S100 and CD34 positive spindle cell tumors of the uterine cervix with EGFR mutation: a hitherto unrecognized neoplasm phenotypically and epigenetically overlapping with "NTRK-rearranged spindle cell neoplasms" of the uterus.

NTRK-rearranged spindle cell neoplasm represents an emerging entity included in the latest 5th edition of WHO classification of both soft tissue and female genital tumors. By immunohistochemistry, they are commonly positive for CD34, S100 protein, and CD30 and typically harbor fusions of kinase genes such as NTRK1/2/3, RET, and BRAF. In the gynecological tract, they typically affect the uterine cervix or uterine body. Most of the reported cases had fibrosarcoma-like morphology, occasionally showing perivascular and stromal hyalinization with only a few cases showing a less cellular spindle cell proliferation. Except for one case with RET fusion, all other gynecological cases harbored exclusively NTRK1/2/3 fusions. Besides kinase gene fusions, the analogous tumors in soft tissues may also harbor activating EGFR or BRAF point mutations, but no such case has been described in the uterus. Herein we are reporting two cases from the uterine cervix showing morphology and molecular features previously unreported at this anatomic site. The patients were 46 and 34 years old and clinically presented with unremarkable cervical polyps each measuring 8 mm in diameter. Histologically, both cases had a rounded polypoid outline and were composed of hypocellular proliferation of bland spindle cells lacking mitotic activity and growing in a fibrotic stroma which was punctuated by prominent small vessels with thick hyalinized walls. Immunohistochemically, both showed a diffuse expression of CD34, CD30, and S100 protein, whereas SOX10 was negative. Both cases harbored exon 20 EGFR mutation and did not reveal any fusions or significant copy number changes. The patient in case 1 was treated by hysterectomy with salpingectomy with no other residual tumor detected, and she was alive and well 27 months after the diagnosis. The patient in case 2 had no other known tumors at the time of diagnosis, but no follow-up is available. We believe the reported cases represent a hitherto unrecognized variant of "NTRK-rearranged spindle cell neoplasms" of the uterine cervix with novel EGFR mutations.

Glucagon-like peptide-1 receptor agonists and kidney outcomes.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained increasing attention for their potential benefits in people with type 2 diabetes mellitus (T2DM) with chronic kidney disease (CKD). Most supportive evidence of a kidney-protective effect of the GLP-1RA class of medications has been derived from kidney-related outcomes reported from cardiovascular outcome trials (CVOTs). GLP-1RAs have been shown to reduce albuminuria, mitigate cardiovascular risk, and possibly attenuate estimated glomerular filtration rate (eGFR) decline. The kidney-protective effects of GLP-1RAs are thought to be attributed to their anti-inflammatory, antioxidant, and vasodilatory properties. Despite these promising findings, the use of GLP-RAs has yet to be definitively shown to slow progression to chronic kidney failure in people with T2DM. The Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW trial) is the first major trial assessing the potential of a GLP-1RA to slow progression of kidney disease in people with established CKD to clinically important kidney end points. On March 5, 2024, the top line result from FLOW was announced with semaglutide 1.0 mg being reported to reduce the primary end point of the trial by a significant 24% compared with placebo. Here, we summarize the kidney outcomes reported from CVOTs for the GLP-1RA class of medication and briefly describe kidney outcomes from other major GLP-1RAs trials. We also discuss a potential role of the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide, as a kidney-protective agent.

Trousseau's Syndrome in Lung Cancer Patients: A Retrospective Study in a Japanese Community Hospital.

