Effect of early dose reduction of osimertinib on efficacy in the first-line treatment for EGFR-mutated non-small cell lung cancer.

Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.

Upfront Use of First-/Second-Generation EGFR-TKI Followed by Osimertinib Shows Better Prognosis than Upfront Osimertinib Therapy in Japanese Patients with Non-small-cell Lung Cancer with Exon 19 Deletion: A Single-Center Retrospective Study.

Clinical evidence on the increased efficacy of sequential epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) is limited. This study aimed to compare the efficacy of upfront use of first-/second-generation TKI followed by osimertinib with upfront osimertinib therapy for each representative EGFR mutation in Japanese patients with NSCLC. Patients with EGFR-mutated NSCLC were classified into two groups: first-/second-generation TKI followed by osimertinib (sequential TKI group) and upfront osimertinib groups. The total time to treatment failure (TTF) of TKI therapies, progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated. Of the 74 patients included in the analysis, 38 and 34 patients had exon 19 deletion and L858R, respectively, and other two patients had minor mutations. The sequential TKI group had a significantly longer TTF than the upfront osimertinib group in overall patients (33.2 vs. 11.2 months; p = 0.007) and in the subgroup of exon 19 deletion (36.7 vs. 10.0 months; p = 0.004), but not in the subgroup of L858R (22.6 vs. 15.6 months; p = 0.37). The similar tendency was observed in PFS. OS of the sequential TKI group was significantly longer compared with the upfront osimertinib group in overall patients, the subgroup of exon 19 deletion, and the subgroup of L858R. The upfront use of first-/second-generation TKI followed by osimertinib is one of the feasible and effective strategies in Japanese patients with EGFR-mutated NSCLC, especially in patients with exon 19 deletion.

Association of STAT3, CYP3A5, and ABCG2 Polymorphisms With Osimertinib-induced Adverse Events in NSCLC Patients.

BACKGROUND/AIM: Osimertinib is a key drug for treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Genetic differences may be associated to adverse events (AEs) induced by osimertinib. This retrospective observational multicenter study evaluated the association of genotypes, including STAT3 -1697C>G, CYP3A5 6986A>G, and ABCG2 421C>A, with the incidence of osimertinib-induced AEs in patients with EGFR mutation-positive NSCLC. PATIENTS AND METHODS: A total of 85 patients treated with osimertinib (Institution A: 33 patients, Institution B: 52 patients) were enrolled in the study. Single nucleotide polymorphisms were determined by real-time PCR, and the incidence of AEs was compared for each genotype. RESULTS: Paronychia incidence was 59% for the CC genotype, 19% for the CG genotype, and 19% for the GG genotype at STAT3 -1697C>G. A genotype-related trend was observed (Cochran-Armitage test, p=0.009). Multivariate analysis showed that the CC genotype at STAT3 -1697C>G and female sex were significant independent factors associated with paronychia [odds ratio (OR)=6.41, 95% confidence interval (CI)=1.94-21.20 and OR=3.40, 95%CI=1.03-11.22, respectively]. The incidence of diarrhea was 53% for the CC genotype, 30% for the AC genotype, and 29% for the AA genotype at ABCG2 421C>A, and a genotype-related trend was observed (p=0.048). However, the CC genotype at ABCG2 421C>A was not a significant independent factor associated with diarrhea in multivariate analysis. No significant associations were detected between other polymorphisms and the incidence of AEs. CONCLUSION: STAT3 -1697C>G may be a novel risk factor for osimertinib-induced paronychia in patients with NSCLC.

Atypical spatial frequency dependence of visual metacognition among schizophrenia patients.

