resonance (NMR) spectroscopy that included relaxation time measurement was utilized to evaluate the yellow coloration of evaporated samples (EVPs) of indomethacin (IMC) with commercially available folded sheet mesoporous materials (TMPS). Colorimetric analysis by visible light reflection spectroscopy clarified the color differences in each sample: deep yellow-colored melt-quenched amorphous IMC, a slightly yellow-colored EVP of TMPS-1.5 (pore size: 1.8nm), and a yellow-colored EVP of TMPS-7 (pore size: 7.3nm). The color of EVPs changed from yellow to white after washing with ethanol, indicating the reversible coloration without a chemical reaction. Powder X-ray diffractometry and differential scanning calorimetry demonstrated that the EVPs of TMPS-7 entrapped greater amounts of amorphous IMC into the mesopore than TMPS-1.5. The amount of amorphous IMC in the mesopores could affect the strength of yellow coloration. Solid-state (13)C NMR spectroscopy that included spin-lattice relaxation time (T(1)) measurement revealed that the mobility of the aromatic rings of amorphous IMC in TMPS mesopores was higher than that in melt-quenched amorphous IMC. The difference in color between amorphous IMC in TMPS mesopores and melt-quenched amorphous IMC can be explained by their distinct intramolecular π-conjugation systems.     

Formulation and characterization of DNA-polyethylenimine-dextran sulfate nanoparticles.

Polyethylenimine (PEI) is a promising non-viral gene delivery polymer that produces high transfection efficiency both in vitro and in vivo. The use of PEI, however, is hindered by its toxicity, reflecting its polycationic nature. In an attempt to decrease this charge-dependent cytotoxicity, a polyanionic polymer, dextran sulfate (DS), has been incorporated into self-assembling PEI-DNA complexes with zinc as stabilizing agent. Spherical particles with a mean particle size of approximately 200 nm and a polydispersity index of 0.2 were achieved using the following optimal conditions: PEI solutions at pH 8, PEI/DS mass ratios of >or=2, and 25 microM zinc sulfate. Plasmid DNA was completely condensed within the nanoparticles as confirmed by an ethidium bromide accessibility assay. This result correlates well with DNase protection studies which find partial protection of the DNA nanoparticles from degradation by the enzyme. The DNA was incorporated into the PEI-DS particles with a high efficiency (>95%) and maintained a primarily supercoiled B-form as determined by gel electrophoresis and circular dichroism. The cytotoxicity of the DNA nanoparticles appeared to decrease as the amount of DS in the formulation was increased and they produced moderate transfection activities that were only modestly inhibited by the presence of serum.