Trousseau's syndrome is a cancer-associated thromboembolism that significantly impacts patients' prognosis and quality of life (QOL). This study aimed to investigate the frequency, characteristics, and prognosis of Trousseau's syndrome in lung cancer patients at a Japanese community hospital and examine the effects of therapeutic agents on this condition. We retrospectively reviewed the electronic medical records of lung cancer patients diagnosed with thrombotic complications at the time of diagnosis in our department between August 2013 and April 2019. Patients' characteristics, thromboembolism sites, treatments, and prognosis were analyzed. Among 956 lung cancer patients, 19 (2%) had Trousseau's syndrome. The median age was 65 years, and adenocarcinoma was the most common histologic type (78.9%). The most common site of thromboembolism was the brain (84.2%). The median survival time was 84 days, and 52.6% of patients died within 90 days of diagnosis. Patients who survived longer than 90 days tended to have a higher frequency of non-adenocarcinoma histology, EGFR gene mutations, and therapeutic induction with immune checkpoint inhibitors (ICI). Trousseau's syndrome in lung cancer patients is associated with poor prognosis. Histologic type, EGFR mutation status, and treatment with ICI may influence the prognosis. Future larger-scale studies are needed to validate these potential prognostic factors and to develop personalized treatment strategies.

Genomic signature for oligometastatic disease in non-small cell lung cancer patients with brain metastases.

Purpose/objectives: Biomarkers for extracranial oligometastatic disease remain elusive and few studies have attempted to correlate genomic data to the presence of true oligometastatic disease. Methods: Patients with non-small cell lung cancer (NSCLC) and brain metastases were identified in our departmental database. Electronic medical records were used to identify patients for whom liquid biopsy-based comprehensive genomic profiling (Guardant Health) was available. Extracranial oligometastatic disease was defined as patients having ≤5 non-brain metastases without diffuse involvement of a single organ. Widespread disease was any spread beyond oligometastatic. Fisher's exact tests were used to screen for mutations statistically associated (p<0.1) with either oligometastatic or widespread extracranial disease. A risk score for the likelihood of oligometastatic disease was generated and correlated to the likelihood of having oligometastatic disease vs widespread disease. For oligometastatic patients, a competing risk analysis was done to assess for cumulative incidence of oligometastatic progression. Cox regression was used to determine association between oligometastatic risk score and oligoprogression. Results: 130 patients met study criteria and were included in the analysis. 51 patients (39%) had extracranial oligometastatic disease. Genetic mutations included in the Guardant panel that were associated (p<0.1) with the presence of oligometastatic disease included ATM, JAK2, MAP2K2, and NTRK1, while ARID1A and CCNE1 were associated with widespread disease. Patients with a positive, neutral and negative risk score for oligometastatic disease had a 78%, 41% and 11.5% likelihood of having oligometastatic disease, respectively (p<0.0001). Overall survival for patients with positive, neutral and negative risk scores for oligometastatic disease was 86% vs 82% vs 64% at 6 months (p=0.2). Oligometastatic risk score was significantly associated with the likelihood of oligoprogression based on the Wald chi-square test. Patients with positive, neutral and negative risk scores for oligometastatic disease had a cumulative incidence of oligometastatic progression of 77% vs 35% vs 33% at 6 months (p=0.03). Conclusions: Elucidation of a genomic signature for extracranial oligometastatic disease derived from non-invasive liquid biopsy appears feasible for NSCLC patients. Patients with this signature exhibited higher rates of early oligoprogression. External validation could lead to a biomarker that has the potential to direct local therapies in oligometastatic patients.

Design, synthesis, and evaluation of dual son of sevenless 1 (SOS1) and epidermal growth factor receptor (EGFR) inhibitors for the treatment of cancers.

The treatment of KRAS mutant tumors remains challenging and dual-targeted small-molecule drugs are considered to be innovative therapeutic alternatives. Herein, we discovered a series of SOS1 and EGFR dual inhibitors by employing a fused pharmacophore strategy and structural optimization. Notably, compound 4 exhibited potent SOS1 (IC50 = 8.3 nM) and EGFR (IC50 = 14.6 nM) inhibitory activities and markedly inhibited the proliferation of other KRAS-mutant cancer cell lines. Furthermore, Western blot analysis confirmed that compound 4 effectively reduced the level of downstream p-ERK. These results indicated that compound 4 could serve as a potential compound for treating KRAS mutant tumors.

