A real-world pharmacovigilance study of amivantamab-related cardiovascular adverse events based on the FDA adverse event reporting system (FAERS) database.

Amivantamab is the first dual-specificity antibody targeting EGFR and MET, which is approved for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. Cardiovascular toxicities related to amivantamab have not been reported in the CHRYSALIS study. However, the occurrence of cardiovascular events in the real world is unknown. To comprehensively investigate the clinical characteristics, onset times, and outcomes of cardiovascular toxicities associated with amivantamab. The Food and Drug Administration Adverse Event Reporting System (FAERS) database from 1st quarter of 2019 to the 2nd quarter of 2023 was retrospectively queried to extract reports of cardiovascular adverse events (AEs) associated with amivantamab. To perform disproportionality analysis, the reporting odds ratios (RORs) and information components (ICs) were calculated with statistical shrinkage trans-formation formulas and a lower limit of the 95% confidence interval (CI) for ROR (ROR025) > 1 or IC (IC025) > 0 with at least 3 reports was considered statistically significant. A total of 20,270,918 eligible records were identified, among which 98 records were related to cardiovascular events associated with amivantamab. 4 categories of cardiovascular events exhibited positive signals: venous thrombotic diseases, abnormal blood pressure, arrhythmia, and pericardial effusion. Venous thrombotic diseases and abnormal blood pressure were the two most common signals. The median time to onset (TTO) for cardiovascular AEs was 33 days. The cumulative incidence within 90 days was 100% for cardiac failure, 75% for stroke, 63.16% for arrhythmia, 50% for sudden death, and 44.18% for venous thrombotic diseases. Death accounted for 16.3% of all cardiovascular AEs associated with amivantamab. The mortality rates for Major Adverse Cardiovascular Events (MACE) were up to 60%. This pharmacovigilance study systematically explored the cardiovascular adverse events of amivantamab and provided new safety signals based on past safety information. Early and intensified monitoring is crucial, and attention should be directed towards high-risk signals.

Ubiquitin-Specific Protease 43 Impacts Pancreatic Ductal Adenocarcinoma Prognosis by Altering Its Proliferation and Infiltration of Surrounding Immune Cells.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer, and the therapy options for PDAC remain restricted. The distinctive tumor immunological microenvironment (TIME) of PDAC, comprising a high number of stromal cells and a limited infiltration of cytotoxic T lymphocytes (CTLs), rendered immunotherapy ineffective. The protein level of ubiquitin-specific protease 43 (USP43) was a prognostic predictor in numerous cancers; however, its function in PDAC is limited. This article focuses on the influence of USP43 expression on PDAC prognosis and TIME alteration. Methods: Based on TCGA database and tissue microarray staining, the expression of USP43 in PDAC was evaluated. The association between USP43 and prognosis was then investigated using tissue samples and online databases. In PDAC tumor tissues, the correlation between USP43 expression and clinicopathological characteristics, immune cell infiltration, and prognosis was investigated. The expression of USP43 in PDAC cell lines was evaluated using quantitative polymerase chain reaction. Using a cell counting kit-8 (CCK-8) and a cell colony formation test, the viability of the cells was determined. On the basis of online databases and tissue samples, the link between USP43 and immune cell infiltration around PDAC was also examined. For statistical analyses, the software GraphPad, R, and SPSS 26.0 were utilized. Results: The expression of USP43 was considerably higher in PDAC compared to normal pancreatic tissue in both the TCGA database and the tissue microarrays of PDAC patients (P < 0.001). High USP43 expression was associated with poor overall survival in both the TCGA database and the tissue microarray of PDAC patients (P = 0.046 and 0.021, respectively). USP43 overexpression promoted PANC-1 cell proliferation (P = 0.0018), but USP43 knockdown decreased PANC02 cell proliferation (P < 0.001). According to the TCGA database, USP43 is associated with T cell activation and inhibits CD8+ T cell activation in PDAC, as proven by a study of cell lines. Moreover, in both TCGA and PDAC cell lines, USP43 expression was negatively linked with the chemokine signaling pathway. Conclusions: Overexpression of USP43 is a potential prognostic indicator for PDAC patients. USP43 is a potential biomarker associated with T cell activation, suppression of CD8+ T cell enrichment, and the cytokine signal pathway. Future multicenter studies are needed to confirm our findings and their potential application in the treatment of PDAC patients.

