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Plasma epidermal growth factor receptor mutation (EGFRm) circulating tumor DNA (ctDNA) dynamics exhibit promise in predicting outcomes in patients with EGFRm-advanced non-small cell lung cancer (NSCLC). However, there remains limited trial-level data on integrating ctDNA monitoring into clinical practice. We performed a prospective, multicenter trial to investigate the relationship between EGFRm ctDNA dynamic changes and clinical outcomes in NSCLC patients with EGFRm. Ninety-eight treatment-naive EGFRm-advanced NSCLC patients were recruited and administered icotinib until disease progression. Plasma samples were collected at baseline and four weeks after icotinib administration. ctDNA was analyzed using a droplet-digital polymerase chain reaction. At baseline, 71.4% of patients had detectable EGFRm ctDNA. Among them, 45.9% of patients' ctDNA became undetectable within four weeks of treatment. These patients demonstrated significantly longer progression-free survival (PFS) and overall survival (OS) than those with detectable ctDNA after treatment (P = 0.004 and < 0.001, respectively) and were comparable to those with undetectable ctDNA at both baseline and four weeks. ctDNA detectable at four weeks emerged as a poor independent risk factor for PFS and OS. Patients whose ctDNA became undetectable after treatment had outcomes similar to those with initially undetectable ctDNA, underscoring the predictive value of ctDNA dynamics in treatment efficacy. Registry and the Registration No. of the study/trial: ChiCTR-DDD-17013131. Date of registration: 2017-10-27. [ABSTRACT FROM AUTHOR]

Purpose: To establish an explainable 18F-FDG PET/CT-derived prediction model to identify EGFR mutation status and subtypes (EGFR wild, EGFR-E19, and EGFR-E21) in lung adenocarcinoma (LUAD). Methods: Baseline 18F-FDG PET/CT images of 478 patients with LUAD from 2 hospitals were collected. Data from hospital A (n = 390) was randomly split into a training group (n = 312) and an internal test group (n = 78), with data from hospital B (n = 88) utilized for external test. Further, a total of 4,760 handcrafted radiomics features (HRFs) were extracted from PET/CT scans. Candidates for the prediction model were constructed by cross-combinations of 11 feature selection methods and 7 classifiers. The optimal model was determined by combining the results of cross-center data validation and model visualization (Yellowbrick). The predictive performance was assessed via receiver operating characteristic curve, confusion matrix and classification report. Four explainable artificial intelligence technologies were used for optimal model interpretation. Results: Sex and SUVmax were selected as clinical risk factors, which were then combined with 8 robust PET/CT HRFs to establish the models. The optimal performance was obtained by combining a light gradient boosting machine classifier with random forest feature selection method achieving an optimal performance with a macro-average AUC of 0.75 in the internal test group and 0.81 in the external test group. Conclusion: The explainable EGFR mutation status prediction model have certain clinical practicability and good generalization performance, which may help in the timely selection of treatment options and prognosis prediction in patients with LUAD. [ABSTRACT FROM AUTHOR]

Objective: To investigate the prognostic value of 18F-FDG PET-based intensity, volumetric features, and deep learning (DL) across different generations of PET scanners in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma receiving tyrosine kinase inhibitor (TKI) treatment. Methods: We retrospectively analyzed the pre-treatment 18F-FDG PET of 217 patients with advanced-stage lung adenocarcinoma and actionable EGFR mutations who received TKI as first-line treatment. Patients were separated into analog (n = 166) and digital (n = 51) PET cohorts. 18F-FDG PET-derived intensity, volumetric features, ResNet-50 DL of the primary tumor, and clinical variables were used to predict progression-free survival (PFS). Independent prognosticators were used to develop prediction model. Model was developed and validated in the analog and digital PET cohorts, respectively. Results: In the analog PET cohort, female sex, stage IVB status, exon 19 deletion, SUVmax, metabolic tumor volume, and positive DL prediction independently predicted PFS. The model devised from these six prognosticators significantly predicted PFS in the analog (HR = 1.319, p < 0.001) and digital PET cohorts (HR = 1.284, p = 0.001). Our model provided incremental prognostic value to staging status (c-indices = 0.738 vs. 0.558 and 0.662 vs. 0.598 in the analog and digital PET cohorts, respectively). Our model also demonstrated a significant prognostic value for overall survival (HR = 1.198, p < 0.001, c-index = 0.708 and HR = 1.256, p = 0.021, c-index = 0.664 in the analog and digital PET cohorts, respectively). Conclusions: Combining 18F-FDG PET-based intensity, volumetric features, and DL with clinical variables may improve the survival stratification in patients with advanced EGFR-mutated lung adenocarcinoma receiving TKI treatment. Implementing the prediction model across different generations of PET scanners may be feasible and facilitate tailored therapeutic strategies for these patients. [ABSTRACT FROM AUTHOR]

We addressed the heteromerization of the epidermal growth factor receptor (EGFR) with G-protein coupled receptors (GPCR) on the basis of angiotensin-II-receptor-subtype-1(AT1R)-EGFR interaction as proof-of-concept and show its functional relevance during synergistic nuclear information transfer, beyond ligand-dependent EGFR transactivation. Following in silico modelling, we generated EGFR-interaction deficient AT1R-mutants and compared them to AT1R-wildtype. Receptor interaction was assessed by co-immunoprecipitation (CoIP), Förster resonance energy transfer (FRET) and fluorescence-lifetime imaging microscopy (FLIM). Changes in cell morphology, ERK1/2-phosphorylation (ppERK1/2), serum response factor (SRF)-activation and cFOS protein expression were determined by digital high content microscopy at the single cell level. FRET, FLIM and CoIP confirmed the physical interaction of AT1R-wildtype with EGFR that was strongly reduced for the AT1R-mutants. Responsiveness of cells transfected with AT1R-WT or –mutants to angiotensin II or EGF was similar regarding changes in cell circularity, ppERK1/2 (direct and by ligand-dependent EGFR-transactivation), cFOS-expression and SRF-activity. By contrast, the EGFR-AT1R-synergism regarding these parameters was completely absent for in the interaction-deficient AT1R mutants. The results show that AT1R-EGFR heteromerisation enables AT1R-EGFR-synergism on downstream gene expression regulation, modulating the intensity and the temporal pattern of nuclear AT1R/EGFR-information transfer. Furthermore, remote EGFR transactivation, via ligand release or cytosolic tyrosine kinases, is not sufficient for the complete synergistic control of gene expression. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

We aimed to develop and validate a deep learning-based system using pre-therapy computed tomography (CT) images to detect epidermal growth factor receptor (EGFR)-mutant status in patients with non-small cell lung cancer (NSCLC) and predict the prognosis of advanced-stage patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKI). This retrospective, multicenter study included 485 patients with NSCLC from four hospitals. Of them, 339 patients from three centers were included in the training dataset to develop an EfficientNetV2-L-based model (EME) for predicting EGFR-mutant status, and the remaining patients were assigned to an independent test dataset. EME semantic features were extracted to construct an EME-prognostic model to stratify the prognosis of EGFR-mutant NSCLC patients receiving EGFR-TKI. A comparison of EME and radiomics was conducted. Additionally, we included patients from The Cancer Genome Atlas lung adenocarcinoma dataset with both CT images and RNA sequencing data to explore the biological associations between EME score and EGFR-related biological processes. EME obtained an area under the curve (AUC) of 0.907 (95% CI 0.840–0.926) on the test dataset, superior to the radiomics model (P = 0.007). The EME and radiomics fusion model showed better (AUC, 0.941) but not significantly increased performance (P = 0.895) compared with EME. In prognostic stratification, the EME-prognostic model achieved the best performance (C-index, 0.711). Moreover, the EME-prognostic score showed strong associations with biological pathways related to EGFR expression and EGFR-TKI efficacy. EME demonstrated a non-invasive and biologically interpretable approach to predict EGFR status, stratify survival prognosis, and correlate biological pathways in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Binding kinetics play an important role in cancer diagnosis and therapeutics. However, current methods of quantifying binding kinetics fail to consider the three-dimensional environment that drugs and imaging agents experience in biological tissue. In response, a methodology to assay agent binding and dissociation in 3-D tissue culture was developed using paired-agent molecular imaging principles. To test the methodology, the uptakes of ABY-029 (an IRDye 800CW-labeled epidermal growth factor receptor (EGFR)-targeted antibody mimetic) and IRDye-700DX carboxylate in 3-D spheroids were measured in four different human cancer cell lines throughout staining and rinsing. A compartment model (optimized for the application) was then fit to the kinetic curves of both imaging agents to estimate binding and dissociation rate constants of the EGFR-targeted ABY-029 agent. A statistically significant correlation was observed between apparent association rate constant (k3) and the receptor concentration experimentally and in simulations (r = 0.99, p < 0.05). A statistically significant difference was found between effective k3 (apparent rate constant of ABY-029 binding to EGFR) values for cell lines with varying levels of EGFR expression (p < 0.05), with no significant difference found between cell lines and controls for other fit parameters. Additionally, a similar binding affinity profile compared to a gold standard method was determined by this model. This low-cost methodology to quantify imaging agent or drug binding affinity in clinically relevant 3-D tumor spheroid models can be used to guide timing of imaging in molecular guided surgery and could have implications in drug development. [ABSTRACT FROM AUTHOR]