Near-infrared photoimmunotherapy for osteosarcoma targeting epidermal growth factor receptor.

Osteosarcoma is the most common bone tumor, and it possesses high metastatic propensity. Although systemic chemotherapy has improved its prognosis, improvements in survival rates have stalled in recent years. Moreover, the prognosis of patients with metastatic osteosarcoma remains poor. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective cancer therapy that induces immunogenic cell death (ICD), and the therapeutic effects spread to distant metastatic sites. Therefore, NIR-PIT could be useful in both primary and metastatic osteosarcoma treatment. In this study, we investigated the efficacy of NIR-PIT targeting epidermal growth factor receptor (EGFR) in osteosarcoma. The cytotoxic effects of NIR-PIT in osteosarcoma cell lines with different EGFR expression levels (MG63; high, Saos-2; low) were evaluated. NIR-PIT-induced cell death was dependent on the EGFR expression level. After NIR-PIT, swelling and bleb formation, the characteristic morphological changes induced by NIR-PIT associated with necrosis caused by the influx of extracellular fluid, were observed. In addition, the release of the ICD markers lactate dehydrogenase and ATP was detected after NIT-PIT. NIR-PIT significantly suppressed tumor growth in tumor-bearing mice. This study revealed that NIR-PIT targeting EGFR has therapeutic effects and induces ICD in osteosarcoma; thus, it is potentially a novel therapeutic strategy for primary and metastatic osteosarcoma.

Molecular Testing in Gliomas: What is Necessary in Routine Clinical Practice?

PURPOSE OF REVIEW: A number of molecular characteristics are essential for accurate diagnosis and prognostication in glioma. RECENT FINDINGS: The 2021 WHO classification of brain tumors and recent Food and Drug Administration (FDA) pathology agnostic drug approvals highlight the importance of molecular testing in the management of glioma. For diffuse gliomas, it is important to identify IDH mutations, given the favorable clinical behavior and potential for using FDA approved IDH inhibitors in the near future. MGMT promoter methylation testing is the most established molecular marker for response to temozolomide in IDH wild-type glioblastoma and in turn impacts overall survival. Moreover, identification of certain mutations and molecular markers, such as BRAF V600E, hypermutation or elevated tumor-mutational burden and NTRK fusions allow for the use of FDA approved agents that are tumor-agnostic. Finally, molecular testing opens options for clinical trials that are essential for diseases with limited treatment options like gliomas.

Annual change in eGFR in renal hypouricemia: a retrospective pilot study.

BACKGROUND: Extremely low uric acid (UA) levels or increased urinary UA (Uua) excretion might be risk factors for kidney disease in renal hypouricemia (RHU) patients, but their relationship with kidney dysfunction is unclear. This study investigated time-dependent changes in eGFR in RHU patients. METHODS: This multicenter retrospective study assessed UA metabolism and changes in eGFR (median 5.5 years) in 13 RHU patients. We then compared eGFR change in 7 of 13 RHU patients whose eGFR could be measured for 4 years with those in normouricemic group (n = 31). In addition, 7 RHU patients were divided into two groups based on URAT1 gene mutations: homozygote and compound heterozygote mutations (Homo/Com group, n = 3), and wild-type and heterogeneous mutations (WT/Hetero group, n = 4). RESULTS: In 13 RHU patients, the median and mean serum UA (SUA) were 0.8 (0.4-2.5) and 1.1 ± 0.7 mg/dL. The median and mean Uua were 44.3 (12.7-141.1) and 49.7 ± 36.2 mg/dL. The median and mean urinary urate clearance (Cua/Ccr) were 46.8 (11.3-73.6) and 43.3 ± 19.7%. Over 4 years, eGFR did not change in the RHU group but declined in the normouricemic group. Annual mean eGFR decline and change rate in the RHU group were the same as those in the normouricemic group (- 1.09 ± 1.11 vs. - 1.09 ± 1.92 mL/min/1.73 m2/year, p = 0.996) (- 1.74 ± 1.96 vs. - 1.36 ± 2.10%, p = 0.664). And no significant difference was found in eGFR decline or change rate between Homo/Com and WT/Hetero groups (- 0.33 ± 1.03 vs. - 1.67 ± 0.85 mL/min/1.73 m2/year, p = 0.116) (- 0.61 ± 1.62 vs. - 2.59 ± 1.91%, p = 0.210). CONCLUSION: RHU from URAT1 genetic mutation may not show eGFR decline over 4 consecutive years.

