Journal of Chemotherapy最新文献

Immune checkpoint inhibitors (ICIs) have shown promise in the treatment of gastric and oesophageal cancers (GEC). Despite their promising efficacy, ICIs have been associated with unique side effects known as immune-related adverse events (IRAEs). Several studies have shown improved treatment responses in patients with IRAEs compared to those without IRAEs in various cancer types such as melanoma and non-small cell lung cancer. We performed a single-institution retrospective study to characterize IRAE incidence and association with treatment response in advanced GEC. We identified 70 patients with GEC who received ICI therapy; 20 (29%) developed an IRAE of any magnitude. The most common were colitis (35%) hypothyroidism (25%) and pneumonitis (20%). Median PFS and OS were not statistically different between IRAE and nonIRAE groups (10.4 vs. 11.3 months p = 0.6 and 11.0 vs. 12.9 months p = 1.0, respectively). This is in contrast to studies in other cancer types that have suggested association between IRAE and improved outcomes.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are the recommended front-line therapy for treatment-naïve patients with advanced stage EGFR mutated Non-Small Cell Lung Cancer (NSCLC), with better tolerance and outcomes compared to chemotherapy. However, patients inevitably develop resistance to EGFR-TKI. The extent of progression free survival depends on intrinsic or acquired on-target/off-target mechanisms of EGFR-TKI resistance. Overcoming these acquired rearrangements remains challenging in modern precision medicine. In case of disease progression during treatment with an EGFR-TKI, rebiopsy is recommended to search for a potential resistance mechanism. However, the therapeutic potential of these resistance mechanisms represents an unmet need in thoracic oncology. CasePresentation: We present a case of a 78-year-old woman with stage IVB EGFR-mutated NSCLC in whom an acquired RET Gene Fusion was identified as the EGFR-independent resistance mechanism. Additionally, a combined therapy of Osimertinib and Selpercatinib showed a durable oncological response with 14 months of progression free survival in the absence of adverse events. Conclusion: Addition of Selpercatinib to Osimertinib in an EGFR-mutated NSCLC patient with an acquired RET fusion was well tolerated and created a clinical benefit. Further prospective investigation into these novel combination strategies is needed as resistance mechanisms could serve as possible targets for new therapy approaches.

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.

Immunotherapy has been advanced through multiple approaches, including immunogenic cytokines, monoclonal antibodies, therapeutic vaccinations, adoptive cell transfer, stem cell transplantation, and oncolytic viruses. This review analyses various strategies in genomics, transcriptomics, single-cell techniques, computational analysis, big data, and imaging technologies for the identification of tumour microbiota and microenvironments. Immunotherapy is becoming acknowledged as a feasible cancer treatment method, facilitating innovative cancer medicines and personalized medicine techniques.

To promote the accurate administration of linezolid, this study aimed to evaluate its dosage regimens in critically ill patients with varying renal functions. This evaluation was based on a combined analysis of pharmacokinetic (PK), pharmacodynamic (PD), and toxicodynamic (TD) indices. The percentage of therapeutic target attainment (PTTA) was used as the index for PK/PD/TD, defined as simultaneously meeting two PK/PD criteria (AUC_0-24h/MIC ≥ 100 and C_ss between 2.6-7.8 mg/L) and adjusted for toxicity probability, with MICs ranging from 0.5 to 8 mg/L. The recommended doses of linezolid for patients: 600 mg every 12 h for normal renal function or mild renal impairment, 300 mg every 12 h for severe renal impairment, 450 mg every 12 h for moderate renal impairment, and 600 mg every 8 h for supra-normal renal function. In conclusion, specific dosing regimens should be adopted for patients with varying renal functions, combined with therapeutic drug monitoring, to ensure the safety and efficacy of linezolid.

