Exploration of cytotoxicity of iodoquinazoline derivatives as inhibitors of both VEGFR-2 and EGFRT790M: Molecular docking, ADMET, design, and syntheses.

Novel inhibitors of epidermal growth factor receptor (EGFR)T790M/vascular endothelial growth factor receptor-2 (VEGFR-2) were synthesized based on the iodoquinazoline scaffold linked to different heteroaromatic, aromatic, and/or aliphatic moieties. The novel derivatives were in vitro examined for anticancer activities against A549, HCT116, michigan cancer foundation-7 (MCF-7), and HepG2 cells. Molecular modeling was applied to discover their orientation of binding with both VEGFR-2 and EGFR active sites. Compounds 8d, 8c, 6d, and 6c indicated the highest cytotoxicity with IC50 = 6.00, 6.90, 6.12 and 6.24 µM, 7.05, 7.35, 6.80, and 6.80 µM, 5.75, 7.50, 6.90, and 6.95 µM, and 6.55, 7.88, 7.44, and 7.10 µM against the A549, HepG2, HCT116, and MCF-7 cell lines, correspondingly. The cytotoxicity against normal VERO (normal african green monkey kidney cells) of the extremely active eight compounds 6a-d and 8a-d was evaluated. Our compounds exhibited low toxicity concerning normal VERO cells with IC50 = 45.66-51.83 µM. Furthermore, inhibition assays for both the EGFRT790M and VEGFR-2 enzymes were done for all compounds. Remarkable inhibition of EGFRT790M activity was achieved with compounds 6d, 8d, 6c, and 8c at IC50 = 0.35, 0.42, 0.48, and 0.50 µM correspondingly. Moreover, remarkable inhibition of VEGFR-2 activity was achieved with compounds 8d, 8c, 6d, and 6c at IC50 = 0.92, 0.95, 1.00, and 1.20 µM correspondingly. As planned, derivatives 6d, 8d, 6c, and 8c presented exceptional inhibition of both EGFRT790M/VEGFR-2 activities. Finally, in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were made for the highly active four compounds 6c, 6d, 8c, and 8d in comparison with erlotinib and sorafenib as reference standards.

Clinical Effectiveness and Safety of Transarterial Chemoembolization: Hepatic Artery Infusion Chemotherapy Plus Tyrosine Kinase Inhibitors With or Without Programmed Cell Death Protein-1 Inhibitors for Unresectable Hepatocellular Carcinoma-A Retrospective Study.

BACKGROUND: Locoregional treatment with transarterial chemoembolization (TACE) or hepatic artery infusion chemotherapy (HAIC) and systemic targeted immunotherapy with tyrosine kinase inhibitors (TKI) and programmed cell death protein-1 (PD-1) inhibitors in the treatment of unresectable hepatocellular carcinoma (uHCC) have achieved promising efficacy. The retrospective study aimed to evaluate the efficacy and safety of TACE and HAIC plus TKI with or without PD-1 for uHCC. PATIENTS AND METHODS: From November 2020 to February 2024, the data of 44 patients who received TACE-HAIC + TKI + PD-1 (THKP group) and 34 patients who received TACE-HAIC + TKI (THK group) were retrospectively analyzed. Primary outcomes were overall survival (OS) and progress-free survival (PFS), and secondary outcomes were objective response rate (ORR), disease control rate (DCR), conversion rates, and adverse events (AEs). RESULTS: A total of 78 patients were recruited in our single-center study. The patients in THKP group had prolonged median OS [25 months, 95% confidence interval (CI) 24.0-26.0 vs 18 months, 95% CI 16.1-19.9; p = 0.000278], median PFS [16 months, 95% CI 14.1-17.9 vs 12 months 95% CI 9.6-14.4; p = 0.004] and higher ORR (38.6% vs 23.5%, p = 0. 156) and DCR (88.6% vs 64.7%, p = 0.011) compared with those in THK group. Multivariate analysis showed that treatment option and alpha-fetoprotein (AFP) level were independent prognostic factors of OS and PFS. The frequency of AEs were similar between the two groups. CONCLUSIONS: The THKP group had better efficacy for uHCC than the THK group, with acceptable safety.

Oral lichenoid drug eruption due to osimertinib for lung cancer.

