UNASSIGNED: In cases where rebiopsy fails to find the epidermal growth factor receptor (EGFR) T790M mutation, the criteria for selecting patients for repeated rebiopsy remains unclear. This study aimed to assess the impact of repeated rebiopsy on T790M mutation detection in non-small cell lung cancer (NSCLC) patients.
UNASSIGNED: Patients with advanced EGFR-mutated NSCLC between January 2018 and December 2021 at three-referral hospitals in South Korea underwent retrospective review. Of 682 patients who had rebiopsy after disease progression, T790M mutation status was assessed in plasma circulating tumor DNA (ctDNA) and/or tumor tissues.
UNASSIGNED: The overall T790M positivity rate increased from 40.8% after the first rebiopsy to 52.9% following multiple rebiopsies in the entire study population. Longer duration of initial EGFR TKI use (OR 1.792, ≥8 months vs. <8 months, p=0.004), better EGFR TKI responses (OR 1.611, complete or partial response vs. stable disease, p=0.006), presence of bone metastasis (OR 2.286, p<0.001) were correlated with higher T790M positivity. Longer EGFR TKI use and better responses increased T790M positivity in repeated tissue rebiopsy, while bone metastasis favored liquid rebiopsy. Additionally, T790M status has been shown to be positive over time through repeated rebiopsies ranging from several months to years, suggesting its dynamic nature.
UNASSIGNED: In this study, among patients who initially tested negative for T790M in rebiopsy, repeated rebiopsies uncovered an additional 23.5% T790M positivity. Particularly, it is suggested that repeated rebiopsies may be valuable for patients with prolonged EGFR TKI usage, better responses to treatment, and bone metastasis.

OBJECTIVE: This retrospective study was undertaken to assess the predictive efficacy of 18F-FDG PET/CT -derived radiomic features concerning the co-mutation status of epidermal growth factor receptor (EGFR) and TP53 in LUAD.
METHODS: A cohort of 150 LUAD patients underwent pretreatment 18F-FDG PET/CT scans with known mutation status of EGFR and TP53 were collected. The feature extraction based on their PET/CT images utilized the Pyradiomics package based on the 3D Slicer. The optimal radiomic features were selected through correlation analysis and the Gradient Boosting Decision Tree (GBDT) algorithm, followed by the construction of the radiomic model. The clinical model incorporated meaningful clinical variables, whereas the complex model integrated both the radiomic and clinical models. The area under the receiver operating characteristic curve (AUC) facilitated the comparison of prediction performance across the three models. The DCA gauged the clinical utility of these models.
RESULTS: The patient cohort was randomly allocated into a training set (n = 105) and a validation set (n = 45) in a 7:3 ratio. Eleven PET and eleven CT optimal radiomic features were selected to construct the radiomic model. The model showed a good ability to discriminate the co-occurrence of EGFR and TP53, with AUC equal to 0.850 in the training set, and 0.748 in the validation set, compared with 0.750 and 0.626 for the clinical model. The complex model exhibited the highest AUC values, with 0.880 and 0.794 in both sets, but there were no significant differences compared to the radiomic model. The DCA revealed favorable clinical value.
CONCLUSIONS:

Classical and mixed congenital mesoblastic nephroma (CMN) are characterized by an internal tandem duplication (ITD) of the EGFR gene, in contrast to cellular CMN that usually harbors an ETV6::NTRK3 gene fusion. This same fusion occurs in infantile fibrosarcoma, and this tumor can be considered as the soft tissue equivalent of cellular CMN. A soft tissue equivalent of classic/mixed CMN remains undefined at the genetic level. Since classical CMN resembles fibromatosis of soft tissue histologically, we asked whether fibromatosis in children might show EGFR ITD. ITD was investigated using the polymerase chain reaction and primers for exons 18 and 25 of the EGFR gene. Seven of the eight cases of classical or mixed CMN were positive by this approach, but none of the five cellular CMNs. Of 11 cases of fibromatosis (six plantar, two digital, and three desmoid), none were positive for EGFR ITD. Within the limits of this small study, we conclude that pediatric fibromatosis is likely not characterized by EGFR ITD. There are isolated reports of pediatric soft tissue tumors that harbor EGFR ITD, but these have the appearance of infantile fibrosarcoma or mixed CMN rather than fibromatosis. We did not find any such cases, since all 14 cases of infantile fibrosarcoma in our study had an ETV6::NTRK3 fusion. The soft tissue tumors with EGFR ITD are not a morphologic match for the low-grade histology of classical CMN. Whether they have a similar favorable biology or behave more like fibrosarcoma with an ETV6::NTRK3 fusion or an alternative fusion involving other kinases remains to be determined.