Toxoplasmosis is a worldwide parasitic disease infecting about one-third of the human population. At present, licensed medications are incapable of curing human chronic infection. The present work aimed to evaluate for the first time the combination between (spiramycin and human platelet rich plasma), in addition to (spiramycin and silver-nanoparticles) in treating murine experimental toxoplasmosis using parasitological, biochemical, histopathological and immunohistochemical studies. Seventy-seven Swiss albino male mice divided into seven groups according to the treatment used as follows: (GI): control negative; (GII): control infected; (GIII): spiramycin; (GIV): Silver nanoparticles (AgNPs); (GV): Human platelet-rich plasma (HPRP); (GVI): combined spiramycin and AgNPs; (GVII): combined spiramycin and HPRP. Obtained results demonstrated that (spiramycin and AgNPs) treated group showed significant reduction of T. gondii tissue cysts number, the lowest level of serum malondialdehyde, remarkable improvement in pathological changes in different tissues of mice e.g. brain and liver and weak expression of EGFR in brain tissues of mice compared to control infected group. Moreover, AgNPs administered alone produced minimal anti-Toxoplasma results, whereas their combination with spiramycin exhibited significant therapeutic efficacy. In conclusion, combination therapy of spiramycin and AgNPs may represent a unique possible adjuvant therapy for reducing the pathogenic, toxic, and inflammatory consequences of toxoplasmosis on the brain and liver tissues in immunocompetent mice, and the expression of EGFR in brain tissues of mice is a good tool for evaluating the therapeutic improvement of murine toxoplasmosis. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor alpha (TNF-α), an abundant inflammatory cytokine in the tumor microenvironment (TME), is linked to breast cancer growth and metastasis. In this study, we established MCF10A cell lines incubated with TNF-α to investigate the effects of continuous TNF-α exposure on the phenotypic change of normal mammary epithelial cells. The established MCF10A-LE cell line, through long-term exposure to TNF-α, displayed cancer-like features, including increased proliferation, migration, and sustained survival signaling even in the absence of TNF-α stimulation. Unlike the short-term exposed cell line MCF10A-SE, MCF10A-LE exhibited elevated levels of epidermal growth factor receptor (EGFR) and subsequent TNF receptor 2 (TNFR2), and silencing of EGFR or TNFR2 suppressed the cancer-like phenotype of MCF10A-LE. Notably, we demonstrated that the elevated levels of NAD(P)H oxidase 4 (NOX4) and the resulting increase in reactive oxygen species (ROS) were associated with EGFR/TNFR2 elevation in MCF10A-LE. Furthermore, mammosphere-forming capacity and the expression of cancer stem cell (CSC) markers increased in MCF10A-LE. Silencing of EGFR reversed these effects, indicating the acquisition of CSC-like properties via EGFR signaling. In conclusion, our results reveal that continuous TNF-α exposure activates the EGFR/TNFR2 signaling pathway via the NOX4/ROS axis, promoting neoplastic changes in mammary epithelial cells within the inflammatory TME. [ABSTRACT FROM AUTHOR]

Objective: To determine whether quantitative parameters of detector-derived dual-layer spectral computed tomography (DLCT) can reliably identify epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC). Methods: Patients with NSCLC who underwent arterial phase (AP) and venous phase (VP) DLCT between December 2021 and November 2022 were subdivided into the mutated and wild-type EGFR groups following EGFR mutation testing. Their baseline clinical data, conventional CT images, and spectral images were obtained. Iodine concentration (IC), iodine no water (INW), effective atomic number (Zeff), virtual monoenergetic images, the slope of the spectral attenuation curve (λHU), enhancement degree (ED), arterial enhancement fraction (AEF), and normalized AEF (NAEF) were measured for each lesion. Results: Ninety-two patients (median age, 61 years, interquartile range [51, 67]; 33 men) were evaluated. The univariate analysis indicated that IC, normalized IC (NIC), INW and ED for the AP and VP, as well as Zeff and λHU for the VP were significantly associated with EGFR mutation status (all p < 0.05). INW(VP) showed the best diagnostic performance (AUC, 0.892 [95% confidence interval {CI}: 0.823, 0.960]). However, neither AEF (p = 0.156) nor NAEF (p = 0.567) showed significant differences between the two groups. The multivariate analysis showed that INW(AP) and NIC(VP) were significant predictors of EGFR mutation status, with the latter showing better performance (p = 0.029; AUC, 0.897 [95% CI: 0.816, 0.951] vs. 0.774 [95% CI: 0.675, 0.855]). Conclusion: Quantitative parameters of DLCT can help predict EGFR mutation status in patients with NSCLC. Critical relevance statement: Quantitative parameters of DLCT, especially NIC(VP), can help predict EGFR mutation status in patients with NSCLC, facilitating appropriate and individualized treatment for them. Key Points: Determining EGFR mutation status in patients with NSCLC before starting therapy is essential. Quantitative parameters of DLCT can predict EGFR mutation status in NSCLC patients. NIC in venous phase is an important parameter to guide individualized treatment selection for NSCLC patients. [ABSTRACT FROM AUTHOR]

The mammalian skin and its appendages depend on tightly coordinated differentiation of epithelial cells. Epidermal growth factor receptor (EGFR) pathway substrate 8 (EPS8) like 1 (EPS8L1) is enriched in the epidermis among human tissues and has also been detected in the epidermis of lizards. Here, we show by the analysis of single-cell RNA-sequencing data that EPS8L1 mRNA is co-expressed with filaggrin and loricrin in terminally differentiated human epidermal keratinocytes. Comparative genomics indicated that EPS8L1 is conserved in all main clades of mammals, whereas the orthologous gene has been lost in birds. Using a polyclonal antibody against EPS8L1, we performed an immunohistochemical screening of skin from diverse mammalian species and immuno-electron microscopy of human skin. EPS8L1 was detected predominantly in the granular layer of the epidermis in monotremes, marsupial, and placental mammals. The labeling was partly associated with cell membranes, and it was evident along the perimeter of keratinocytes at the transition with the cornified layer of the epidermis, similar to involucrin distribution. Basal, spinous, and the fully mature cornified layers lacked immunolabeling of EPS8L1. In addition to the epidermis, the hair follicle inner root sheath (IRS) was immunolabeled. Both epidermal granular layer and IRS contribute to the barrier function of the skin, suggesting that EPS8L1 is involved in the regulation of these barriers. [ABSTRACT FROM AUTHOR]

Purpose: Evaluate overall survival (OS), RAS, BRAF, and MSI frequencies in patients with metastatic colorectal cancer (mCRC), refractory to chemotherapy, and finally treated with cetuximab. Methods: A retrospective cohort study to evaluate 211 mCRC patients with wild-type KRAS treated with cetuximab. BRAF V600E, KRAS, NRAS gene mutations, and MSI status were identified using PCR techniques in a population of pre-treated patients who were refractory to fluoropyrimidines, oxaliplatin, and irinotecan. In addition, we evaluated the mutation frequency of the BRAF and NRAS genes and the MSI status of this population. Uni- and multivariate analyses were performed for independent prognostic factors of OS. Results: The median OS was 10.4 months, 6.6 months for patients with right and 11.5 months for left colon cancers (p = 0.02). The frequencies of mutations were BRAF at 3.9% (median OS of 4.9 months), NRAS at 3.38% (median OS of 6.9 months), and MSI-High status at 3.3% (median OS of 4.6 months). The OS, NRAS, and MSI frequencies were similar to those found in other studies that evaluated cetuximab in poly-treated patients and were associated with lower survival rates in univariate analyses. The frequency of BRAF mutations was lower than that found in previous studies. The only variable that remained significant for OS in the multivariate model was tumour laterality, with patients with right colon cancer presenting a worse prognosis (HR = 2.81). Conclusion: Although BRAF, NRAS mutations, and MSI-High status were associated with shorter OS in univariate analyses, only tumour laterality remained an independent prognostic factor in the multivariate analysis. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the associations between the clinical characteristics and effectiveness of anti-PD-1 inhibitors in patients with EGFR-sensitive mutations, aiming to identify the potential subgroup of patients who might benefit from anti-PD-1 inhibitor treatment. Patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-sensitive mutations who received subsequent anti-PD-1 inhibitors in combination with chemotherapy/antiangiogenic agents or alone after progression to tyrosine kinase inhibitors (TKIs) were screened. Clinical characteristics, including hematological parameters, were investigated for potential correlations with clinical outcomes. Subgroup and multivariate analyses were used for further confirmation of the relationship. Kaplan–Meier curves and Cox survival regression models using the log-rank test were used for progression-free survival (PFS) and overall survival (OS) assessments between the groups. Multiple regression analysis was performed using the standard regression coefficient values. The Wilcoxon test was used for the analysis of the variation in NLR. P ≤ 0.05 was considered to indicate statistical significance. This study was a retrospective study. Twenty-two patients met the inclusion criteria and were included in the study. The median PFS was 3.05 months (95% CI, 2.9–10.2 months). The median OS was 7.30 months (95% CI, 5.2–18.1 months). PFS in low neutrophil to lymphocyte ratio (NLR ≤ 4) was significantly longer than high NLR (NLR > 4, 5.7 months versus 2.0 months, HR, 0.35, 95% CI, 0.08–0.63, P = 0.0083). The OS in the low NLR group was also significantly better than that in the high NLR group (OS, 21.3 months versus 5.0 months, HR, 0.33; 95% CI, 0.09–0.74; P = 0.0163). In the multivariate analysis, NLR was the only significant factor for OS benefits (β = 3.535, 95% CI, 1.175–10.636, P = 0.025). Further investigation revealed that front-line TKIs exposure may contribute to the elevation or decrease of NLR, and finally lead to different efficacy outcomes by anti-PD-1 inhibitors. The findings suggest that a portion of advanced NSCLC patients with low NLR characteristics (NLR ≤ 4), even those harboring EGFR-sensitive mutations, could benefit from anti-PD-1 inhibitors as further line treatment after progression to EGFR-TKIs. [ABSTRACT FROM AUTHOR]