INTRODUCTION: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR) are linked with side effects involving skin and mucosa. Herein, we present a unique case of oral lichenoid drug eruption (LDE) in a patient treated with osimertinib. CASE REPORT: A 75-year-old woman was diagnosed with metastatic EGFR-mutated lung adenocarcinoma, and started on osimertinib 80 mg PO daily. At 24 months of therapy, the patient developed a painful, red, and white striated oral lesion involving the left buccal mucosa and the adjacent buccal aspect of gingivae. Biopsy showed oral LDE. Causality assessment between osimertinib and the oral LDE via Naranjo Adverse Drug Reaction probability scale revealed a score of 5. MANAGEMENT AND OUTCOME: Osimetinib discontinuation was not felt to be in the best interest of the patient. Therefore, diphenhydramine HCL mouthwash every 6 h PRN (before meals) was started. Spicy and hot foods were discontinued. At a four-week follow-up visit, the patient reported moderate improvement in her symptoms. CONCLUSION: Oral LDEs are considered premalignant lesions as they can transform into squamous cell carcinoma; therefore, regular follow-up is needed. Awareness of this potential side effect of osimertinib would also prevent unnecessary (and potentially costly) work-up and lead to its prompt diagnosis and treatment.

Cheminformatics-based identification of phosphorylated RET tyrosine kinase inhibitors for human cancer.

Background: Rearranged during transfection (RET), an oncogenic protein, is associated with various cancers, including non-small-cell lung cancer (NSCLC), papillary thyroid cancer (PTC), pancreatic cancer, medullary thyroid cancer (MTC), breast cancer, and colorectal cancer. Dysregulation of RET contributes to cancer development, highlighting the importance of identifying lead compounds targeting this protein due to its pivotal role in cancer progression. Therefore, this study aims to discover effective lead compounds targeting RET across different cancer types and evaluate their potential to inhibit cancer progression. Methods: This study used a range of computational techniques, including Phase database creation, high-throughput virtual screening (HTVS), molecular docking, molecular mechanics with generalized Born surface area (MM-GBSA) solvation, assessment of pharmacokinetic (PK) properties, and molecular dynamics (MD) simulations, to identify potential lead compounds targeting RET. Results: Initially, a high-throughput virtual screening of the ZINC database identified 2,550 compounds from a pool of 170,269. Subsequent molecular docking studies revealed 10 compounds with promising negative binding scores ranging from -8.458 to -7.791 kcal/mol. MM-GBSA analysis further confirmed the potential of four compounds to exhibit negative binding scores. MD simulations demonstrated the stability of CID 95842900, CID 137030374, CID 124958150, and CID 110126793 with the target receptors. Conclusion: These findings suggest that these selected four compounds have the potential to inhibit phosphorylated RET (pRET) tyrosine kinase activity and may represent promising candidates for the treatment of various cancers.

Anaplastic Lymphoma Kinase-Tyrosine Kinase Inhibitor Treatment for Metastatic Non-small Cell Lung Cancer Throughout the Entire Gestation Period.

Non-small cell lung cancer (NSCLC) occasionally develops in younger, fertile patients. This early-onset NSCLC tends to have more oncogenic driver mutations than in aged patients. Among early-onset NSCLC patients, pregnancy is very rare. However, there are some patients who were able to balance tyrosine kinase inhibitor (TKI) administration and pregnancy. Here, we report a case of a pregnancy under alectinib hydrochloride (a second-generation anaplastic lymphoma kinase (ALK)-TKI) administration throughout the entire gestational period for ALK-rearranged metastatic lung adenocarcinoma. The patient was an Asian female in her early 20s who became aware of her pregnancy after diagnosis and the start of alectinib administration. She intended to have the baby despite the necessity of continuing her treatment and the unknown risks involved. A multidisciplinary team (thoracic surgeon, obstetrics, pediatrics, and so on) was organized to support the patient, baby, and family. There were no obvious signs of tumor progression during pregnancy. She gave birth at 41 weeks and one day of gestation. There was no placental metastasis. Alectinib concentration at delivery was 155 ng/mL in maternal blood, 22.1 ng/mL in umbilical cord venous blood, 20.1 ng/mL in amniotic fluid, and 11.8 ng/mL in colostrum. The baby had been exposed to alectinib throughout the entire pregnancy; however, fetal growth curve parameters remained within the normal ranges and the baby developed without anatomical or neurodevelopmental anomalies or fetal metastasis for the first 13 months of age.

