Journal of Chemotherapy最新文献

This retrospective study investigated whether piperacillin/tazobactam (PIPC/TAZ) monotherapy affects renal function compared to cefepime (CFPM) or meropenem (MEPM) monotherapy. Hospitalized patients who received PIPC/TAZ, CFPM, or MEPM monotherapy between April 2021 and December 2022 were enrolled in this study. We used inverse probability of treatment weighting (IPTW) to balance baseline characteristics and compare the incidence of acute kidney injury (AKI). Overall, 259, 104, and 98 patients were enrolled in the PIPC/TAZ, CFPM, and MEPM groups, respectively. After applying IPTW, PIPC/TAZ administration was found to be significantly associated with an increased risk of AKI (odds ratio [OR]: 6.75, 95% confidence interval [CI]: 1.30-34.8, p = 0.023 compared to CFPM; and OR: 7.71, 95% CI: 1.00-59.2, p = 0.049 compared to MEPM). PIPC/TAZ monotherapy may be associated with a higher risk of AKI than CFPM or MEPM monotherapy.

ROS1 gene fusions are oncogenic driver in 1-2% non-small cell lung cancer (NSCLC). This report presents the first case of a novel SNX25-ROS1 fusion mutation in a 56-year-old female with lung adenocacinoma, presenting with headaches and behavioral changes. Imaging revealed a primary tumor in the lung and metastasis to lymph nodes, brain, and bones. Histopathological examination confirmed the diagnosis of lung adenocarcinoma, classified as cT3N3M1 (Stage IV). Next-generation sequencing identified a previously unreported SNX25-ROS1 fusion mutation. A fusion was identified in exon 1 of the SNX25 gene and exon 31 of the ROS1 gene. The fusion occurs within ROS1 intron 31, and the complete kinase domain is retained. Based on this finding, the patient was initiated on targeted therapy with entrectinib. Follow-up imaging at six months demonstrated significant reduction in the primary lung tumor size, regression of metastatic lesions, and resolution of intracranial edema. The patient exhibited marked clinical improvement with no significant treatment-related adverse events. This case report identifies a novel SNX25-ROS1 fusion mutation in NSCLC, showing strong sensitivity to ROS1-targeted therapy. It highlights the importance of molecular profiling in detecting rare genetic alterations and underscores the therapeutic potential of targeted treatments for NSCLC with unique molecular subtypes.

Bladder cancer is a prevalent and lethal malignancy worldwide, with treatment options often limited by the development of chemoresistance, especially to cisplatin-based regimens. In this study, we identified ubiquitin-specific protease 54 (USP54) as a novel regulator of bladder cancer cell proliferation, stemness, and cisplatin resistance. USP54 expression was consistently downregulated in both clinical bladder cancer specimens and cell lines. Functional experiments demonstrated that USP54 overexpression inhibited cancer cell growth, attenuated CSC-like properties, and restored cisplatin sensitivity in resistant cells by promoting drug-induced apoptosis. Mechanistically, USP54 directly interacted with SIRT6 and facilitated its deubiquitination, leading to increased SIRT6 protein stability. This post-translational stabilization of SIRT6 was shown to mediate the tumor-suppressive functions of USP54 in bladder cancer progression and chemoresistance. Together, these results uncover the USP54-SIRT6 axis as a previously unrecognized regulatory pathway controlling stemness and cisplatin response in bladder cancer.

Glioblastoma is an aggressive brain tumor with median survival under 2 years despite standard therapy. At recurrence, treatment options are limited, and regorafenib has emerged as a promising option. A systematic search was conducted through Pubmed, Cochrane Library, Embase, and Web of Science for studies on regorafenib in adult recurrent glioblastoma, and a single-arm meta-analysis with random-effects model was performed to pool the data. Across ten studies (724 patients), median overall survival (OS) was 7.2 months and median progression-free survival (PFS) was 2.6 months, with a 12-month OS of 22.5% and a 6-month PFS of 14.9%. Disease control rate (DCR) was 36.1%, including stable disease (SD) of 26.6% and a partial response of 8.5%; progressive disease occurred in 60.9%, and grade 3-4 adverse events in 31.4%. Meta-regression suggested MGMT methylation was associated with improved OS, PFS, DCR, and SD, while male sex was associated with better OS and SD. Overall, regorafenib demonstrated a predictable safety profile in recurrent glioblastoma, with outcomes potentially improved in male patients with MGMT-methylated tumors.

Cyclophosphamide is a chemotherapeutic agent widely used in breast cancer management. As a prodrug, its therapeutic efficacy and toxicity are profoundly influenced by host genetic variations that govern its metabolism, detoxification, DNA repair, and cellular transport mechanisms. This review examines pharmacogenomic landscape of cyclophosphamide in breast cancer, with focus on key genes and polymorphisms. A comprehensive literature review was conducted to identify genetic variants affecting cyclophosphamide metabolism (CYP2B6, CYP3A4, CYP3A5, CYP2C9, and CYP2C19), detoxification (ALDH1A1, GSTM1, GSTT1, and GSTP1), DNA repair (XRCC1, ERCC1, ERCC2, and MGMT), and transport (ABCB1 and SLCO1B1). Clinical correlations with drug response and adverse effects were analyzed. Polymorphisms in CYP2B6 (6, 9) and CYP3A5 (3) significantly alter activation and systemic exposure. Null variants in GSTM1 and GSTT1 are linked to increased drug toxicity due to impaired detoxification. DNA repair gene variants, such as XRCC1 Arg399Gln and ERCC2 Lys751Gln, influence treatment response and risk of side effects.