Background: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site. The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for EAI045, thus increasing the potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential, and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium. Results: 2-(5-fluoro-2-hydroxyphenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of EAI045, respectively. [11C]EAI045 was synthesized using [11C]CO in a palladium-catalyzed ring closure in a 10 ± 1% radiochemical yield (decay corrected to end of [11C]CO2 production), > 97% radiochemical purity and 26 ± 1 GBq/µmol molar activity (determined at end of synthesis) in 51 min. [3H]EAI045 was synthesized by a tritium-halogen exchange in a 0.2% radiochemical yield, 98% radiochemical purity, and 763 kBq/nmol molar activity. The ability of [11C]EAI045 to differentiate between L858R/T790M mutated EGFR expressing H1975 xenografts and wild-type EGFR expressing A549 xenografts was evaluated in female nu/nu mice. The uptake was statistically significantly higher in H1975 xenografts compared to A549 xenografts (0.45 ± 0.07%ID/g vs. 0.31 ± 0.10%ID/g, P = 0.0166). The synergy in inhibition between EAI045 and cetuximab was evaluated in vivo and in vitro. While there was some indication that cetuximab influenced the uptake of [3H]EAI045 in vitro, this could not be confirmed in vivo when tumor-bearing mice were administered cetuximab (0.5 mg), 24 h prior to injection of [11C]EAI045. Conclusions: EAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [11C]EAI045 may be able to distinguish between mutated and non-mutated EGFR in non-small cell lung cancer mouse models. Cetuximab was hypothesized to increase EAI045 uptake; however, no significant effect was observed on the uptake of [11C]EAI045 in vivo or [3H]EAI045 in vitro in H1975 xenografts and cells. [ABSTRACT FROM AUTHOR]

Background: Targeted therapies against programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) have revolutionized the management in recent years. There is paucity of data on the significance of PD-L1 expression in NSCLC from India. We aimed to study the prevalence of PD-L1 expression and its relation with different clinico-pathological parameters in advanced NSCLC from a tertiary care center in Eastern India. Methods: All consecutive patients with advanced NSCLC diagnosed from January 2020 to December 2021 were prospectively evaluated for PD-L1 expression in formalin fixed-paraffin embedded tumor tissue specimens using immunohistochemistry analysis. A PD-L1 expression of < 1%, 1–49%, and ≥ 50% were considered negative, low, and high expression positive respectively, and association with various parameters was performed. Results: Out of the 94 patients (mean age 59.6 ± 14 years and 63.8% males), PD-L1 positivity was seen in 42 (44.7%) patients, with low positivity (1–49%) in 29 patients and high positivity (≥ 50%) in 13 patients. Epidermal Growth Factor Receptor (EGFR) mutations were seen in 28 patients (29.8%). There were no significant differences in PD-L1 positivity with respect to gender, age, and molecular mutation status. PD-L1 positivity was significantly associated with tobacco use (p = 0.04), advanced tumor stage (p < 0.001), and higher nodal stage (p < 0.001). Median overall survival in the cohort was 17 months and it was not significantly different between the PD-L1 positive and negative groups. Conclusions: Forty-five percent of advanced NSCLC patients in our cohort showed positive PD-L1 expression and it is associated with tobacco use and aggressive tumor characteristics. [ABSTRACT FROM AUTHOR]

The disruptor of telomeric silencing 1-like (DOT1L), a specific histone methyltransferase that catalyzed methylation of histone H3 on lysine 79, was associated with the pathogenesis of many diseases, but its role in peritoneal fibrosis remained unexplored. Here, we examined the role of DOT1L in the expression and activation of protein tyrosine kinases and development of peritoneal fibrosis. We found that a significant rise of DOT1L expression in the fibrotic peritoneum tissues from long-term PD patients and mice. Inhibition of DOT1L significantly attenuated the profibrotic phenotypic differentiation of mesothelial cells and macrophages, and alleviated peritoneal fibrosis. Mechanistically, RNA sequencing and proteomic analysis indicated that DOT1L was mainly involved in the processes of protein tyrosine kinase binding and extracellular matrix structural constituent in the peritoneum. Chromatin immunoprecipitation (ChIP) showed that intranuclear DOT1L guided H3K79me2 to upregulate EGFR in mesothelial cells and JAK3 in macrophages. Immunoprecipitation and immunofluorescence showed that extranuclear DOT1L could interact with EGFR and JAK3, and maintain the activated signaling pathways. In summary, DOT1L promoted the expression and activation of tyrosine kinases (EGFR in mesothelial cells and JAK3 in macrophages), promoting cells differentiate into profibrotic phenotype and thus peritoneal fibrosis. We provide the novel mechanism of dialysis-related peritoneal fibrosis (PF) and the new targets for clinical drug development. DOT1L inhibitor had the PF therapeutic potential. [ABSTRACT FROM AUTHOR]

Purpose: The ADAURA trial demonstrated the superiority of osimertinib over a placebo with regard to disease-free survival, showing it to be indicated as an adjuvant therapy for treatment of non–small cell lung cancer with mutated epidermal growth factor receptor (EGFR). The aim of the present study was to conduct a cost-utility analysis and an analysis of the budgetary impact of adjuvant therapy with osimertinib in patients with non–small cell lung cancer with mutated EGFR who had undergone resection surgery with curative intent. Methods: Analyses were based on the outcomes of the ADAURA clinical trial and were conducted through a Spanish National Health Service perspective. The outcome measures used were quality-adjusted life years (QALY). Results: The average overall cost of adjuvant treatment with osimertinib over a period of 100 months in the overall sample of trial patients (stages IB-IIIA) was 220,961 €, compared with 197,849 € in the placebo group. Effectiveness, estimated according to QALY, was 6.26 years in the osimertinib group and 5.96 years in the placebo group, with the incremental cost-utility ratio being 77,040 €/QALY. With regard to the budgetary impact, it was estimated that, in 2021, approximately 1130 patients would be subsidiaries to receive osimertinib. This pertains to a difference of 17,375,330 € over 100 months to fund this treatment relative to no treatment. Conclusion: Taking into account a Spanish threshold of 24,000 €/QALY, the reduction in the acquisition cost of osimertinib will have to be greater than 10%, to obtain a cost-effective alternative. [ABSTRACT FROM AUTHOR]

Sorafenib (SOR) is a molecular targeting agent commonly utilized as a primary treatment for advanced and inoperable hepatocellular carcinoma (HCC). Regrettably, the effectiveness of SOR is frequently hindered by the resistance of multiple HCC cases. The current investigation endeavors to examine the potential of the natural product quercetin (QUE) in reversing the acquired resistance of SOR-resistant cells, known as Huh7R, to SOR. Moreover, this study aims to elucidate the underlying molecular mechanism that contributes to this phenomenon. The results demonstrated that QUE significantly impeded proliferation and stimulated apoptosis in Huh7R cells, while also suppressing the growth of transplanted tumors. The impact of QUE enhanced the efficacy of SOR treatment for Huh7R. Additionally, bioinformatic and western blot analyses indicated that the underlying mechanisms may be associated with EGFR tyrosine kinase inhibitor resistance, the PI3K-AKT signaling pathway, and HCC. Furthermore, molecular docking and dynamics simulation assays revealed that QUE exhibited strong affinity and stability towards its hub targets, EGFR and AKT1. It is noteworthy that the activation of EGFR by its ligand, EGF, mitigated the effects of co-treatment with QUE and SOR. These findings suggest that QUE might potentially serve as a therapeutic agent in treating as well as facilitating SOR against Huh7R cells, which has substantial clinical and research implications for the treatment of acquired resistance to SOR in HCC. [ABSTRACT FROM AUTHOR]