RIOK3 promotes mTORC1 activation by facilitating SLC7A2-mediated arginine uptake in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis. Reprogramming of amino acid metabolism is one of the characteristics of PDAC, in which arginine metabolism is significantly altered in PDAC cells and is involved in important signaling pathways. Current studies have identified arginine deprivation as a potential strategy for PDAC treatment. In this study, we performed Liquid Chromatograph Mass Spectrometer (LC-MS)-based non-targeted metabolomic analysis on PDAC cell lines with stable Rio Kinase 3 (RIOK3) knockdown and PDAC tissues with different RIOK3 expressions and found that RIOK3 expression was significantly correlated with arginine metabolism in PDAC. Subsequent RNA sequencing (RNA-Seq) and Western blot analysis showed that RIOK3 knockdown significantly inhibited the expression of arginine transporter solute carrier family 7 member 2 (SLC7A2). Further studies revealed that RIOK3 promoted arginine uptake, mechanistic target of rapamycin complex 1 (mTORC1) activation, cell invasion, and metastasis in PDAC cells via SLC7A2. Finally, we found that patients with high expression of both RIOK3 and infiltrating Treg cells had a worse prognosis. Overall, our study found that RIOK3 in PDAC cells promotes arginine uptake and mTORC1 activation through upregulation of SLC7A2 expression, and also provides a new therapeutic target for therapeutic strategies targeting arginine metabolism.

Case Report: A long-term survival case of diffuse large B-cell lymphoma with left ventricular infiltration and spinal cord compression.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and may occur with lymph node and/or extranodal involvement. However, DLBCL with intracardiac mass is exceedingly rare. In the reported literature, the intracardiac infiltration of DLBCL mostly involves the right ventricle. Lymphoma that invades the heart has an aggressive nature, with symptoms that are easily ignored initially and can lead to multiple complications in severe cases, resulting in a poor prognosis. Early screening and diagnosis may significantly improve the survival rate. Early diagnosis may significantly improve outcomes. Case summary: We presented a 68-year-old woman with back pain. PET/CT suggested increased FDG metabolism in the left ventricle, right adrenal gland, right erector spinae intramuscularis, multiple bones and multiple lymph nodes. Contrast-enhanced ultrasound showed a left ventricular apical mass with ventricular septum thickening. Cardiac MRI suggested a 1.6*1.1*2.1 cm mass in the apical-central portion of the left ventricle. Biopsy of the right neck mass confirmed the pathologic diagnosis of diffuse large B-cell lymphoma. However, before the pathologic diagnosis was confirmed, the patient was paralyzed due to spinal cord compression caused by the progression of bone metastases. Subsequently, pathology confirmed the diagnosis of diffuse large B-cell lymphoma, and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was treated immediately as first-line therapy. In addition, glucocorticoids and mannitol dehydration were administered to relieve the symptoms of spinal cord compression. After 8 cycles of R-CHOP, the tumor at all sites had almost complete regression. The patient was able to walk normally and had no tumor-related symptoms. Conclusions: We present a case of DLBCL with a very high tumor load that involved multiple organs, including the left ventricle, but exhibited no cardiac-related symptoms. The combination of various imaging modalities is valuable for the diagnosis of cardiac infiltration. The mass in the left ventricle almost completely regressed after R-CHOP treatment, and no recurrence has occurred in the 5 years of follow-up so far.

Lenvatinib as second-line treatment in patients with unresectable hepatocellular carcinoma: A retrospective analysis.

Objective: The purpose of this study is to determine the efficacy and safety of lenvatinib as second-line therapy in Chinese patients with unresectable hepatocellular carcinoma (HCC). Methods: We performed a retrospective analysis of Chinese patients with unresectable HCC who received second-line treatment of lenvatinib at three institutions from November 2018 to February 2022. Demographic and clinicopathologic characteristics, data on the treatment regimens were obtained from medical records. Tumor response was evaluated every 4-6 weeks by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: In total, 50 patients with unresectable HCC who received second-line treatment of lenvatinib were enrolled in this study. The objective response rate (ORR) was 18.0% and the disease control rate (DCR) was 74.0%, respectively. The duration of response (DoR) was 6.0 months. The median progression-free survival (PFS) and overall survival (OS) were 5.0 and 8.5 months, respectively. Patients who received ICIs combined with anti-angiogenic inhibitors as first-line therapy, achieving CR/PR at first-line therapy, with PFS≥6months at first-line therapy had a higher DCR. Univariate and multivariate analysis showed that AFP (ng/ml)<400, absence of extrahepatic metastasis, Child-Pugh A, tumor number<3, ICIs combined with anti-angiogenic inhibitors as first-line therapy, CR/PR to first-line therapy, and PFS≥6months at first-line therapy were independent factors of favorable PFS. Univariate analysis showed that absence of extrahepatic metastasis, tumor number<3, ICIs combined with anti-angiogenic inhibitors as first-line therapy, and PFS≥6months at first-line therapy were significantly associated with longer OS. Multivariate analysis showed that absence of extrahepatic metastasis, Child-Pugh A, tumor number<3, CR/PR to first-line therapy and PFS≥6months at first-line therapy were independent prognostic factors of OS. The majority of AEs were grade 1-2, and were reversible. Grade 3/4 AEs occurred in 12 patients (24.0%) and were mostly connected with hand-foot skin reactions (10.0%), and 10 patients had lenvatinib dose reductions. Two toxicity-related treatment interruptions were attributed to grade 3 hand-foot skin reaction, and grade 4 proteinuria, respectively. Conclusion: This study confirms the efficacy and safety of lenvatinib as second-line therapy after progression on sorafenib or ICIs combined with anti-angiogenic inhibitors.