BACKGROUND: Co-amplification of EGFR and EGFRvIII, a tumor-specific truncation mutant of EGFR, represent hallmark genetic lesions in glioblastoma.
METHODS: We used phospho-proteomics, RNA-sequencing, TCGA data and glioblastoma cell culture and mouse models to study the signal transduction mediated by EGFR and EGFRvIII.
RESULTS: We report that EGFR and EGFRvIII stimulate the innate immune defense receptor Toll-like Receptor 2 (TLR2); and that knockout of TLR2 dramatically improved survival in orthotopic glioblastoma xenografts. EGFR and EGFRvIII activated TLR2 in a ligand-independent manner, promoting tumor growth and immune evasion. We show that EGFR and EGFRvIII cooperate to activate the Rho-associated protein kinase ROCK2, which modulated malignant progression both by activating TLR2 and WNT signaling, and through remodeling the tumor microenvironment.
CONCLUSIONS: Together, our findings show that EGFR and EGFRvIII cooperate to drive tumor progression through ROCK2 and downstream WNT-β-catenin/TLR2 signaling pathways.

UNASSIGNED: In the United States, diabetic kidney disease (DKD) affects about one-third of individuals with type 2 diabetes, causing significant economic burdens on the health care system and affecting patients\' quality of life.
UNASSIGNED: The aim of the study was to quantify the burden of care in patients at different stages of DKD and to monitor shifts in healthcare costs throughout these stages.
UNASSIGNED: This study used data from the Veterans Affairs National database, focusing on US veterans diagnosed with DKD between January 2016 and March 2022. Aggregated all-cause health care costs per month were summarized using descriptive statistics. We used a generalized linear model to calculate the cost of DKD patent care based on the stages, dialysis phase, and kidney replacement therapy.
UNASSIGNED: The cohort of 685,288 patients with DKD was predominantly male (96.51%), White (74.42%), and non-Hispanic (93.54%). The mean (SD) per-patient per-month costs were $1,597 ($3,178), $1,772 ($4,269), $2,857 ($13,072), $3,722 ($12,134), $5,505 ($14,639), and $6,999 ($16,901) for stages 1, 2, 3a, 3b, 4 and 5 respectively. The average monthly expenditure for patients receiving long-term dialysis was $12,299. Costs peaked sharply during the first month of kidney replacement therapy at $38,359 but subsequently decreased to $6,636 after 1 year.
UNASSIGNED: The economic implications of DKD are profound, emphasizing the need for efficient early detection and disease management strategies. Preventing patients from progressing to advanced DKD stage will minimize the economic repercussions of DKD and will assist health care systems in optimizing resource allocation.
Diabetic kidney disease (DKD) places a substantial burden on health care systems in the United States. In part of our effort to close the knowledge gap around the disease burden, care cost analysis for the patients with DKD was performed for US veterans. Along with stage progression, overall care costs per-patient per-month drastically increases from $1,597 (stage 1) to $6,999 (stage 5). Monthly costs exceeded $10,000 once veterans started to receive long-term dialysis. The quantitative summary will help health care systems efficiently allocate resources across various disease sectors.

BACKGROUND: Mutations in the epidermal growth factor receptor (EGFR) gene are the most common targetable gene alterations in non-small cell lung cancer (NSCLC). In Japan, approximately 40% of patients who undergo surgical resection for non-squamous NSCLC have EGFR mutations. However, no long-term studies have been conducted including a large number of EGFR-positive NSCLC patients with postoperative recurrence (PR).
METHODS: We conducted a retrospective observational study of the data of EGFR-positive NSCLC patients with PR who had undergone surgery at the Shizuoka Cancer Center between October 2002 and November 2017. We evaluated post-recurrence overall survival (PRS) and postoperative overall survival (POS) using the Kaplan-Meier method and identify any associations between the clinical variables at recurrence and PRS using univariate and multivariate analysis.
RESULTS: We enrolled 162 patients. The median observation time for PRS was 4.95 years (range, 0.82-13.25) and POS was 5.81 years (range, 2.84-16.71). The median PRS was 5.17 years (95% confidence interval [CI], 3.90-5.61) and POS was 7.07 years (95% CI, 5.88-8.01). Univariate analysis identified male sex (median PRS: 3.32 vs. 5.39 years; p < 0.05), bone metastasis (median PRS: 2.43 vs. 5.33 years; p < 0.05), and central nervous system (CNS) metastasis (median PRS: 3.05 vs. 5.39 years; p < 0.05) and multivariate analysis identified bone metastasis (hazard ratio [HR], 2.01; 95% CI, 1.23-3.28; p < 0.05) and CNS metastasis (HR, 1.84; 95% CI, 1.14-2.98; p < 0.05) as poor prognostic factors. The pattern of recurrence (oligo vs. non-oligo recurrence) was not a prognostic factor. Logistic regression analysis revealed the association between sex and the presence bone/CNS metastasis at recurrence.
CONCLUSIONS: Our data may help visualize future prospects and determine the timing of osimertinib initiation. New treatment strategies need to be developed for patients with bone/CNS metastasis at the first recurrence.