Although altered early stages of visual processing have been reported among schizophrenia patients, how such atypical visual processing may affect higher-level cognition remains largely unknown. Here we tested the hypothesis that metacognitive performance may be atypically modulated by spatial frequency (SF) of visual stimuli among individuals with schizophrenia, given their altered magnocellular function. To study the effect of SF on metacognitive performance, we asked patients and controls to perform a visual detection task on gratings with different SFs and report confidence, and analyzed the data using the signal detection theoretic measure meta-d'. Control subjects showed better metacognitive performance after yes- (stimulus presence) than after no- (stimulus absence) responses ('yes-response advantage') for high SF (HSF) stimuli but not for low SF (LSF) stimuli. The patients, to the contrary, showed a 'yes-response advantage' not only for HSF but also for LSF stimuli, indicating atypical SF dependency of metacognition. An fMRI experiment using the same task revealed that the dorsolateral prefrontal cortex (DLPFC), known to be crucial for metacognition, shows activity mirroring the behavioral results: decoding accuracy of perceptual confidence in DLPFC was significantly higher for HSF than for LSF stimuli in controls, whereas this decoding accuracy was independent of SF in patients. Additionally, the functional connectivity of DLPFC with parietal and visual areas was modulated by SF and response type (yes/no) in a different manner between controls and patients. While individuals without schizophrenia may flexibly adapt metacognitive computations across SF ranges, patients may employ a different mechanism that is independent of SF. Because visual stimuli of low SF have been linked to predictive top-down processing, this may reflect atypical functioning in these processes in schizophrenia.

White matter microstructural alterations across four major psychiatric disorders: mega-analysis study in 2937 individuals.

Identifying both the commonalities and differences in brain structures among psychiatric disorders is important for understanding the pathophysiology. Recently, the ENIGMA-Schizophrenia DTI Working Group performed a large-scale meta-analysis and reported widespread white matter microstructural alterations in schizophrenia; however, no similar cross-disorder study has been carried out to date. Here, we conducted mega-analyses comparing white matter microstructural differences between healthy comparison subjects (HCS; N = 1506) and patients with schizophrenia (N = 696), bipolar disorder (N = 211), autism spectrum disorder (N = 126), or major depressive disorder (N = 398; total N = 2937 from 12 sites). In comparison with HCS, we found that schizophrenia, bipolar disorder, and autism spectrum disorder share similar white matter microstructural differences in the body of the corpus callosum; schizophrenia and bipolar disorder featured comparable changes in the limbic system, such as the fornix and cingulum. By comparison, alterations in tracts connecting neocortical areas, such as the uncinate fasciculus, were observed only in schizophrenia. No significant difference was found in major depressive disorder. In a direct comparison between schizophrenia and bipolar disorder, there were no significant differences. Significant differences between schizophrenia/bipolar disorder and major depressive disorder were found in the limbic system, which were similar to the differences in schizophrenia and bipolar disorder relative to HCS. While schizophrenia and bipolar disorder may have similar pathological characteristics, the biological characteristics of major depressive disorder may be close to those of HCS. Our findings provide insights into nosology and encourage further investigations of shared and unique pathophysiology of psychiatric disorders.

Nasal Drug Absorption from Powder Formulations: Effect of Fluid Volume Changes on the Mucosal Surface.

The effect of changes in the mucosal fluid volume on the nasal drug absorption of powder formulations was evaluated using warfarin (WF), piroxicam (PXC), and norfloxacin (NFX) as model drugs. Lactose and sodium chloride (NaCl), which are water soluble and small-sized chemicals that increase osmotic pressure after dissolution, were used as excipients to change the mucosal fluid volume. The in vitro study using a Madin-Darby canine kidney (MDCK) cell monolayer indicated that lactose and NaCl, sprayed over the surface of air interface monolayers, increased the fluid volume on the monolayer surface and enhanced the transepithelial transport of the model drugs. The in vivo animal study indicated that the nasal absorption of PXC is enhanced by lactose and NaCl after nasal administration of the powder formulations. This is likely due to the enhanced dissolution of PXC on fluid-rich nasal mucosa and an increase in the effective surface area for drug permeation, which lead to better nasal absorption. However, both excipients failed to increase the nasal absorption of WF and NFX. To clarify the mechanism of the drug-dependent effect of lactose and NaCl, the nasal residence of the formulation was examined using FD70 as a non-absorbable marker. The nasal clearance of FD70 was enhanced by lactose and NaCl, leading to a decrease in the nasal drug absorption. Lactose and NaCl caused no damage to the nasal tissue. These results indicate that the addition of water-soluble excipients such as lactose to powder formulations can enhance the nasal absorption of highly permeable but poorly soluble drugs.