Finerenone's Impact on Major Adverse Cardiovascular Events in Chronic Kidney Disease and Type 2 Diabetes Mellitus: A Systematic Review.

Chronic kidney disease (CKD) impacts about 10% of adults globally and substantially elevates the risk of major adverse cardiovascular events (MACE), such as heart attacks, strokes, cardiovascular-related deaths, and hospital admissions due to heart failure. The interplay between CKD and cardiovascular disease (CVD) leads to poor health outcomes. Nevertheless, there is a scarcity of systematic reviews focusing on the effectiveness of finerenone, a new non-steroidal mineralocorticoid receptor antagonist (MRA), in lowering these risks. In this systematic review, we aim to evaluate the impact of finerenone on reducing MACE in individuals with CKD and type 2 diabetes mellitus (T2DM). CKD pathophysiology involves hyperglycemia, hypertension, and dyslipidemia, leading to glomerular hyperfiltration, inflammation, and fibrosis. Traditional treatments, including angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and sodium-glucose cotransporter-2 inhibitors (SGLT2i), often fall short in preventing cardiovascular events. Steroidal MRAs like spironolactone and eplerenone, while effective in reducing proteinuria, are limited by hyperkalemia risks. Finerenone offers a more selective mechanism, reducing sodium retention, inflammation, and fibrosis, with a lower risk of hyperkalemia. We searched five electronic databases comprehensively, identifying studies consistently demonstrating that finerenone significantly reduces MACE and improves renal outcomes by reducing albuminuria and slowing the fall in estimated glomerular filtration rate (eGFR). However, limitations include study heterogeneity, short follow-up periods, and potential publication bias. In conclusion, finerenone shows promise as a therapeutic option for CKD and T2DM, reducing MACE and improving renal outcomes. Further research is needed to understand its long-term benefits and safety across diverse populations.

Deciphering the Dynamics of EGFR-TKI Resistance in Lung Cancer: Insights from Bibliometric Analysis.

Background: EGFR-TKI resistance poses a significant challenge in the treatment landscape of non-small cell lung cancer (NSCLC), prompting extensive research into mechanisms and therapeutic strategies. In this study, we conduct a bibliometric analysis to elucidate evolving research hotspots and trends in EGFR-TKI resistance, offering insights for clinical interventions and scientific inquiries. Methods: Publications spanning from 1996 to 2024, focusing on EGFR-TKI resistance in NSCLC, were sourced from the Web of Science Core Collection. Utilizing VOSviewer 1.6.19, CiteSpace 6.2. R2, and Scimago Graphica 1.0.35, we analyzed these articles to identify countries/regions and institutions, Journals, publications, key contributors, collaborations, and emerging topics. Results: An analysis of 8051 articles by 38,215 researchers from 86 countries shows growing interest in EGFR-TKI resistance mechanisms. Since 1996, publications have steadily increased, surpassing 500 per year after 2016, with a sharp rise in citations. Research articles make up 84% of publications, emphasizing scholarly focus. Global collaboration, especially among researchers in China, the US, and Japan, is strong. Leading institutions like Dana-Farber and Harvard, along with journals such as "Lung Cancer", are key in sharing findings. Professors Yi-Long Wu and William Pao are prominent contributors. Keyword analysis reveals core themes, including first-generation EGFR-TKIs, emerging agents like osimertinib, and research on the T790M mutation. Conclusion: EGFR-TKI resistance remains a critical issue in NSCLC treatment, driving ongoing research efforts worldwide. Focusing future research on clear identification of resistance mechanisms will guide post-resistance treatment strategies, necessitating further exploration, alongside the validation of emerging drugs through clinical trials. Moreover, "chemo+" treatments following EGFR-TKI resistance require more clinical data and real-world evidence for assessing safety and patient outcomes. As research advances, a multidisciplinary approach will be key to overcoming these challenges. Continued innovation in treatment could greatly enhance patient survival and quality of life.