Medulloblastoma (MB) is a heterogeneous group of malignant pediatric brain tumors, divided into molecular groups with distinct biological features and prognoses. Currently available therapy often results in poor long-term quality of life for patients, which will be afflicted by neurological, neuropsychiatric, and emotional sequelae. Identifying novel therapeutic agents capable of targeting the tumors without jeopardizing patients' quality of life is imperative. Rosmarinic acid (RA) is a plant-derived compound whose action against a series of diseases including cancer has been investigated, with no side effects reported so far. Previous studies have not examined whether RA has effects in MB. Here, we show RA is cytotoxic against human Daoy (IC50 = 168 μM) and D283 (IC50 = 334 μM) MB cells. Exposure to RA for 48 h reduced histone deacetylase 1 (HDAC1) expression while increasing H3K9 hyperacetylation, reduced epidermal growth factor (EGFR) expression, and inhibited EGFR downstream targets extracellular-regulated kinase (ERK)1/2 and AKT in Daoy cells. These modifications were accompanied by increased expression of CDKN1A/p21, reduced expression of SOX2, and a decrease in proliferative rate. Treatment with RA also reduced cancer stem cell markers expression and neurosphere size. Taken together, our findings indicate that RA can reduce cell proliferation and stemness and induce cell cycle arrest in MB cells. Mechanisms mediating these effects may include targeting HDAC1, EGFR, and ERK signaling, and promoting p21 expression, possibly through an increase in H3K9ac and AKT deactivation. RA should be further investigated as a potential anticancer agent in experimental MB. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with an overall poor prognosis after diagnosis. Conventional treatment includes resection, chemotherapy with temozolomide (TMZ), and concomitant radiotherapy (RT). The recent success of immunotherapy approaches in other tumor entities, particularly with immune checkpoint inhibitors, could not be clinically transferred to GBM treatment so far. Therefore, preclinical analyses of the expression of both immune-suppressive and immune-stimulatory checkpoint molecules following treatment of human glioblastoma cells with RT and/or temozolomide is needed to design feasible radio(chemo)immunotherapy trials for GBM in the future. Methods: Five human glioblastoma cell lines (H4, HROG-06, U118, U138, U251) were analyzed regarding their clonogenic survival and cell death forms after chemotherapy (CT) with TMZ and/or normofractionated RT (5 × 2 Gy) via multicolor flow cytometry. Further, the tumor cell surface expression of immune-activating (OX40L, CD137L, CD70, and ICOSL) and immune-suppressive (PD-L1, PD-L2, HVEM) checkpoint molecules and of an oncogenic molecule (EGFR) were measured via multicolor flow cytometry after CT and RT alone or after RCT. Results: Normofractionated RT and not TMZ was the trigger of induction of predominantly necrosis in the glioblastoma cells. Notably, clonogenicity did not correlate with cell death induction by RT. The basal expression level of immune-suppressive PD-L1, PD-L2, and HVEM varied in the analyzed glioblastoma cells. RT, but not TMZ, resulted in a significant upregulation of PD-L1 and PD-L2 in all tumor cells investigated. Also, the expression of HVEM was increased after RT in most of the GBM cell lines. In contrast, normofractionated RT individually modulated expression of the stimulating immune checkpoint molecules CD70, CD137L, OX40L, and ICOSL1. The oncogenic factor EGFR was significantly increased by irradiation in all examined cell lines, albeit to a different extent. None of the investigated molecules were downregulated after the treatments. Conclusion: Normofractionated radiotherapy modulates the immunogenic as well as the oncogenic phenotype of glioblastoma cells, partly individually. Therefore, not only PD-L1 and PD-L2, but also other immunogenic molecules expressed on the surface of glioblastoma cells could serve as targets for immune checkpoint blockade in combination with RT in the future. [ABSTRACT FROM AUTHOR]

Opinion statement: With the development of molecular biology and histology techniques, targeted therapy for non-small cell lung cancer (NSCLC) has emerged, which is highly effective and has marginal side effects. Epidermal growth factor receptor (EGFR) was the first driver gene discovered, whose three generations of therapeutic use have its characteristics and benefits in clinical practice. However, cardiovascular complications by EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in preclinical studies have been increasingly reported, including heart failure, cardiomyopathy, and QT prolongation, among others. Cardiotoxicity of targeted drugs significantly affects the therapeutic effect of NSCLC and has become the second leading cause of death in NSCLC. The aim of the present review was to recognize the potential cardiotoxicity of third-generation targeted drugs in the treatment of NSCLC and their associated mechanisms to help clinicians identify and prevent it early in the treatment, minimize the cardiotoxicity of targeted drugs, and improve the therapeutic effect of patients. [ABSTRACT FROM AUTHOR]

Purpose: SIBP04 is a bevacizumab biosimilar, and bevacizumab combined with carboplatin and paclitaxel in advanced non-squamous non-small-cell lung cancer (nsqNSCLC) has been recommended as the first-line treatment choice. However, the efforts of bevacizumab combined with carboplatin and paclitaxel for nsqNSCLC patients with EGFR mutation remained unclear. Here we report an EGFR mutation subgroup analysis of a prospective, randomized phase III clinical trial (NCT05318443). Methods: In this randomized, double-blind, multi-center, parallel controlled, phase III clinical trial, locally advanced, metastatic NSCLC patients were enrolled, and EGFR expression was examined and considered as a stratification factor. All patients received 4 to 6 cycles of paclitaxel and carboplatin plus SIBP04 or bevacizumab 15 mg/kg intravenously followed by SIBP04 15 mg/kg maintenance until intolerable toxicity, disease progression or death. Patients with EGFR mutation and wild-type were assessed for progression-free survival (PFS) and overall survival (OS). Results: EGFR expression was examined in 398 NSCLC patients (142 with EGFR mutation, 256 with EGFR wild type). PFS in EGFR mutation patients was significantly longer than EGFR wild-type patients (10.91 vs. 7.82 months; HR = 0.692, 95% CI 0.519–0.921, P = 0.011). The median OS in patients with EGFR mutation was not reached while that of EGFR wild-type group was 17.54 months (HR = 0.398, 95% CI 0.275–0.575, P < 0.001). However, there were no significant differences in objective response rate (61.97% vs. 55.86%, P = 0.237) or disease control rate (90.14% vs. 89.84%, P = 0.925). Conclusion: Bevacizumab combined with chemotherapy significantly prolonged the PFS and OS of advanced nsqNSCLC patients with EGFR mutation. [ABSTRACT FROM AUTHOR]

Introduction: Docetaxel is an established standard therapy after osimertinib and platinum-based doublet chemotherapy (Pt-doublet) for locally advanced or metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor gene (EGFR) mutation. To facilitate future therapeutic developments in these patients after treatment with osimertinib and Pt-doublet, we estimated the outcomes of currently used post-treatment therapies. Methods: Data of patients with NSCLC who received at least one medication after osimertinib and Pt-doublet between April 2008 and August 2021 were extracted from the Medical Data Vision claims database. The duration of treatment (DoT) (first treatment after osimertinib and Pt-doublet) and overall survival (OS) were estimated. The index date was the first day on which the medication was prescribed. Results: In total, 731 patients (mean age 64 years) were screened. The most frequent post-treatments were docetaxel-based chemotherapy (30.2%), immune checkpoint inhibitor (ICI) alone or in combination (17.2%), first-/second-generation EGFR-tyrosine kinase inhibitors (16.7%), osimertinib (16.3%), and Pt-doublet (5.2%). The median DoT and OS (95% confidence interval) of all post-treatments were 3.5 (3.27, 3.77) and 10.3 (9.3, 12.1) months, respectively, reflecting the median DoT (3.8 months) and OS (10.0 months) of docetaxel-based chemotherapy. Among all post-treatment regimens, ICIs resulted numerically the shortest [2.77 (2.33, 3.00) months] and osimertinib the longest [4.40 (3.47, 5.67) months] median DoT. The median OS was shortest in patients post-treated with ICIs [7.07 (5.40, 9.90) months] and longest in patients rechallenged with Pt-doublet (12.27 months), followed by patients post-treated with osimertinib (11.70 months). In a subset analysis of patients who received first-line osimertinib and second-line Pt-doublet as well as Pt-doublet immediately after osimertinib, those post-treated with ICIs had the shortest median DoT. Conclusion: Given the limited real-world efficacy on EGFR-mutant NSCLC resistant to osimertinib and platinum-based chemotherapy, the development of more highly potent post-treatment therapies is warranted. [ABSTRACT FROM AUTHOR]

Purpose: ASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non–small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study. Methods: Adults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0–2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety. Results: A total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53–0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1–12.5) and 13.9 months (95% CI 13.1–15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively. Conclusion: Osimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified. Clinical trial number: NCT02474355. [ABSTRACT FROM AUTHOR]

Purpose: Epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) are associated with poor prognosis and resistance to traditional therapies in patients with non–small cell lung cancer (NSCLC). We aimed to elucidate the characteristics and treatment patterns to improve outcomes among this population in Taiwan. Methods: Patients with advanced or recurrent NSCLC harboring EGFR ex20ins from 2011 to 2021 were reviewed. The treatment groups were classified as platinum-based chemotherapy (PtC), EGFR tyrosine kinase inhibitor (TKI), and others. The response to therapy, objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and factors associated with survival were analyzed. Results: Among the 71 patients, most were never-smoking males with stage IVB adenocarcinoma. The most common first-line (1L) regimen was PtC, followed by TKI. The most common second-line (2L) regimen was TKI. The median PFS of 1L treatment was 5.03 months, and the median OS was 18.43 months. Compared with that of TKI, 1L PtC use was associated with a higher ORR (26.3% vs. 9.1%) and DCR (60.5% vs. 18.2%) and a longer PFS (5.37 vs. 3.13 months, p = 0.044). PFS was also significantly longer in the 2L PtC group than in the 2L TKI group (4.73 vs. 2.25 months, p = 0.047). No patients receiving an immune checkpoint inhibitor–based regimen exhibited a therapeutic response. Conclusion: This study demonstrated the heterogeneous clinical characteristics and treatment pattern of NSCLC patients with EGFR ex20ins, underscoring the need for more effective therapies for this distinct molecular subtype. [ABSTRACT FROM AUTHOR]