Clinical and laboratory remission with rituximab in anti-MuSK-positive myasthenia gravis.

BACKGROUND: Increasing data are available on the use and efficacy of rituximab (RTX) in patients with anti-muscle-specific tyrosine kinase (MuSK)-positive myasthenia gravis (MG), especially those steroid-dependent or unresponsive to traditional immunotherapies. AIMS: We aimed to evaluate the clinical characteristics and treatment responses of adult patients with generalized anti-MuSK-positive MG treated with RTX. METHODS: We retrospectively recruited 16 patients who were on RTX, between January 2010 and September 2023. RTX was given 1000 mg/day intravenously twice, two weeks apart. Maintenance treatment was administered at intervals of 3-6 months based on clinical evaluation. The outcome was assessed by Myasthenia Gravis Foundation of America (MGFA) and Myasthenia Gravis Status and Treatment Intensity (MGSTI) scores. Additionally, anti-MuSK antibody levels were retested after treatment in all patients except one. RESULTS: Twelve patients were female. The mean age at disease onset was 35.3 ± 17.3 years. The median duration between disease onset and RTX administration was 2.4 years (min-max: 0.5-36.5 years). The worst MGFA class before RTX was between IIIb-V. After RTX treatment, 81.3% of patients achieved MGFA minimal manifestations or better and MGSTI level 1 or better. Anti-MuSK antibodies became negative in 12 patients, while they remained positive in three. The changes in antibody levels seemed associated with clinical outcomes. CONCLUSIONS: RTX is an effective treatment in anti-MuSK-positive MG. Furthermore, our results support the inhibition of antibody production by RTX and we recommend monitoring anti-MuSK antibody titers to follow disease progression and treatment response.

Anlotinib potentiates anti-PD1 immunotherapy via transferrin receptor-dependent CD8+ T-cell infiltration in hepatocellular carcinoma.

BACKGROUND: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. OBJECTIVE: This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC. METHODS: Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. RESULTS: The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC. CONCLUSIONS: Our findings highlight anlotinib's potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. HIGHLIGHTS: Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.

Spleen tyrosine kinase (SYK): an emerging target for the assemblage of small molecule antitumor agents.

INTRODUCTION: Spleen tyrosine kinase (SYK), a nonreceptor tyrosine kinase, has emerged as a vital component in the complex symphony of cancer cell survival and division. SYK activation (constitutive) is documented in various B-cell malignancies, and its inhibition induces programmed cell death. Also, in some instances, it acts as a tumor suppressor. AREAS COVERED: Involvement of the SYK in the cancer growth, specifically in the progression of chronic lymphocytic leukemia (CLL), diffuse large B cell lymphomas (DLBCLs), acute myeloid leukemia (AML), and multiple myeloma (MM) is discussed. Therapeutic strategies to target SYK in cancer, including investigational SYK inhibitors, combinations of SYK inhibitors with other drugs targeting therapeutically relevant targets, and recent advancements in constructing new structural assemblages as SYK inhibitors, are also covered. EXPERT OPINION: The SYK inhibitor field is currently marred by the poor translation rate of SYK inhibitors from preclinical to clinical studies. Also, dose-limited toxicities associated with the applications of SYK inhibitors have been evidenced. Thus, the development of new SYK inhibitory structural templates in the need of the hour. To accomplish the aforementioned, interdisciplinary teams should incessantly invest efforts to expand the size of the armory of SYK inhibitors.

Exploring the multifaceted antitumor activity of axitinib in lung carcinoids.