Non-invasive, fast, and high-performance EGFR gene mutation prediction method based on deep transfer learning and model stacking for patients with Non-Small Cell Lung Cancer.

Purpose: To propose an intelligent, non-invasive, highly precise, and rapid method to predict the mutation status of the Epidermal Growth Factor Receptor (EGFR) to accelerate treatment with Tyrosine Kinase Inhibitor (TKI) for patients with untreated adenocarcinoma Non-Small Cell Lung Cancer. Materials and methods: Real-world data from 521 patients with adenocarcinoma NSCLC who performed a CT scan and underwent surgery or pathological biopsy to determine EGFR gene mutation between January 2021 and July 2022, is collected. Solutions to the problems that prevent the model from achieving very high precision, namely: human errors made during the annotation of the database and the low precision of the output decision of the model, are proposed. Thus, among the 521 analyzed cases, only 40 were selected as patients with EGFR gene mutation and 98 cases with wild-type EGFR. Results: The proposed model is trained, validated, and tested on 12,040 2D images extracted from the 138 CT scans images where patients were randomly partitioned into training (80 %) and test (20 %) sets. The performance obtained for EGFR gene mutation prediction was 95.22 % for accuracy, 960.2 for F1_score, 95.89 % for precision, 96.92 % for sensitivity, 94.01 % for Cohen kappa, and 98 % for AUC. Conclusion: An EGFR gene mutation status prediction method, with high-performance thanks to an intelligent prediction model entrained by highly accurate annotated data is proposed. The outcome of this project will facilitate rapid decision-making when applying a TKI as an initial treatment.

Alleviative effects of green-fabricated zinc oxide nanoparticles on acrylamide-induced oxidative and inflammatory reactions in the rat stomach via modulating gastric neuroactive substances and the MiR-27a-5p/ROS/NF-κB axis.

Little is known about the effects of acrylamide (AMD) on the stomach. So, this study evaluated the effect of oral AMD exposure (20 mg/kg b.wt) on oxidative status, apoptotic, and inflammatory reactions in rat's stomach for 60 days. To explore novel targets of AMD toxicity, a more detailed molecular and immune-expression study was performed. Besides, the possible protective effect of green synthesized zinc oxide nanoparticles (G-ZNP) (10 mg/kg b.wt) was explored. The results revealed that AMD significantly provoked oxidative and lipid peroxidative damage of the stomach in terms of increased ROS and MDA but reduced SOD, CAT, GSH, and GSH/GSSG. Additionally, the stomachs of AMD-exposed rats showed a significant increment of PGE2 but reduced NO. Histopathologically, AMD induced a significant increase in PAS stain and the immunoexpression of iNOS and NF-κB in the glandular stomach. A significant upregulation of CART, VACHT, EGFR, caspase-3, NOS-1, and miR-27a-5p was evident in the stomach of the AMD group. Yet, G-ZNP oral dosing significantly rescued the AMD-induced oxidative damage, apoptotic reaction, inflammatory effect, and altered miR-27a-5p and gene expressions in the stomach. Conclusively, these findings demonstrated the efficacy of G-ZNP in protecting against the harmful impacts of acrylamide on stomach tissues.