OBJECTIVE: To study the effects of losartan, an angiotensin II receptor blocker, in the SCC4 and SCC25 human tongue squamous cell carcinoma cell lines.
METHODS: Cell proliferation was measured by MTS/PMS activity and trypan blue exclusion assays. The levels of the cell proliferation marker, cyclin D1, were analyzed by western blotting. Apoptosis was assessed by caspase-3 activation and Annexin V-FITC/propidium iodide double staining. Activation of epidermal growth factor receptor (EGFR) and ERK1/2 was validated by western blotting.
RESULTS: Moderate concentrations of losartan enhanced the proliferation of SCC4 and SCC25 cells. However, high losartan concentrations induced apoptosis in SCC4 cells. Losartan activated the EGFR/ERK1/2/cyclin D1 signaling axis, which in turn promoted cell proliferation. Afatinib (EGFR inhibitor) and U0126 (ERK1/2 inhibitor) abolished losartan-induced cell proliferation. In contrast, UC2288 (p21 inhibitor) enhanced it.
CONCLUSIONS: Losartan exhibited dual effects on tongue squamous cell carcinoma cells. Moderate losartan concentrations facilitated cell proliferation, whereas high concentrations induced cytotoxicity in tongue carcinoma cells.

Recently approved RET tyrosine kinase inhibitors (TKIs) have shown promising therapeutic effects against RET-rearranged non-small cell lung cancer (NSCLC) or RET-mutated thyroid cancer. However, resistance develops, limiting long-term efficacy. Although many RET-TKI resistance mechanisms, such as secondary mutations in RET or activation of bypass pathways, are known, some primary or acquired resistance mechanisms are unclear. Here, human genome-wide CRISPR/Cas9 screening was performed to identify genes related to drug-tolerant persister cells. Patient-derived cells with RET-fusion were introduced genome-wide sgRNA library and treated with RET-TKI for 9 days, resulting in the discovery of several candidate genes. Knockout of MED12 or MIG6 significantly increased residual drug-tolerant persister cells under RET-TKI treatment. MIG6 loss induced significant EGFR activation even with low concentrations of EGFR ligands and led to resistance to RET-TKIs. EGFR inhibition with afatinib or cetuximab in combination with RET TKIs was effective in addressing drug persistence. By contrast, a KIF5B-RET positive cells established from a RET-rearranged NSCLC patient, showed significant resistance to RET-TKIs and high dependence on EGFR bypass signaling. Consistently, knocking out EGFR or RET led to high sensitivity to RET or EGFR inhibitor respectively. Here, we have provided a comprehensive analysis of adaptive and acquired resistance against RET-rearranged NSCLC.

Non-small cell lung cancer (NSCLC) remains a significant challenge, as it is one of the leading causes of cancer-related deaths, and the development of resistance to anticancer therapy makes it difficult to treat. In this study, we investigated the anticancer mechanism of deoxybouvardin (DB), a cyclic hexapeptide, in gefitinib (GEF)-sensitive and -resistant NSCLC HCC827 cells. DB inhibited the viability and growth of HCC827 cells in a concentration- and time-dependent manner. In vitro kinase assay showed DB inhibited epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition (MET), and AKT, and their phosphorylation was suppressed in HCC827 cells treated with DB. A molecular docking model suggested that DB interacts with these kinases in the ATP-binding pockets. DB induces ROS generation and cell cycle arrest. DB treatment of HCC827 cells leads to mitochondrial membrane depolarization. The induction of apoptosis through caspase activation was confirmed by Z-VAD-FMK treatment. Taken together, DB inhibited the growth of both GEF-sensitive and GEF-resistant NSCLC cells by targeting EGFR, MET, and AKT and inducing ROS generation and caspase activation. Further studies on DB can improve the treatment of chemotherapy-resistant NSCLC through the development of effective DB-based anticancer agents.

UNASSIGNED: Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung carcinomas (NSCLC) are a frequent class of driver mutations, and tyrosine kinase inhibitor (TKI) therapy provides considerable clinical benefits. Using the most effective and also easiest method for EGFR analysis is cost-effective and time-saving. In this study, we aimed to determine which method could be more effective by comparing the incidences of EGFR mutations in cytological and histological samples which were obtained by different methods also, whether there was a difference in the incidences of EGFR mutations between the primary foci, mediastinal lymph nodes, and distant metastatic foci.
UNASSIGNED: We retrospectively reviewed 420 cases of cytological materials, small biopsies, and surgical samples reported as NSCLC underwent EGFR analysis in our department between 2016 and 2022. We collected the data and interpreted the results from two different perspectives.
UNASSIGNED: We identified 36 EGFR mutations in 362 biopsies (9.94%) and 17 in 58 cytology samples (29.31%). There is a significant difference between the two methods (P = 0.01*). We observed 38 EGFR mutations in 320 primary foci (11.87%), 7 EGFR mutations in 36 mediastinal or subcarinal lymph nodes (19.44%), and 8 EGFR mutations in 64 distant metastatic foci (12.50%). A significant difference was also observed in pleural samples (P = 0.005*).
UNASSIGNED: We observed more successful results with cell blocks obtained from liquid-based cytological specimens than with formalin-fixed, paraffin-embedded tissues obtained from resection or otherwise in our clinical routine. Our study results highlight the benefits of cytological specimens in molecular treatments and current therapy modalities.