Introduction: Lung carcinoids (LCs) are a type of neuroendocrine tumor (NET) that originate in the bronchopulmonary tract. LCs account for 20-25% of all NETs and approximately 1-2% of lung cancers. Given the highly vascularized nature of NETs and their tendency to overexpress vascular growth factor receptors (VEGFR), inhibiting angiogenesis appears as a potential therapeutic target in slowing down tumor growth and spread. This study evaluated the long-term antitumor activity and related mechanisms of axitinib (AXI), a VEGFR-targeting drug, in LC cell lines. Methods: Three LC cell lines (NCI-H727, UMC-11 and NCI-H835) were incubated with their respective EC50 AXI concentrations for 6 days. At the end of the incubation, FACS experiments and Western blot analyses were performed to examine changes in the cell cycle and the activation of apoptosis. Microscopy analyses were added to describe the mechanisms of senescence and mitotic catastrophe when present. Results: The primary effect of AXI on LC cell lines is to arrest tumor growth through an indirect DNA damage. Notably, AXI triggers this response in diverse manners among the cell lines, such as inducing senescence or mitotic catastrophe. The drug seems to lose its efficacy when the DNA damage is mitigated, as observed in NCI-H835 cells. Conclusion: The ability of AXI to affect cell viability and proliferation in LC tumor cells highlights its potential as a therapeutic agent. The role of DNA damage and the consequent activation of senescence seem to be a prerequisite for AXI to exert its function.

Efficacy and safety of first- versus second-generation Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia: a systematic review and meta-analysis.

We conducted this first systematic review and meta-analysis to assess the competitive advantage of 2nd-generation Bruton tyrosine kinase inhibitors (BTKi) compared to 1st-generation BTKi in chronic lymphocytic leukemia (CLL). The literature search was conducted from PubMed, Web of Science, Embase databases, and hematology annual conferences. Data of over response rate (ORR), progression-free survival (PFS), and overall survival (OS) were extracted to a pool meta-analysis of efficacy; adverse events (AEs) were also extracted to a pool meta-analysis of safety. Bias risk assessment and meta-analysis were performed by Review Manager 5.3 and STATA 14 software. A total of 3649 patients from 29 cohorts were included. The results showed that the benefits of ORR and 24-month PFS in 2nd-generation BTKi compared to 1st-generation BTKi were not significant in the whole population but only in the relapsed or refractory (R/R) CLL patient subgroup (ORR: 86.4% vs. 76.2%, p = 0.013; 24-month PFS: 76.9% vs. 67.9%, p = 0.004). Any-grade AEs were comparable between 1st- and 2nd-generation BTKi, but grade 3 or higher AEs were significantly less frequent with 2nd-generation BTKi versus 1st-generation BTKi (grade 3 or higher: 53.1% vs. 72.5%; p = 0.002). Headache was more frequent with 2nd-generation BTKi, while diarrhea and atrial fibrillation were more frequent with 1st-generation BTKi. Only for patients with relapsed or refractory CLL did 2nd-generation BTKi have a competitive advantage, while adverse effects still need to be considered. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, Identifier 42022342488.

Syngeneic mouse model of YES-driven metastatic and proliferative hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a disease of high unmet medical need that has become a global health problem. The development of targeted therapies for HCC has been hindered by the incomplete understanding of HCC pathogenesis and the limited number of relevant preclinical animal models. We recently unveiled a previously uncharacterized YES kinase (encoded by YES1)-dependent oncogenic signaling pathway in HCC. To model this subset of HCC, we established a series of syngeneic cell lines from liver tumors of transgenic mice expressing activated human YES. The resulting cell lines (referred to as HepYF) were enriched for expression of stem cell and progenitor markers, proliferated rapidly, and were characterized by high SRC family kinase (SFK) activity and activated mitogenic signaling pathways. Transcriptomic analysis indicated that HepYF cells are representative of the most aggressive proliferation class G3 subgroup of HCC. HepYF cells formed rapidly growing metastatic tumors upon orthotopic implantation into syngeneic hosts. Treatment with sorafenib or the SFK inhibitor dasatinib markedly inhibited the growth of HepYF tumors. The new HepYF HCC cell lines provide relevant preclinical models to study the pathogenesis of HCC and test novel small-molecule inhibitor and immunotherapy approaches.

