Journal of Chemotherapy最新文献

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.

Novel therapeutic interventions are required to address the critical antimicrobial resistance caused by multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infections. This study examines the impact of combining delafloxacin with antibiotics on MDR-PA isolated from various samples. The minimum inhibitory concentrations (MICs) of delafloxacin, alone and in combination with other antibiotics, were determined against forty distinct MDR-PA isolates using the broth microdilution method. Time-kill curve assays were used to determine the bactericidal and synergistic effects of delafloxacin alone and in combination with other antibiotics in vitro against the selected five strains. Our studies showed delafloxacin exhibited four times greater in-vitro activity against MDR-PA strains than levofloxacin compared with both MIC₅₀ and MIC₉₀ results. Delafloxacin + tobramycin and delafloxacin + ceftazidime/avibactam showed synergy in two out of five strains tested at concentrations equal to the MIC. The outcomes of this research also suggest that these combinations may replace therapy for MDR-PA strains.

This cross-sectional study aimed to analyze the associated factors of poor nutrition in non-small cell lung cancer (NSCLC) patients after chemotherapy. Concretely, 176 NSCLC patients who attended our hospital from June 2020 to December 2022 were enrolled. Standard-compliant patients were categorized into nutrition group (n = 38) and malnutrition group (n = 70) according to different nutrition statuses. Baseline characteristics and nutrition level were assessed. Associated factors of poor nutrition were analyzed by logistic regression analysis. There were obvious differences between nutrition group and malnutrition group in terms of age (P = 0.041), body mass index (BMI, p = 0.021), residence (P  = 0.023), per capita monthly income of family (P  = 0.023), tumor staging (P  = 0.017), Karnofsky (KPS) score (P  < 0.001), effect of chemotherapy (P  = 0.045), and nutrition support before chemotherapy only (P  = 0.023) and perichemotherapy (P = 0.011). The higher proportion of NSCLC patients was found in malnutrition group relative to nutrition group in terms of having poor nutritional cognition (67.14% vs. 47.37%, P  = 0.045), and lacking access to vitamins (65.71% vs. 44.74%, P  = 0.047) and trace elements (57.14% vs. 36.84%, P  = 0.044). BMI <18.5 (OR = 3.707, P = 0.007, 95%CI (1.434-9.586)), residence in village (OR = 3.426, P = 0.013, 95%CI (1.291-9.092)), and KPS score ≤70 (OR = 7.608, P < 0.001, 95%CI (2.842-20.367)) were associated factors for poor nutrition. Collectively, BMI, residence, and KPS score were associated factors of poor nutrition in NSCLC patients after chemotherapy.

We report a case of a 66 year-old male with recurrent stage IIIA non-small cell lung cancer (NSCLC) and no prior arthritis or bone disease who developed hypertrophic osteoarthropathy (HOA) prior to immunotherapy treatment. Approximately one month after the first durvalumab infusion and without other interventions for symptom management, the patient reported improvements to his hand pain, with complete resolution of symptoms after five durvalumab treatments. Repeat x-ray after nine cycles of durvalumab showed decreased periosteal thickening of the phalanges bilaterally. He had no evidence of recurrent NSCLC based on serial computed tomography one year after durvalumab initiation. To our knowledge, there are no documented reports on the isolated effect of immune-checkpoint inhibitor (ICI) therapy on HOA. This case suggests that durvalumab may have a positive role in the management of HOA in NSCLC patients. Further research is needed to better understand the interaction of ICIs, HOA and other paraneoplastic syndromes.

Trastuzumab is primarily utilized in the treatment of patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer. This study aimed to investigate the incidence of cardiac toxicity associated with trastuzumab in HER2-positive breast cancer patients at Iran Hospital in 2023, as well as the factors influencing this toxicity. In this cross-sectional study, 200 patients diagnosed with HER2-positive breast cancer and receiving trastuzumab were included. The criteria for heart failure in this study were defined as an ejection fraction (EF) of less than 50% or a decrease of greater than 10% in EF. Descriptive statistics, the chi-square statistical test, Fisher's exact test, and logistic regression analyses were employed to assess the variables. A p-value of less than 0.05 was deemed statistically significant. The mean age of the participants was 51.5 ± 2.5 years. The odds ratio (OR) for the variable of anthracyclines was 1.3 (95% CI: 1.2-1.4); for opium use, the OR was 2.7 (95% CI: 0.9-8.5); for diabetes, the OR was 2.7 (95% CI: 1.2-5.9); for ischemic heart disease, the OR was 3.5 (95% CI: 1.6-7.7); and for hypertension, the OR was 4.8 (95% CI: 2.1-10.7). The OR for obesity was 1.45 (95% CI: 1.01-2.18), and the OR for age was 1.10 (95% CI: 1.01-1.12). No statistically significant association was found between opium use and cardiotoxicity (p = 0.07). This research contributes to the identification of factors that may predict responses to anthracyclines and the potential for cardiotoxicities. Ultimately, this information could inform the development of more personalized treatment strategies.