A new electrochemiluminescence (ECL) cytosensor is proposed for the simultaneous determination of phosphatidylserine (PS) and epidermal growth factor receptor (EGFR) based on the ECL signals of metal-organic framework-5 (MOF-5) loaded CdS quantum dots and N-(aminobutyl)-N-(ethylisoluminol)-polyethylenimine capped Au and Ag nanoparticles. Apoptosis promotes the exposure of PS and reduces the expression of EGFR in cell membranes. Two spatially resolved areas on dual-disk glassy carbon electrodes were designed to eliminate the interference from different ECL probes. Using HepG2 cells treated with resveratrol to induce apoptosis, the cytosensor exhibited high sensitivity, simplicity, and high reproducibility, demonstrating its potential in drug screening and rapid apoptotic cell detection. The strategy reported provides a promising platform for the highly sensitive cytosensing and convenient screening of clinically relevant anticancer drugs. [ABSTRACT FROM AUTHOR]

Purpose: Given the availability of TKIs with high central nervous system efficacy, the question arises as to whether upfront SRS provides additional clinical benefits. The goal of this study was to characterize the clinical outcomes of SRS as salvage therapy for TKI-uncontrolled BMs. Methods: This retrospective study included EGFR-mutant NSCLC patients presenting BMs at the time of primary tumor diagnosis. BMs were categorized into three subgroups, referred to as "Nature of TKI-treated BMs", "TKI-controlled brain metastases ± SRS", and "SRS salvage therapy". The first subgroup analysis characterized the effects of TKIs on tumor behavior. In the second subgroup, we compared outcomes of TKI-controlled BMs treated with TKI alone versus those treated with combined TKI-SRS therapy. The third subgroup characterized the outcomes of TKI-uncontrolled BMs treated with SRS as salvage therapy Clinical outcomes include local and distant tumor control. Results: This study included 106 patients with a total of 683 BMs. TKI treatment achieved control in 63% of local tumors at 24 months. Among the TKI-controlled BMs, local tumor control was significantly higher in the combined TKI-SRS group (93%) than in the TKI-alone group (65%) at 24 months (p < 0.001). No differences were observed between the two groups in terms of distant tumor control (p = 0.832). In dealing with TKI-uncontrolled BMs, salvage SRS achieved local tumor control in 58% of BMs at 24 months. Conclusions: While upfront TKI alone proved highly effective in BM control, this study also demonstrated the outcomes of SRS when implemented concurrently with TKI or as salvage therapy for TKI-uncontrolled BMs. This study also presents a strategy of the precise timing and targeting of SRS to lesions in progression. [ABSTRACT FROM AUTHOR]

Purpose: Patients with EGFR-mutated NSCLC represent a unique subset of lung cancer patients with distinct clinical and molecular characteristics. Previous studies have shown a higher incidence of brain metastases (BM) in this subgroup of patients, and neurologic death has been reported to be as high as 40% and correlates with leptomeningeal disease (LMD). Methods: Between 2012 and 2021, a retrospective review of our prospective registry identified 606 patients with BM from NSCLC, with 170 patients having an EGFR mutation. Demographic, clinical, radiographic, and treatment characteristics were correlated to the incidence of LMD and survival. Results: LMD was identified in 22.3% of patients (n = 38) at a median follow-up of 19 (2–98) months from initial SRS. Multivariate regression analysis showed targeted therapy and a cumulative number of metastases as significant predictors of LMD (p = 0.034, HR = 0.44), (p =.04, HR = 1.02). The median survival time after SRS of the 170 patients was 24 months (CI 95% 19.1–28.1). In a multivariate Cox regression analysis, RPA, exon 19 deletion, and osimertinib treatment were significant predictors of overall survival. The cumulative incidence of neurological death at 2 and 4 years post initial stereotactic radiosurgery (SRS) was 8% and 11%, respectively, and correlated with LMD. Conclusion: The study shows that current-generation targeted therapy for EGFR-mutated NSCLC patients may prevent the development and progression of LMD, leading to improved survival outcomes. Nevertheless, LMD is associated with poor outcomes and neurologic death, making innovative strategies to treat LMD essential. [ABSTRACT FROM AUTHOR]

Purpose: To develop and validate a dynamic contrast-enhanced (DCE) MRI-based radiomics model to predict epidermal growth factor receptor (EGFR) amplification in patients with glioblastoma, isocitrate dehydrogenase (IDH) wildtype. Methods: Patients with pathologically confirmed glioblastoma, IDH wildtype, from January 2015 to December 2020, with an EGFR amplification status, were included. Patients who did not undergo DCE or conventional brain MRI were excluded. Patients were categorized into training and test sets by a ratio of 7:3. DCE MRI data were used to generate volume transfer constant (Ktrans) and extracellular volume fraction (Ve) maps. Ktrans, Ve, and conventional MRI were then used to extract the radiomics features, from which the prediction models for EGFR amplification status were developed and validated. Results: A total of 190 patients (mean age, 59.9; male, 55.3%), divided into training (n = 133) and test (n = 57) sets, were enrolled. In the test set, the radiomics model using the Ktrans map exhibited the highest area under the receiver operating characteristic curve (AUROC), 0.80 (95% confidence interval [CI], 0.65–0.95). The AUROC for the Ve map-based and conventional MRI-based models were 0.74 (95% CI, 0.58–0.90) and 0.76 (95% CI, 0.61–0.91). Conclusion: The DCE MRI-based radiomics model that predicts EGFR amplification in glioblastoma, IDH wildtype, was developed and validated. The MRI-based radiomics model using the Ktrans map has higher AUROC than conventional MRI. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the relationship between the severity of fibrosis in lung tissue and epidermal growth factor receptor (EGFR) positivity in patients who died due to COVID-19 pneumonia, demographic characteristics, comorbidities, biochemical values, and treatments received. Fifty patients who died from COVID-19 pneumonia were included in the study. Demographic data for the patients, laboratory tests, thorax computerized tomography findings, comorbidities, length of stay in the intensive care unit (ICU), intubation times, and treatments given were noted. Postmortem Tru-cut lung biopsy was performed. EGFR positivity was examined and grouped as negative, mild, moderate, and severe. Data were analyzed statistically. EGFR involvement was negative in 11 (22%), mild in 20 (40%), moderate in 13 (26%), and severe in 6 (12%) patients. The mean C-reactive protein (CRP) values, D-dimer values, and mean length of stay in the ICU were found to be significantly different between the groups (p = 0.024; p = 0.003; p = 0.016, respectively). Methylprednisolone dose and the presence of comorbidity did not differ significantly in EGFR involvement (p = 0.79; p = 0.98, respectively). CRP and D-dimer values can be used as a guide to assess the severity of pulmonary fibrosis that develops in severe COVID-19 pneumonia patients. The dose of methylprednisolone used does not make a significant difference in the severity of fibrosis. Trail registration: Clinical Trials.gov identifier date and number 01/13/2022 NCT05290441. [ABSTRACT FROM AUTHOR]

Background: The recent classification of odontogenic keratocysts (OKSs) recognized them as benign neoplasms, although previous findings have revealed their aggressive nature. Immunohistochemical and molecular analyses have investigated OKSs, but the role of epidermal growth factor receptor (EGFR) has not been fully investigated, despite the importance of this oncogene in the process of carcinogenesis in tumors of epithelial origin. The EGFR protein is usually overexpressed, and the EGFR gene is mutated or amplified. Aims of study: This brief review aims to emphasize the importance of EGFR detection in these types of cysts. Methods and results: It was revealed that the majority of the studies examined EGFR protein expression using immunohistochemical methods; however, considering EGFR gene variants, mutations were less explored in the previous period from 1992 to 2023. Although EGFR gene polymorphisms are clinically important, they were not identified in the present study. Conclusions: In light of the current significance of EGFR variants, it would be beneficial to examine them in odontogenic lesions. This would enable resolving of discrepancies about their nature, and potentially enhance classifications OKCs in the future. [ABSTRACT FROM AUTHOR]

The early prediction of overall survival (OS) in patients with lung cancer brain metastases (BMs) after Gamma Knife radiosurgery (GKRS) can facilitate patient management and outcome improvement. However, the disease progression is influenced by multiple factors, such as patient characteristics and treatment strategies, and hence satisfactory performance of OS prediction remains challenging. Accordingly, we proposed a deep learning approach based on comprehensive predictors, including clinical, imaging, and genetic information, to accomplish reliable and personalized OS prediction in patients with BMs after receiving GKRS. Overall 1793 radiomic features extracted from pre-GKRS magnetic resonance images (MRI), clinical information, and epidermal growth factor receptor (EGFR) mutation status were retrospectively collected from 237 BM patients who underwent GKRS. DeepSurv, a multi-layer perceptron model, with 4 different aggregation methods of radiomics was applied to predict personalized survival curves and survival status at 3, 6, 12, and 24 months. The model combining clinical features, EGFR status, and radiomics from the largest BM showed the best prediction performance with concordance index of 0.75 and achieved areas under the curve of 0.82, 0.80, 0.84, and 0.92 for predicting survival status at 3, 6, 12, and 24 months, respectively. The DeepSurv model showed a significant improvement (p < 0.001) in concordance index compared to the validated lung cancer BM prognostic molecular markers. Furthermore, the model provided a novel estimate of the risk-of-death period for patients. The personalized survival curves generated by the DeepSurv model effectively predicted the risk-of-death period which could facilitate personalized management of patients with lung cancer BMs. [ABSTRACT FROM AUTHOR]