FERMT1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by activating EGFR/AKT/ß-catenin and EGFR/ERK pathways.

OBJECTIVE: This study aimed to investigate the effects of fermitin family member 1 (FERMT1) on epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) via the EGFR/AKT/ß-catenin and EGFR/ERK pathways. METHODS: The expression of FERMT1 encoding protein kindlin-1 in HCC tissues was determined by immunohistochemistry, and FERMT1 mRNA expression in HCC tissues and cell lines was analyzed by qRT-PCR. After the FERMT1 expression of SNU182 and SNU387 interfered with siRNA, the cell viability, invasion, migration, and EMT were tested by CCK-8, transwell invasion, scratching, immunofluorescence/WB, respectively. Similarly, the effects of FERMT1 on the viability and metastasis of HCC were investigated in transplanted tumor and lung metastasis mouse models. The protein expressions of EGFR/AKT/ß-catenin and EGFR/ERK pathways were analyzed by WB. In addition, the relationship between FERMT1 and EGFR was further determined by immunofluorescence double staining and Co-IP. RESULTS: FERMT1 was significantly upregulated in HCC, and silencing FERMT1 inhibited the viability, invasion, migration, and EMT of HCC. Silencing FERMT1 also inhibited the activation of EGFR/AKT/ß-catenin and EGFR/ERK pathways. In addition, inhibition of EGFR, AKT, or ERK confirmed that EGFR/AKT/ß-catenin and EGFR/ERK pathways were involved in the promoting effects of FERMT1 on HCC. Co-IP and immunofluorescence experiments confirmed the targeting relationship between FERMT1 and EGFR. CONCLUSION: FERMT1 was highly expressed in HCC and promoted viability, invasion, migration, and EMT of HCC by targeting EGFR to activate the EGFR/AKT/ß-catenin and EGFR/ERK pathways. Our study revealed the role of FERMT1 in HCC and suggested that FERMT1 exerts biological effects through activating the EGFR/AKT/ß-catenin and EGFR/ERK pathways.

Comparison of efficacy of gefitinib and osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer in patients with poor performance status.

BACKGROUND: There is a dearth of studies on the efficacy and safety of the tyrosine kinase inhibitors osimertinib (OSI) and gefitinib (GEF) in treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC), even in patients with poor performance status (PS). METHODS: We retrospectively reviewed and compared data of 113 patients with EGFR mutation-positive NSCLC with Eastern Cooperative Oncology Group PS 2-4 who were administered OSI 80 mg/day or GEF 250 mg/day from May 2016 to March 2022. RESULTS: The GEF group (39 patients; median age: 74 years) included 20 patients with a PS of 2, 17 with a PS of 3, and 2 with a PS of 4. The OSI group (74 patients; median age: 76 years) included 48 patients with a PS of 2, 24 with a PS of 3, and 2 with a PS of 4. The overall response rates were 69% and 66% in the GEF and OSI groups, respectively. The disease control and PS improvement rates were 89% and 51% in both groups, respectively. The median progression-free survival in the GEF and OSI groups was 6.9 and 9.2 months, respectively (p = 0.15). The OSI group experienced better overall survival than the GEF group (median: 20.9 vs. 13.0 months, p = 0.0031). The incidence of pneumonitis was 10% and 11% in the GEF and OSI groups, respectively. One treatment-related death owing to pneumonitis occurred in the GEF group. CONCLUSIONS: OSI may be a useful treatment for untreated EGFR mutation-positive NSCLC with poor PS.

Advancements in fourth-generation EGFR TKIs in EGFR-mutant NSCLC: Bridging biological insights and therapeutic development.