Immune checkpoint inhibitor (ICI) genes and aging in malignant melanoma patients: a clinicogenomic TCGA study.

BACKGROUND: Cancer diagnoses and deaths among the elderly (65 +) are expected to increase significantly over the next decade. Immune checkpoint inhibitors specifically target ICI genes and enhance immune system function. However, poor outcomes may be associated with aging. METHODS: We downloaded the Genomic Data Commons from the Cancer Genome Atlas (TCGA) and collected gene expression data from malignant melanoma (MM) tissues, the third level as the primary site. The CKTTD ICI genes database were applied and validated using the GEO database and lab experiments. RESULTS: In 414 patients, 13 ICI genes were obtained as risk gene signature by univariate and multivariate Cox hazard models and were associated with poor survival in the older group. At 1, 3, and 5 years (79%, 76%, and 76%, respectively), we investigate TNFRFS4 gene and age prediction using novel nomogram-associated aging (HR = 1.79, P 0.001, CI = 1.32-2.45) with higher sensitivity testing.TNFRSF4 gene expression was significantly high in younger (15 years interval) MM patients (P < 0.001). By correlation analysis, a significant negative association was determined (P < 0.001). The validation of gene correlation from GEO (GSE59455) and (GSE22153) was obtained as external validation. We tested the TNFRSF4 protein levels by IHC in 14 melanoma tissue samples. TNFRSF4 expression was observed to be lower expressed in the older of melanoma tissues, and higher in the younger age group (P = 0.02). Besides the connectivity of ICI gene proteins, the biological processes of cell aging, aging, and the immune system were found to be highly related. CONCLUSIONS: Along with the risk score evaluation, the ICI gene (TNFRSF4) was identified as a tumor suppressor gene related to inequalities in age survival and associated with immune cell infiltrations. The aging responses of melanoma patients and related gene expression need further investigation in order to identify potential therapeutic targets.

Tissue metabolomics identified new biomarkers for the diagnosis and prognosis prediction of pancreatic cancer.

Pancreatic cancer (PC) is burdened with a low 5-year survival rate and high mortality due to a severe lack of early diagnosis methods and slow progress in treatment options. To improve clinical diagnosis and enhance the treatment effects, we applied metabolomics using ultra-high-performance liquid chromatography with a high-resolution mass spectrometer (UHPLC-HRMS) to identify and validate metabolite biomarkers from paired tissue samples of PC patients. Results showed that the metabolic reprogramming of PC mainly featured enhanced amino acid metabolism and inhibited sphingolipid metabolism, which satisfied the energy and biomass requirements for tumorigenesis and progression. The altered metabolism results were confirmed by the significantly changed gene expressions in PC tissues from an online database. A metabolites biomarker panel (six metabolites) was identified for the differential diagnosis between PC tumors and normal pancreatic tissues. The panel biomarker distinguished tumors from normal pancreatic tissues in the discovery group with an area under the curve (AUC) of 1.0 (95%CI, 1.000-1.000). The biomarker panel cutoff was 0.776. In the validation group, an AUC of 0.9000 (95%CI = 0.782-1.000) using the same cutoff, successfully validated the biomarker signature. Moreover, this metabolites panel biomarker had a great capability to predict the overall survival (OS) of PC. Taken together, this metabolomics method identifies and validates metabolite biomarkers that can diagnose the onsite progression and prognosis of PC precisely and sensitively in a clinical setting. It may also help clinicians choose proper therapeutic interventions for different PC patients and improve the survival of PC patients.

RIOK3 promotes pancreatic ductal adenocarcinoma cell invasion and metastasis by stabilizing FAK.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer, characterized by a high metastatic burden. RIO Kinase 3 (RIOK3) has been shown to promote invasion and metastasis of PDAC by cytoskeleton remodeling, but the exact mechanism is still unknown. In this study, we analyzed transcriptome sequencing data from RIOK3 stable knockdown PANC-1 cells and TCGA-PDAC data and discovered that RIOK3 was substantially related to focal adhesion signaling in PDAC. Additionally, silencing RIOK3 dramatically decreased Focal Adhesion Kinase (FAK) protein expression and phosphorylation (Tyr397 and Tyr925 sites). Immunoprecipitation assay verified the interaction of RIOK3 and FAK. Furthermore, RIOK3 considerably increased the protein stability of FAK protein but not FAK-Y925F protein. The biological function of RIOK3 in increasing PDAC cell invasion and migration was shown to be dependent on FAK activation. Moreover, we discovered that RIOK3 mutations were mainly characterized by amplification. RIOK3 mRNA was found to be significantly elevated in PDAC tissues and was associated with a poor prognosis. Furthermore, RIOK3 mRNA was significantly upregulated in later T-stage, pre-existing lymph node metastases, and later pathological stage samples. Overall, our study found that RIOK3 promotes PDAC cell invasion and metastasis by stabilizing FAK protein expression and upregulating its phosphorylation. This also provides a new target for therapeutic modalities targeting FAK.