Opinion Statement: Epidermal growth factor receptor (EGFR) is commonly overexpressed in many head and neck squamous cell carcinomas (HNSCC). With the success of EGFR inhibition in other cancer types, there was optimism for efficacy in HNSCC. Unfortunately, the clinical outcomes of EGFR-directed therapy have not provided overwhelming benefit. In the curative-intent setting, cisplatin has proven superior over cetuximab, an EGFR monoclonal antibody, in multiple large trials, and cisplatin should continue to be the treatment of choice when administered with definitive or adjuvant radiation. For cisplatin-ineligible patients, we prefer carboplatin-based treatment over cetuximab. We reserve cetuximab for a small group of patients who are eligible for radiation and systemic treatment but have contraindications to any platinum therapy. The role of EGFR inhibitors in the recurrent/metastatic setting is more robust. Although supplanted by immunotherapy as front-line treatment, cetuximab remains a meaningful second-line option for patients who have progressed on immune checkpoint inhibitors. Overall, EGFR-directed therapies have been of modest value in the treatment of both locally advanced and metastatic HNSCC. The future of EGFR-directed therapies will likely develop from exploring combination therapies, especially with immunotherapy. Early evidence suggests synergistic effects allowing for a more robust immune response, which holds promise for novel regimens in the treatment of HNSCC. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity. Mutations in the EGFR gene, including deletions in exon 19 and the mutation L858R, induce responsiveness of non-small cell lung cancer (NSCLC) to a group of drugs known as tyrosine kinase inhibitors. Here, we report the development of the CRISPR-based fluorescent reporter (CBFR) assay including a two-step strategy combining PCR amplification and Cas12a-driven cleavage to detect the delE746_A750 subtype of EGFR exon 19 deletions. Sensitivity and specificity of the CBFR assay were analyzed with different concentrations of fluorescence reporter and different amounts of PCR product. The results demonstrated that increasing the fluorescent reporter to 4 μM and the PCR product to 5 μl enhanced sensitivity. The CBFR assay could detect EGFR exon 19 deletion even with a frequency of 1% in samples. In clinical NSCLC samples, optimized CBFR assay enabled visual detection of the delE746_A750 subtype in less than 1 h. The CBFR assay provides a sensitive, specific, and simple strategy designed based on a straightforward and inexpensive process. We suggest that the CBFR assay could serve as a diagnostic approach to detect mutations, deletions, and pathogens in underequipped laboratories and promote personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: The high incidence of epidermal growth factor receptor (EGFR) mutations is usually found in female patients with lung adenocarcinoma who have never-smoked. However, reports concerning male patients are scarce. Thus, this study aimed to explore a novel approach based on 18F-fluoro-2-deoxy-2-deoxyglucose (18F-FDG) PET/CT and serum tumor markers (STMs) to determine EGFR mutation status in male patients with non-small-cell lung cancer (NSCLC). Methods: A total of 121 male patients with NSCLC were analyzed between October 2019 and March 2022. All patients underwent 18F-FDG PET/CT scan before treatment and monitored 8 STMs (cytokeratin 19 fragment [CYFRA21-1], squamous cell carcinoma-related antigen [SCC-Ag], carcinoembryonic antigen [CEA], neuron-specific enolase [NSE], carbohydrate antigen [CA] 50, CA125, CA72-4, and ferritin). A comparison was done between EGFR mutant and wild-type patients in terms of the maximum standardized uptake value of primary tumors (pSUVmax) and 8 STMs. We performed receiver operating characteristic (ROC) curve and multiple logistic regression analyses to determine predictors for EGFR mutation status. Results: EGFR mutations were detected in 39 patients (32.2%). Compared with patients with EGFR wild-type, EGFR-mutant patients had lower concentrations of serum CYRFA21-1 (2.65 vs. 4.01, P = 0.002) and SCC-Ag (0.67 vs. 1.05, P = 0.006). No significant differences of CEA, NSE, CA 50, CA125, CA72-4 and ferritin were found between the two groups. The presence of EGFR mutations was significantly associated with low pSUVmax (< 8.75), low serum SCC-Ag (< 0.79 ng/mL) and CYFRA21-1 (< 2.91 ng/mL) concentrations. The area under ROC curve values were 0.679, 0.655, 0.685 and 0.754, respectively, for low CYFRA21-1, SCC-Ag, pSUVmax and the combination of these three factors. Conclusions: We demonstrated that low concentrations of CYFRA21-1 and SCC-Ag, as well as low pSUVmax, were associated with EGFR mutations, and that the combination of these factors resulted in a higher differentiation of EGFR mutation status in male patients with NSCLC. [ABSTRACT FROM AUTHOR]

Background: This study aims to construct radiomics models based on [18F]FDG PET/CT using multiple machine learning methods to predict the EGFR mutation status of lung adenocarcinoma and evaluate whether incorporating clinical parameters can improve the performance of radiomics models. Methods: A total of 515 patients were retrospectively collected and divided into a training set (n = 404) and an independent testing set (n = 111) according to their examination time. After semi-automatic segmentation of PET/CT images, the radiomics features were extracted, and the best feature sets of CT, PET, and PET/CT modalities were screened out. Nine radiomics models were constructed using logistic regression (LR), random forest (RF), and support vector machine (SVM) methods. According to the performance in the testing set, the best model of the three modalities was kept, and its radiomics score (Rad-score) was calculated. Furthermore, combined with the valuable clinical parameters (gender, smoking history, nodule type, CEA, SCC-Ag), a joint radiomics model was built. Results: Compared with LR and SVM, the RF Rad-score showed the best performance among the three radiomics models of CT, PET, and PET/CT (training and testing sets AUC: 0.688, 0.666, and 0.698 vs. 0.726, 0.678, and 0.704). Among the three joint models, the PET/CT joint model performed the best (training and testing sets AUC: 0.760 vs. 0.730). The further stratified analysis found that CT_RF had the best prediction effect for stage I–II lesions (training set and testing set AUC: 0.791 vs. 0.797), while PET/CT joint model had the best prediction effect for stage III–IV lesions (training and testing sets AUC: 0.722 vs. 0.723). Conclusions: Combining with clinical parameters can improve the predictive performance of PET/CT radiomics model, especially for patients with advanced lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background: Driver molecular aberrations, such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) gene rearrangement, play an important role in the oncogenesis and progression of non-squamous non-small-cell lung cancers (NSCLC). Therefore, this study aimed to detect the incidence of driver mutations among non-squamous NSCLC. Patients and methods: This was a retrospective-prospective cohort study on 131 patients with non-squamous NSCLC. Data on age, smoking status, chest symptoms, method of lung cancer diagnosis, molecular testing, including EGFR mutations in formalin-fixed paraffin-embedded (FFPE) tumor tissue and serum circulating tumor DNA using next-generation sequencing and ALK gene rearrangement by FFPE tumor tissue, and follow-up data regarding treatment modalities and outcomes were collected. Results: The median age of the patients was 57 years (range: 32–79 years). Out of 131 patients, 97 were males (74%), and 90 (68.7%) were smokers. Among 128 patients tested, 16 (12.5%) had EGFR mutations detected with either technique by formalin-fixed paraffin-embedded (FFPE) tumor tissue or/and serum circulating tumor DNA using next-generation sequencing, and 6 (4.7%) had ALK rearrangement by FFPE tumor tissue. The majority (62.6%) presented with metastatic disease. Among the 102 patients who received first-line systemic therapy, the objective response rate was 50.0% in mutated NSCLC versus 14.6% in non-mutated (p < 0.001). Among the eight mutated patients who received first-line tyrosine kinase inhibitors (TKIs), 7 patients achieved either complete response or partial response. Among the 22 mutated patients, the median overall survival was 3 months in those who did not receive targeted therapy versus not reached in those who received any type of targeted therapy (p < 0.001). Conclusion: Screening patients with newly diagnosed non-squamous NSCLC for driver mutations is essential for major prognostic and therapeutic implications. Early administration of TKIs in mutated patients significantly improves disease outcomes. [ABSTRACT FROM AUTHOR]

B7 homolog 3 protein (B7-H3), an immune checkpoint molecule belonging to the B7 family, has been studied as a target for the development of anti-cancer treatment; however, changes in B7-H3 expression during the clinical course remain unknown. This retrospective study aimed to investigate changes in B7-H3 expression of lung cancer specimens in patients with advanced lung cancer following various anti-cancer treatments. The immunohistochemistry (IHC) score was evaluated on a 0–3 scale, and B7-H3 expression was considered positive for grade ≥ 2. The difference in IHC scores before and after anti-cancer treatment was defined as the change in B7-H3 expression. Among 160 patients with lung cancer who received anti-cancer treatment, 88 (55%) and 101 (63%) had B7-H3 expression before and after anti-cancer treatment, respectively. Before treatment, B7-H3 expression was significantly more common in squamous cell carcinoma specimens than in adenocarcinoma specimens (95% vs. 49%, P < 0.001). Of the 19 patients with squamous cell carcinoma, 18 (95%) continued to have high (IHC score: 3) B7-H3 expression following treatment. In contrast, of the 130 patients with adenocarcinoma, 46 (35%) and 17 (13%) showed an increased and a decreased expression, respectively. Patients who received targeted therapy had a significant increase in B7-H3 expression compared with those who received chemotherapy alone (P = 0.015). Overall, squamous cell carcinoma specimens maintained high B7-H3 expression during the clinical course, whereas adenocarcinoma specimens showed changes in expression following anti-cancer treatments. Our results provide the basis for further studies on the development of anti-cancer treatments targeting B7-H3. [ABSTRACT FROM AUTHOR]