Immunostaining and gene expression of epidermal growth factor receptors (HER1/HER2) in canine cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is a neoplasm type often diagnosed in dogs. However, studies focused on further investigating its molecular biology, mainly biomarkers to help implementing new therapies, remain scare in the literature. Thus, immunostaining and the gene expression of epidermal growth factor receptors (HER1 and HER2) in canine cSCC presenting different cell differentiation degrees were herein assessed. Thirty-two (32) canine cSCC were selected, classified based on to their cell differentiation degree and subjected to immunohistochemical study to assess HER1 and HER2 immunostaining intensity and distribution. In addition, HER1 and HER2 gene expression was investigated through real-time PCR. Membranous and cytoplasmic immunostaining were observed in both markers. HER2 prevailed in poorly differentiated cSCC; there was positive protein expression correlation between both markers. Mean HER1 gene expression was higher in moderately differentiated, whereas mean HER2 gene expression was higher in poorly differentiated cSCC. Moreover, there was gene expression correlation between markers, regardless of cell differentiation degree. Thus, HER2 protein immunostaining and gene expression were higher in poorly differentiated canine cSCC and it enabled understanding that increase observed in this epidermal growth factor receptor is proportional to this neoplasm's cell differentiation degree in canine species. Results in the current study helped better understanding canine cSCC's molecular biology; however, it is relevant studying other markers aiming to investigate signaling pathways.

Case report: Pathological complete response to neoadjuvant brigatinib in stage III non-small cell lung cancer with ALK rearrangement.

Purpose: The use of neoadjuvant anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) has not been extensively explored. The current case report highlights the notable pathological complete response (pCR) achieved following neoadjuvant brigatinib therapy in a patient with stage IIIA ALK-positive non-small cell lung cancer (NSCLC). Case presentation: A 32-year-old male presented with incidental lung lesions, ultimately diagnosed as clinical stage T3N1M0, IIIA NSCLC with an ALK gene rearrangement. Following a multidisciplinary discussion, the patient opted for neoadjuvant brigatinib therapy, which significantly reduced the tumor size. Subsequently, surgery with curative intent was performed, revealing pCR with no residual tumor cells. The patient remained disease-free during a 13-month follow-up period. Conclusion: This case report provides compelling evidence of pCR following brigatinib therapy in ALK-positive NSCLC, suggesting that surgery after neoadjuvant therapy with brigatinib may offer a safe and effective approach for patients with ALK-positive NSCLC.

Understanding the treatment response and resistance to targeted therapies in non-small cell lung cancer: clinical insights and perspectives.

Lung cancer remains the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with a generally poor prognosis. In recent years, advances in targeted therapy and sequencing technology have brought significant improvement in the therapeutic outcomes of patients with advanced NSCLC. Targeted inhibitors directed against specific mutated or rearranged oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and receptor tyrosine kinase ROS proto-oncogene 1(ROS1) among others, exhibit promising anti-tumor activity. Unfortunately, some patients develop acquired resistance and disease progression soon after initial remission. Despite the continuous development of new drugs and strategies to overcome drug resistance, it is still a major challenge in the treatment of NSCLC. The landscape of targeted therapy for NSCLC is evolving rapidly in response to the pace of scientific research. This study aimed to provide a comprehensive review of tumor target antigens and agents related to targeted therapy in NSCLC.

Metformin reduces basal subpopulation and attenuates mammary epithelial cell stemness in FVB/N mice.

Metformin shows promise in breast cancer prevention, but its underlying mechanisms remain unclear. This study investigated the impact of metformin on the repopulation dynamics of mammary epithelial cells (MECs) and the signaling pathways in non-tumorigenic FVB/N mice. This study aimed to enhance our understanding of the role of metformin in reducing the susceptibility of MECs in premalignant tissues to oncogenic factors. In this study, female mice were administered 200 mg/kg/day of metformin via intraperitoneal (i.p.) injection from 8 to 18 weeks of age. After this treatment period, morphogenesis, flow cytometry, analyses of MEC stemness, and RNA sequencing were performed. The study findings indicated that metformin treatment in adult mice reduced mammary gland proliferation, as demonstrated by decreased Ki67+ cells and lateral bud formation. Additionally, metformin significantly reduced both basal and mammary repopulating unit subpopulations, indicating an impact on mammary epithelial cell repopulation. Mammosphere, colony-forming cell, and 3D culture assays revealed that metformin adversely affected mammary epithelial cell stemness. Furthermore, metformin downregulated signaling in key pathways including AMPK/mTOR, MAPK/Erk, PI3K/Akt, and ER, which contribute to its inhibitory effects on mammary proliferation and stemness. Transcriptome analysis with RNA sequencing indicated that metformin induced significant downregulation of genes involved in multiple critical pathways. KEGG-based pathway analysis indicated that genes in PI3K/Akt, focal adhesion, ECM-receptor, small cell lung cancer and immune-modulation pathways were among the top groups of differentially regulated genes. In summary, our research demonstrates that metformin inhibits MEC proliferation and stemness, accompanied by the downregulation of intrinsic signaling. These insights suggest that the regulatory effects of metformin on premalignant mammary tissues could potentially delay or prevent the onset of breast cancer, offering a promising avenue for developing new preventive strategies.