Third-generation EGFR tyrosine kinase inhibitor (TKIs) have revolutionized the treatment landscape for patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations, with improved long-term outcomes compared to first-generation TKIs. Nevertheless, disease progression inevitably occurs, limiting osimertinib long-term efficacy. Indeed, the molecular biology underlying acquired resistance to first-line osimertinib is multifaceted and includes the emergence of on-target and off-target alterations. EGFR-C797S mutation represents the most frequent mechanism of on-target resistance and hinders drug binding to the target site. EGFR-independent resistance includes the activation of alternative signaling pathways, such as MET amplification and HER2 mutations, and histological transformation. In this setting, chemotherapy is the current therapeutic option, with modest clinical outcomes. Therefore, the development of novel therapeutic strategies to overcome resistance to osimertinib is a major challenge. In this setting, fourth-generation TKIs are emerging as an interesting therapeutic option to overcome on-target resistance. Preclinical drug development has led to the discovery of thiazole-amid inhibitors, which activity is mediated by the allosteric inhibition of EGFR, resulting in high specificity towards mutant-EGFR. Early phase 1/2 clinical trials are ongoing to elucidate their activity also in the clinical setting. Aim of this review is to provide a state-of-the-art analysis on preclinical development of fourth-generation EGFR-TKIs and promising preliminary clinical data.

Virtual screening, molecular dynamics simulations, and in vitro validation of EGFR inhibitors as breast cancer therapeutics.

A high abundance of Epidermal Growth Factor Receptor (EGFR) in malignant cells makes them a prospective therapeutic target for basal breast tumors. Although EGFR inhibitors are in development as anticancer therapeutics, there exists limitations due to the dose-limiting cytotoxicity that limits their clinical utilization, thereby necessitating the advancement of effective inhibitors. In the present study, we have developed common pharmacophore hypotheses using 30 known EGFR inhibitors. The best pharmacophore hypothesis DHRRR_1 was utilized for virtual screening (VS) of the Phase database containing 4.3 × 106 fully prepared compounds. The top 1000 hits were further subjected to ADME filtration followed by structure-based VS and Molecular Dynamics (MD) simulation investigations. Based on pharmacophore hypothesis matching, XP glide score, interactions between ligands and active site residues, ADME properties, and MD simulations, the five best hits (SN-01 through SN-05) were preferred for in-vitro cytotoxicity studies. All the molecules except SN-02 exhibited cytotoxicity in Triple Negative Breast Cancer (TNBC) cells. These potential EGFR inhibitors effectively downregulated the EGF-induced proliferation, migration, in-vitro tumorigenic capability, and EGFR activation (pEGFR) in the TNBCs. Additionally, in combination with doxorubicin, the identified EGFR inhibitors significantly decreased the EGF-induced proliferation. SN-04, and SN-05 in the presence of a lower concentration of doxorubicin markedly increased the apoptotic markers expression in the TNBCs, an effect which was comparable to a higher concentration of doxorubicin treatment, alone. These observations suggest that both SN-04 and/or SN-05 can improve the efficacy of chemotherapeutic drug, doxorubicin at a lower concentration to avert the higher dose of chemotherapeutic-induced side effects during breast cancer treatment.

First-line treatment of EGFR-mutated non-small cell lung cancer with brain metastases: a systematic review and meta-analysis.

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433-0.973) and 0.682 (95% CI: 0.464-0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511-1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14-3.4) and PFS 2.13 (95% CI: 1.28-3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation.

Deep learning-based analysis of EGFR mutation prevalence in lung adenocarcinoma H&E whole slide images.