Summary: The objective of this study was to evaluate the safety and tolerability of DS-1205c, an oral AXL-receptor inhibitor, in combination with osimertinib in metastatic or unresectable EFGR-mutant non-small cell lung cancer (NSCLC) patients who developed disease progression during EGFR tyrosine kinase inhibitor (TKI) treatment. An open-label, non-randomized phase 1 study was conducted in Taiwan, in which 13 patients received DS-1205c monotherapy at a dosage of 200, 400, 800, or 1200 mg twice daily for 7 days, followed by combination treatment with DS-1205c (same doses) plus osimertinib 80 mg once daily in 21-day cycles. Treatment continued until disease progression or other discontinuation criteria were met. At least one treatment-emergent adverse event (TEAE) was reported in all 13 patients treated with DS-1205c plus osimertinib; with ≥ 1 grade 3 TEAE in 6 patients (one of whom also had a grade 4 increased lipase level), and 6 patients having ≥ 1 serious TEAE. Eight patients experienced ≥ 1 treatment-related AE (TRAE). The most common (2 cases each) were anemia, diarrhea, fatigue, increased AST, increased ALT, increased blood creatinine phosphokinase, and increased lipase. All TRAEs were non-serious, with the exception of an overdose of osimertinib in 1 patient. No deaths were reported. Two-thirds of patients achieved stable disease (one-third for > 100 days), but none achieved a complete or partial response. No association between AXL positivity in tumor tissue and clinical efficacy was observed. DS-1205c was well-tolerated with no new safety signals in patients with advanced EGFR-mutant NSCLC when administered in combination with the EFGR TKI osimertinib. ClinicalTrials.gov; NCT03255083. [ABSTRACT FROM AUTHOR]

The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC. [ABSTRACT FROM AUTHOR]

Purpose: In nonmetastatic head and neck cancer treatment, surgical margin status is the most important prognosticator of recurrence and patient survival. Fresh frozen sectioning (FFS) of tissue margins is the standard of care for intraoperative margin assessment. However, FFS is time intensive, and its accuracy is not consistent among institutes. Mapping the epidermal growth factor receptor (EGFR) using paired-agent imaging (PAI) has the potential to provide more consistent intraoperative margin assessment in a fraction of the time as FFS.Procedures: PAI was carried out through IV injection of an anti-epidermal growth factor receptor (EGFR) affibody molecule (ABY-029, eIND 122,681) and an untargeted IRDye680LT carboxylate. Imaging was performed on 4 µm frozen sections from three oral squamous cell carcinoma xenograft mouse models (n = 24, 8 samples per cell line). The diagnostic ability and tumor contrast were compared between binding potential, targeted, and untargeted images. Confidence maps were constructed based on group histogram-derived tumor probability curves. Tumor differentiability and contrast by confidence maps were evaluated.Results: PAI outperformed ABY-029 and IRDye 680LT alone, demonstrating the highest individual receiver operating characteristic (ROC) curve area under the curve (PAI AUC: 0.91, 0.90, and 0.79) and contrast-to-noise ratio (PAI CNR: 1, 1.1, and 0.6) for FaDu, Det 562, and A253. PAI confidence maps (PAI CM) maintain high tumor diagnostic ability (PAI CMAUC: 0.91, 0.90, and 0.79) while significantly enhancing tumor contrast (PAI CMCNR: 1.5, 1.3, and 0.8) in FaDu, Det 562, and A253. Additionally, the PAI confidence map allows avascular A253 to be differentiated from a healthy tissue with significantly higher contrast than PAI. Notably, PAI does not require additional staining and therefore significantly reduces the tumor delineation time in a 5 [Formula: see text] 5 mm slice from ~ 35 min to under a minute.Conclusion: This study demonstrated that PAI improved tumor detection in frozen sections with high diagnostic accuracy and rapid analysis times. The novel PAI confidence map improved the contrast in vascular tumors and differentiability in avascular tumors. With a larger database, the PAI confidence map promises to standardize fluorescence imaging in intraoperative pathology-assisted surgery (IPAS). [ABSTRACT FROM AUTHOR]

Purpose: Non-specific uptake and retention of molecular targeted agents and heterogeneous tissue optical properties diminish the ability to differentiate between tumor and normal tissues using molecular targeted fluorescent agents. Paired-agent imaging (PAI) can increase the diagnostic ability to detect tumor tissue by mitigating these non-specific effects and providing true molecular contrast by co-administration of an untargeted control imaging agent with a targeted agent. This study evaluates the suitability of available clinically translatable untargeted agents for the translation of PAI in fluorescence-guided surgery using an affibody-based targeted imaging agent (ABY-029). Experimental: Design: Three untargeted agents that fluoresce near 700 nm and exhibit good clinical safety profiles (methylene blue, IRDye 700DX, and IRDye 680LT) were tested in combination with the clinically tested IRDye 800CW–labeled anti-epidermal growth factor receptor (EGFR) affibody molecule, ABY-029 (eIND 122,681). Properties of the untargeted agent important for human use and integrity of PAI were tested: (1) plasma protein binding; (2) fluorescence signal linearity in in vitro whole blood dilution; (3) in vivo pharmacokinetic matching to targeted agent in negative control tissue; and (4) in vivo diagnostic accuracy of PAI vs single agent imaging (SAI) of ABY-029 alone in orthotopic oral head and neck squamous cell carcinomas. Results: IRDye 680LT outperformed IRDye 700DX and methylene blue with the highest signal linearity (R2 = 0.9998 ± 0.0002, 0.9995 ± 0.0004, 0.91 ± 0.02, respectively), the highest fluorescence yield in whole blood at 1 μM (104.42 ± 0.05, 103.68 ± 0.09, 101.9 ± 0.2, respectively), and the most closely matched ABY-029 pharmacokinetics in EGFR-negative tissues (binding potential error percentage = 0.31% ± 0.37%, 10.25% ± 1.30%, and 8.10% ± 5.37%, respectively). The diagnostic ability of PAI with ABY-029 and IRDye 680LT outperformed conventional SAI with an area-under-the-receiver-operating-characteristic curve (AUC) value of 0.964 vs. 0.854, and 0.978 vs. 0.925 in the Odyssey scanning system and Pearl wide field imaging system, respectively. Conclusion: PAI is a highly promising methodology for increasing detection of tumors in fluorescence-guided surgery. Although not yet clinically approved, IRDye 680LT demonstrates promise as an untargeted agent when paired with ABY-029. The clinical translation of PAI to maximize tumor excision, while minimizing normal tissue removal, could improve both patient survival and life quality. [ABSTRACT FROM AUTHOR]

Purpose: The goal of fluorescence-guided surgery (FGS) in oncology is to improve the surgical therapeutic index by enhancing contrast between cancerous and healthy tissues. However, optimal discrimination between these tissues is complicated by the nonspecific uptake and retention of molecular targeted agents and the variance of fluorescence signal. Paired-agent imaging (PAI) employs co-administration of an untargeted imaging agent with a molecular targeted agent, providing a normalization factor to minimize nonspecific and varied signals. The resulting measured binding potential is quantitative and equivalent to in vivo immunohistochemistry of the target protein. This study demonstrates that PAI improves the accuracy of tumor-to-healthy tissue discrimination compared to single-agent imaging for in vivo FGS. Procedures: PAI using a fluorescent anti-epidermal growth factor receptor (EGFR) affibody molecule (ABY-029, eIND 122,681) with untargeted IRDye 700DX carboxylate was compared to ABY-029 alone in an oral squamous cell carcinoma xenograft mouse model at 3 h after dye administration (n = 30). Results: PAI significantly enhanced tumor discrimination, as compared to ABY-029 alone in low EGFR-expressing tumors and highly heterogeneous populations including multiple cell lines with varying expression (diagnostic accuracy: 0.908 vs. 0.854 and 0.908 vs. 0.822; and ROC curve AUC: 0.963 vs. 0.909 and 0.957 vs. 0.909, respectively) indicating a potential for universal FGS image thresholds to determine surgical margins. In addition, PAI achieved significantly higher diagnostic ability than ABY-029 alone 0.25–5-h post injection and exhibited a stronger correlation to EGFR expression heterogeneity. Conclusion: The quantitative receptor delineation of PAI promises to improve the surgical therapeutic index of cancer resection in a clinically relevant timeline. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor (EGFR) is involved in strong association with malignant proliferation, which has been shown to play a central role in the development and progression of non-small cell lung cancer and other solid tumors. The tumor-suppressor protein MIG6 is a negative regulator of EGFR kinase activity by binding at the activation interface of asymmetric dimer of EGFR kinase domain to disrupt EGFR dimerization and then inactivate the kinase. The protein adopts two discrete fragments 1 and 2 to directly interact with EGFR. It is revealed that the MIG6 fragment 2 is intrinsically disordered in free unbound state, but would fold into a well-structured β-hairpin when binding to EGFR, thus characterized by a so-called coupled folding-upon-binding process, which can be regarded as a compromise between favorable direct readout and unfavorable indirect readout. Here, a 23-mer F2P peptide was derived from MIG6 fragment 2, trimmed into a 17-mer tF2P peptide that contains the binding hotspot region of the fragment 2, and then constrained with an ordered hairpin conformation in free unbound state by disulfide stapling, finally resulting in a rationally stapled/trimmed stF2P peptide that largely minimizes the unfavorable indirect readout effect upon its binding to EGFR kinase domain, with affinity improved considerably upon the trimming and stapling/trimming. These rationally designed β-hairpin peptides may be further exploited as potent anti-lung cancer agents to target the activation event of EGFR dimerization. [ABSTRACT FROM AUTHOR]