Sporadic Parathyroid Carcinoma Treated With Lenvatinib, Exhibiting a Novel Somatic MEN1 Mutation.

Parathyroid carcinoma (PC) is extremely rare and is primarily treated surgically. Chemotherapy is an option for advanced stages, but no standard regimen exists. Emerging research suggests the efficacy of multitarget tyrosine kinase inhibitors (MTKIs) for PC, targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). A 61-year-old Japanese woman presented with a neck mass, diagnosed as PC with pleural and lumbar metastases. After parathyroidectomy and radiation for lumbar metastasis, immunohistochemistry showed VEGFR overexpression, leading to targeted therapy with MTKIs. Despite no actionable mutations on cancer genomic panel test, a novel MEN1 somatic mutation (NM_130801: exon2: c.332delG: p.G111fs*8) was identified, which may affect VEGFR2 expression and tumor epigenetics. Although severe hand-foot syndrome necessitated dose reductions and treatment interruptions, sorafenib treatment managed hypercalcemia with evocalcet and denosumab. Lenvatinib, as second-line therapy, was effective against pleural metastases but caused thrombocytopenia and hematuria, leading to discontinuation and uncontrolled recurrence and metastasis progression. Our case highlights the need for further research on genomic profiling, molecular targets, and therapy response in PC.

Improved survival outcome of curative liver resection for Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma in the era of tyrosine kinase inhibitors.

AIM: This study was undertaken to evaluate the outcome of curative liver resection, (LR) of Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma (BCLC-C HCC) after tyrosine kinase inhibitors (TKIs) became approved as a treatment option for recurrent lesions. METHODS: Sixty-seven patients with BCLC-C HCC who underwent curative LR were enrolled in this study. The patients were classified into two groups according to whether LR was performed before (n = 24) or after (n = 43) TKI approval ("beforeTKI" and "afterTKI" group, respectively). RESULTS: There was no difference in the median disease-free survival time after LR between the beforeTKI and afterTKI groups (5.6 and 7.1 months, respectively; p = 0.435). However, the median survival time after LR was longer in the afterTKI than beforeTKI group (42.7 and 14.9 months, respectively; p = 0.022). Univariate and multivariate analyses showed that the date of LR was the only independent factor affecting postresection survival. When the patients were limited to those with recurrence, there were no differences in the recurrence pattern or progression of HCC at the time of recurrence between the two groups. The only difference in the treatment distribution was the administration of TKIs (14 of 34 patients in afterTKI group and only 1 of 19 patients in beforeTKI group, p < 0.001). CONCLUSION: These data suggest that TKI therapy for recurrent BCLC-C HCC is associated with improved overall survival. Thus, LR could be a promising option for BCLC-C HCC in the current era of TKI therapy.

Unraveling the future: Innovative design strategies and emerging challenges in HER2-targeted tyrosine kinase inhibitors for cancer therapy.

Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor-like protein with tyrosine kinase activity that plays a vital role in processes such as cell proliferation, differentiation, and angiogenesis. The degree of malignancy of different cancers, notably breast cancer, is strongly associated with HER2 amplification, overexpression, and mutation. Currently, widely used clinical HER2 tyrosine kinase inhibitors (TKIs), such as lapatinib and neratinib, have several drawbacks, including susceptibility to drug resistance caused by HER2 mutations and adverse effects from insufficient HER2 selectivity. To address these issues, it is essential to create innovative HER2 TKIs with enhanced safety, effectiveness against mutations, and high selectivity. Typically, SPH5030 has advanced to phase I clinical trials for its strong suppression of four HER2 mutations. This review discusses the latest research progress in HER2 TKIs, with a focus on the structural optimization process and structure-activity relationship analysis. In particular, this study highlights promising design strategies to address these challenges, providing insightful information and inspiration for future development in this field.