EGFR mutations are a major prognostic factor in lung adenocarcinoma. However, current detection methods require sufficient samples and are costly. Deep learning is promising for mutation prediction in histopathological image analysis but has limitations in that it does not sufficiently reflect tumor heterogeneity and lacks interpretability. In this study, we developed a deep learning model to predict the presence of EGFR mutations by analyzing histopathological patterns in whole slide images (WSIs). We also introduced the EGFR mutation prevalence (EMP) score, which quantifies EGFR prevalence in WSIs based on patch-level predictions, and evaluated its interpretability and utility. Our model estimates the probability of EGFR prevalence in each patch by partitioning the WSI based on multiple-instance learning and predicts the presence of EGFR mutations at the slide level. We utilized a patch-masking scheduler training strategy to enable the model to learn various histopathological patterns of EGFR. This study included 868 WSI samples from lung adenocarcinoma patients collected from three medical institutions: Hallym University Medical Center, Inha University Hospital, and Chungnam National University Hospital. For the test dataset, 197 WSIs were collected from Ajou University Medical Center to evaluate the presence of EGFR mutations. Our model demonstrated prediction performance with an area under the receiver operating characteristic curve of 0.7680 (0.7607-0.7720) and an area under the precision-recall curve of 0.8391 (0.8326-0.8430). The EMP score showed Spearman correlation coefficients of 0.4705 (p = 0.0087) for p.L858R and 0.5918 (p = 0.0037) for exon 19 deletions in 64 samples subjected to next-generation sequencing analysis. Additionally, high EMP scores were associated with papillary and acinar patterns (p = 0.0038 and p = 0.0255, respectively), whereas low EMP scores were associated with solid patterns (p = 0.0001). These results validate the reliability of our model and suggest that it can provide crucial information for rapid screening and treatment plans.

Driver gene alterations in NSCLC patients in southern China and their correlation with clinicopathologic characteristics.

Introduction: In this study, we aimed to explore the relationship between clinicopathological features and driver gene changes in Chinese NSCLC patients. Methods: Amplification refractory mutation system PCR was used to detect the aberrations of 10 driver oncogenes in 851 Chinese NSCLC patients, and their correlation with clinicopathological characteristics was also analyzed. Moreover, three models of logistic regression were used to analyze the association between histopathology and EGFR or KRAS mutations. Results: The top two most frequently aberrant target oncogenes were EGFR (48.06%) and KRAS (9.51%). These were followed by ALK (5.41%), HER2 (2.35%), MET (2.23%), RET (2.11%), ROS1 (1.88%), BRAF (0.47%), NRAS (0.24%), and PIK3CA (0.12%). Additionally, 11 (1.29%) patients had synchronous gene alterations in two genes. The main EGFR mutations were exon 21 L858R and exon 19-Del, which accounted for 45.97% and 42.79% of all EGFR mutations, respectively. Logistic regression analysis showed that the frequency of EGFR mutations was positively correlated with women, non-smokers, lung adenocarcinoma, and invasive non-mucinous adenocarcinoma (IA), and negatively correlated with solid nodule, micro-invasive adenocarcinoma, and solid-predominant adenocarcinoma. KRAS mutations were positively associated with men and longer tumor long diameters and negatively correlated with lung adenocarcinoma (P < 0.05 for all). Conclusion: Our findings suggest that the EGFR mutation frequency was higher in women, non-smokers, lung adenocarcinoma, and the IA subtype in lung adenocarcinoma patients, while the KRAS mutation rate was higher in men and patients with longer tumor long diameter and lower in lung adenocarcinoma patients.

EGFRVIII and EGFR targeted chimeric antigen receptor T cell therapy in glioblastoma.

Glioblastoma is the most common primary brain tumor. Although there have been significant advances in surgical techniques, chemo and immunotherapies, and radiation therapy, outcomes continue to be devastating for these patients with minimal improvements in survival. Chimeric antigen receptor T cell therapy is a revolutionary approach that is a new pillar in the treatment of cancer. CAR T cell therapy has produced remarkable results in hematological malignancies; however, multiple limitations currently prevent it from being a first-line therapy, especially for solid tumors. Epidermal growth factor receptor is classically amplified in glioblastoma, and a variant, EGFR variant III, is expressed on glioblastoma, making it an exciting potential target for CAR T cell therapy. Although preclinical has exciting potential, clinical data has been heterogeneous. In this review, we assess the state of field of EGFR-targeted CAR T cells.