Purpose: During lung cancer surgery, it is very important to define tumor boundaries and determine the surgical margin distance. In previous research, systemically application of fluorescent probes can help medical professionals determine the boundaries of tumors and find small tumors and metastases, thereby improving the accuracy of surgical resection. However, there are very few safe and effective probes that can be applied to clinical trials up to now, which limits the clinical application of fluorescence imaging. Here we developed a new technology that can quickly identify the tumor area in the resected lung tissue during the operation and distinguish the tumor boundary and metastatic lymph nodes. Experimental design: For animal studies, a PDX model of lung cancer was established. The tumors, lungs, and peritumoral muscle tissues of tumor-bearing mice were surgically removed and incubated with a probe targeting epidermal growth factor receptor (EGFR) for 20 min, and then imaged by a closed-field near-infrared two-zone (NIR-II) fluorescence imaging system. For clinical samples, ten surgically removed lung tissues and 60 lymph nodes from 10 lung cancer patients undergoing radical resection were incubated with the targeting probe immediately after intraoperative resection and imaged to identify the tumor area and distinguish the tumor boundary and metastatic lymph nodes. The accuracy of fluorescence imaging was confirmed by HE staining and immunohistochemistry. Results: The ex vivo animal imaging experiments showed a fluorescence enhancement of tumor tissue. For clinical samples, our results showed that this new technology yielded more than 85.7% sensitivity and 100% specificity in identifying the tumor area in the resected lung tissue. The average fluorescence tumor-to-background ratio was 2.5 ± 1.3. Furthermore, we also used this technique to image metastatic lymph nodes intraoperatively and showed that metastatic lymph nodes have brighter fluorescence than normal lymph nodes, as the average fluorescence tumor-to-background signal ratio was 2.7 ± 1.1. Calculations on the results of the fluorescence signal in relation to the number of metastatic lymph nodes yielded values of 77.8% for sensitivity and 92.1% for specificity. We expect this new technology to be a useful diagnostic tool for rapid intraoperative pathological detection and margin determination. Conclusions: By using fluorescently labeled anti-human EGFR recombinant antibody scFv fragment to incubate freshly isolated tissues during surgery, the probes can quickly accumulate in lung cancer tissues, which can be used to quickly identify tumor areas in the resected lung tissues and distinguish tumor boundaries and find metastases in lymph nodes. This technology is expected to be used for rapid intraoperative pathological detection and margin determination. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the prognostic potential of the pre-radiotherapy systemic immune-inflammation index (SII) for the survival of advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations, which might provide a basis for optimizing the comprehensive treatment scheme. Methods: A total of 111 lung adenocarcinoma patients with EGFR mutations, who received thoracic radiotherapy, were included in this retrospective study. The primary endpoint of the study was based on the overall survival (OS) of patients. The receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off value of each immune inflammation index. Kaplan–Meier analysis was performed for the comparison of OS. The Cox proportional-hazard model was used for the multivariate and univariate regression analyses to determine the correlations of prognostic factors with the disease. Results: SII was divided into the high SII group (≥ 620.2; 45.95%) and the low SII group (SII < 620.2; 54.05%) based on the optimal cutoff values. The median OS rates were 53.3 and 33.3 months in the low and high SII groups, respectively, showing statistically significant differences (hazard ratio (HR) = 0.459; 95% CI 0.286–0.736; P < 0.001). The multivariate analysis showed that, after adjusting for the significant covariates, the SII values were independently associated with the improved OS of the patients (adjusted HR = 0.444; 95% CI 0.279–0.709; P = 0.001). The low NLR values were associated with the better OS of patients (HR = 0.509; 95% CI 0.326–0.792; P = 0.005) and vice versa (HR = 0.422; 95% CI 0.213–0.836; P < 0.001). The patients in the low LMR group before radiotherapy exhibited longer OS as compared to those in the high LMR group (HR = 0.497; 95% CI 0.308–0.802; P = 0.001). Conclusions: This study showed that these inflammatory indices might have an important prognostic potential for advanced lung adenocarcinoma patients with EGFR mutations, receiving thoracic radiotherapy and might provide a basis for the individualized treatment of these patients. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether radiomic features could improve the accuracy of survival predictions of IDH-wildtype (IDHwt) histological lower-grade gliomas (LGGs) over clinicopathological features.Methods: Preoperative MRI data of 61 patients with IDHwt histological LGGs were included as the institutional training set. The test set consisted of 32 patients from The Cancer Genome Atlas. Radiomic features (n = 186) were extracted using conventional MRIs. The radiomics risk score (RRS) for overall survival (OS) was derived from the elastic net. Multivariable Cox regression analyses with clinicopathological features (including epidermal growth factor receptor [EGFR] amplification and telomerase reverse transcriptase promoter [TERTp] mutation status) and the RRS were performed. The integrated area under the receiver operating curves (iAUCs) from the models with and without the RRS were compared. The net reclassification index (NRI) for 1-year OS was also calculated. The prognostic value of the RRS was evaluated using the external validation set.Results: The RRS independently predicted OS (hazard ratio = 48.08; p = 0.001). Compared with the clinicopathological model alone, adding the RRS had a better OS prediction performance (iAUCs 0.775 vs. 0.910), which was internally validated (iAUCs 0.726 vs. 0.884, 1-year OS NRI = 0.497), and a similar trend was found on external validation (iAUCs 0.683 vs. 0.705, 1-year OS NRI = 0.733). The prognostic significance of the RRS was confirmed in the external validation set (p = 0.001).Conclusions: Integrating radiomics with clinicopathological features (including EGFR amplification and TERTp mutation status) can improve survival prediction in patients with IDHwt LGGs.Key Points: • Radiomics risk score has the potential to improve survival prediction when added to clinicopathological features (iAUCs increased from 0.775 to 0.910). • NRIs for 1-year OS showed that the radiomics risk score had incremental value over the clinicopathological model. • The prognostic significance of the radiomics risk score was confirmed in the external validation set (p = 0.001). [ABSTRACT FROM AUTHOR]

Summary: The effects of polymorphisms in CYP3A4 (20230G > A), CYP3A5 (6986A > G), ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCG2 (421C > A), and ABCC2 (-24C > T) on the area under the concentration–time curve (AUC) of osimertinib in 23 patients with non-small cell lung cancer were investigated. Blood sampling was performed just prior to and at 1, 2, 4, 6, 8, 12, and 24 h after osimertinib administration at the steady-state on day 15 after beginning therapy. The osimertinib AUC0-24 was significantly correlated with age (P = 0.038), serum albumin (P = 0.002), and serum creatinine (P = 0.012). Additionally, there were significant differences in the AUC0-24 of osimertinib among the groups administered vonoprazan, histamine 2-receptor antagonists or esomeprazole, and no acid suppressants (P = 0.021). By contrast, there were no significant differences in the AUC0-24 of osimertinib between genotypes of CYP3A4/5 or ABC transporters. Furthermore, there were no significant differences in the AUC0-24 of osimertinib between patients with diarrhea, skin rash, or hepatotoxicity and those without these conditions. In multivariate analysis, only serum albumin value was an independent factor predicting the AUC0-24 of osimertinib. Analysis of CYP3A4/5 and ABC transporter polymorphisms before osimertinib therapy may not predict the efficacy or side effects of osimertinib. The lower serum albumin values were associated with an increase in the AUC0-24 of osimertinib; however, further studies are needed to assess the factors contributing to the interindividual variability of osimertinib pharmacokinetics. [ABSTRACT FROM AUTHOR]

Summary: Non-medical use of ketamine as an adulterant to ecstasy is more prevalent than amphetamine in Taiwan. Ketamine's effect on immunosuppression might play some functional role in tumor growth, while it is still controversial whether ketamine abuse could increase tumor growth or not. This study aimed to investigate the influence of ketamine addiction in breast tumors and related gene expressions. The effect of ketamine treatment on proliferation, colony formation, migration, and invasion of triple-negative breast cancer cell line EO771 was examined. In addition, a ketamine addiction mice model was established by intraperitoneal injection (IP) of ketamine in mice and used to investigate the effects of ketamine addiction on tumor growth and the possible mechanisms. In the in vitro studies, ketamine treatment at different concentrations did not affect EO771 cell proliferation and colony formation. But ketamine did enhance migration and invasion of EO771 cells. The in vivo experiments showed significantly increased breast tumor volume and weight in ketamine-addicted mice than in normal saline groups. miR-27b-3p level, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor (EGFR) significantly increased in tumors of ketamine addiction mice compared to control mice. In vivo evidence showed that Ketamine might increase tumor growth on the tumor microenvironment, and miR-27b-3p, HER2, and EGFR might play a role in the process. [ABSTRACT FROM AUTHOR]