Nasopharyngeal carcinoma (NPC) is a radiosensitive malignancy, but chemotherapy resistance remains a major challenge. This study investigated the role of RACGAP1, a GTPase regulator often overexpressed in cancers, in NPC progression and chemoresistance. We observed significantly elevated RACGAP1 levels in NPC cell lines compared to normal nasopharyngeal epithelial cells. Functional experiments demonstrated that silencing RACGAP1 effectively inhibited cell proliferation and colony formation, promoted apoptosis, and enhanced cisplatin sensitivity-evidenced by lower IC50 values and increased drug-induced apoptosis. Mechanistically, these antitumor effects were linked to inhibition of HIF-1α signaling. Importantly, restoring HIF-1α expression partially reversed the phenotypic changes caused by RACGAP1 knockdown. In summary, our findings establish that RACGAP1 promotes malignant progression and confers cisplatin resistance in NPC by upregulating HIF-1α, suggesting the RACGAP1/HIF-1α axis as a promising therapeutic target to overcome chemoresistance.

While targeted therapies have remarkably transformed the landscape of lung adenocarcinoma (LUAD) management, the clinical implications of concurrent mutations in EGFR and ERBB2 remain inadequately understood due to their exceptional rarity in patients. This lack of understanding leads to significant uncertainty regarding therapeutic strategies for individuals with such co-mutations, as neither single-agent EGFR tyrosine kinase inhibitors (TKIs) nor HER2-targeted therapies have demonstrated established efficacy in this specific molecular context. Here, we present a compelling case involving a 61-year-old female patient diagnosed with advanced LUAD, with both EGFR L858R (exon 21) and ERBB2 S310F mutations identified through comprehensive next-generation sequencing (NGS). The patient received a treatment regimen consisting of the third-generation EGFR TKI furmonertinib, combined with localized radiotherapy, which resulted in a marked and significant clinical response. Our findings indicate that furmonertinib may effectively address the therapeutic uncertainties associated with EGFR/ERBB2 co-mutations, presenting a promising clinically actionable strategy while we continue to await the advent of more personalized and tailored treatment solutions.

The low survival rate of adult T-cell leukemia/lymphoma (ATL) underscores the critical need for innovative therapeutic agents. While the pharmacokinetics of HDACis have been documented in several hematological neoplasms, there is a notable gap in research regarding their activity against ATL. Given that hypoxia can induce unpredictable effects on lymphoma cells, this study aimed to evaluate the toxic effects of MS-275 and novel analogs on ATL cells in hypoxic condition for the first time. Protein-protein interaction and gene set enrichment analyses were performed, the expression of HIF1A and downstream targets were assessed, and molecular docking was conducted on MS-275 and novel analogs with HIF-1α. For in vitro studies, at first benzamide analogs of MS-275 were synthesized and then, viability of MT-2 cells was evaluated in hypoxic condition. Enrichment analyses confirmed the involvement of hub genes in HIF-1 signaling pathway and volcano plot revealed over expression of HIF1A, GAL3ST1 and CD274. Molecular docking indicated favorable interaction between MS-275 and analogs with HIF-1α PAS-B domain. Results of alamarBlue assay demonstrated that MS-275 and analogs significantly (p < 0.001) reduced viability of MT-2 cells in hypoxic condition. Findings of the present study hold promise for developing new drugs targeting hypoxia-induced changes in ATL.

Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of metastatic NSCLC and have become standard first-line therapy both as monotherapy, for patients with PD-L1 expression ≥50%, and in combination with chemotherapy (CT), regardless of PD-L1 expression. This study used an artificial intelligence technique, the IPDfromKM method, to reconstruct individual patient data from Kaplan-Meier curves of phase III randomised clinical trial results to provide a comparative overview of different first-line chemo-immunotherapy options. Overall survival (OS) was estimated using hazard ratios and restricted mean survival time (RMST). Ten clinical trials were included in the analysis. In the squamous population, combinations of cemiplimab + CT (HR = 0.56), pembrolizumab + CT (HR = 0.67), and nivolumab + ipilimumab + CT (HR = 0.71) significantly improved OS compared with CT alone, with no difference between treatments. At longer follow-up, nivolumab + ipilimumab + CT showed longer RMST compared to pembrolizumab + CT in the PD-L1 < 1% subgroup (24.9 months vs. 22.8 months). In non-squamous NSCLC, the survival benefit of ICIs + CT was much more homogeneous, with similar results across the different options. Overall, pembrolizumab + CT showed the best results both in terms of HR (0.68, 95%CI 0.60-0.77) and RMST at long follow-up (30.4 months in the PDL-1 ≥ 1% subgroup and 24 months in the PDL-1 < 1% population). In conclusion, there are some differences between frontline options for treating metastatic NSCLC based on tumour histology and PD-L1 expression. However, further head-to-head trials and longer follow-up are needed to clarify the clinical impact of these differences.

This study explores the relationship between m6A modification and ferroptosis in intrahepatic cholangiocarcinoma (ICC) and its impact on cisplatin resistance. We established cisplatin-resistant cells. CCK-8 and Transwell assays were conducted to evaluate the effects of METTL3 on drug resistance, migration, and invasion. RT-qPCR and Western blotting were used to measure target gene expression and the effects of overexpression and suppression. RIP, luciferase reporter assay, and other experiments were utilized to investigate the interaction between METTL3 and NRF2. Additionally, rescue experiments were performed to confirm the role of the METTL3/NRF2 axis in tumor drug resistance. METTL3 was found to be highly expressed in cisplatin-resistant cells, enhancing m6A modification levels, stabilizing NRF2 mRNA, and increasing NRF2 protein expression to inhibit ferroptosis. These findings indicate that the METTL3/NRF2 axis inhibits ferroptosis in cisplatin-resistant cells, thereby promoting chemotherapy resistance in ICC. This provides a potential direction for future research and treatment of ICC.