Anti-tumor drugs cause hand-foot syndrome through a variety of pathogenic mechanisms. Some chemotherapeutic medications that can cause HFS include 5FU, doxorubicin, capecitabine, high dose cytarabine, and others. These medications each have a unique mechanism resulting in HFS. The histopathological characteristics, clinical manifestations, and variations in gender, ethnicity, or genetic makeup might also impact the development of HFS as an adverse drug reaction. Even though the disease might not become life-threatening, it is nevertheless vital to manage it with therapeutic interventions or by withholding the medication in order to enhance the patient's outcome. Current developments in pharmacological and non-pharmacological therapeutic approaches for managing symptoms also emphasis the same.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality. LncRNA NORAD is frequently upregulated and positively associated with various cancer progressions. We discovered NORAD was significantly upregulated in CRC tissues and cells. NORAD sponged miR-106a-5p to form a ceRNA complex. MiR-106a-5p was remarkedly downregulated in CRC tumors and cells. Silencing NORAD or overexpression of miR-106a-5p effectively increased cisplatin sensitivity. In the established cisplatin resistant cell line, NORAD was upregulated and miR-106a-5p was downregulated. Furthermore, we disclosed miR-106a-5p directly targeted 3'UTR of CCND1, which is an important cell cycle regulator and is frequently overexpressed in human cancers. Rescue experiments showed restoration of CCND1 in miR-106a-5p-overexpressing CRC cells successfully recovered cisplatin resistance. Finally, restoration of miR-106a-5p in NORAD-overexpressing CRC cells re-sensitized cisplatin resistance by targeting CCND1. Summarily, this study uncovered a NORAD-promoted cisplatin resistance through modulating the miR-106a-5p-CCND1 axis, contributing to developing novel therapy for treating chemoresistant CRC.

Cervical cancer is one of the most common gynecologic malignancies worldwide. 5-Fluorouracil (5-Fu) is a widely used anticancer drug for various cancers, but the development of 5-Fu resistance poses a challenge in treating cervical cancer patients. This study examined the roles and molecular mechanisms of LncRNA-FGD5-AS1 in 5-Fu resistant cervical cancer cells through in vitro and in vivo experiments. We discovered FGD5-AS1 and the RNA methylation reader protein, YTHDF2, were positively associated with 5-Fu resistance in cervical cancer. A positive correlation between FGD5-AS1 and YTHDF2 was found in cervical tumor tissues. Expressions of FGD5-AS1 and YTHDF2 were significantly upregulated in the established 5-Fu resistant cervical cancer cells. MiRNA-microArray analysis screened that FGD5-AS1 downregulated miR-130a-3p expression in cervical cancer cells. Subsequently, we demonstrated FGD5-AS1 acted as a ceRNA by sponging miR-130a-3p, which targeted the 3'UTR of YTHDF2 mRNA. Rescue experiments validated overexpression of FGD5-AS1 increased 5-Fu resistance in cervical cancer cells, which was reversed by miR-130a-3p overexpression. Finally, combining FGD5-AS1 silencing with 5-Fu treatments resulted in a synergistic inhibitory effect (CI < 1) on the viability of cervical cancer cells. This study reveals a FGD5-AS1-miR-130a-3p-YTHDF2 axis that could be a promising therapeutic target for overcoming 5-Fu resistance in cervical cancer.

Anti-PD-1/PD-L1 plus chemotherapy (CT) is considered the standard of care in first line treatment of metastatic NSCLC. However, the clinical benefit of this combination in older patients is controversial. We performed a meta-analysis of phase III randomized trials that compared PD-1/PD-L1 inhibitor plus CT with CT alone in first line of treatment for older patients with advanced NSCLC. Subgroups of patients over 65 and over 75 were analyzed. The outcomes included overall survival (OS) and progression-free survival (PFS). A fixedeffect model was used. We analyzed ten trials with an anti-PD-1 (camrelizumab, cemiplimab, nivolumab, pembrolizumab, tislelizumab or toripalimab) and six trials with an anti-PD-L1 (atezolizumab, durvalumab or sugemalimab), including 3666 patients over the age of 65 (41%) and 282 patients over the age of 75 (<10%). For patients over 65 years of age, anti-PD- 1/PD-L1 + CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.79 [0.72-0.86]; p < 0.00001) and P FS (0.63 [0.58-0.68]; p < 0.00001) compared to CT alone. Survival benefits occurred in both anti-PD-1 and anti-PD-L1 trials. For patients over 75 years of age, OS benefit was not statistically significant (0.88 [0.67-1.16]; p = 0.37). For patients over the age of 65 with untreated NSCLC, the anti-PD-1/PD-L1 combination with CT, compared with CT alone, is associated with significantly improved OS and PFS. Due to the low number of patients, it is difficult to conclude for those over 75.

Dose-limiting toxicities (DLTs) are severe adverse effects that define the maximum tolerated dose of a cancer drug. In addition to the specific mechanisms of each drug, common contributing factors include inflammation, apoptosis, ion imbalances, and tissue-specific enzyme deficiencies. Among various DLTs are bleomycin-induced pulmonary fibrosis, doxorubicin-induced cardiomyopathy, cisplatin-induced nephrotoxicity, methotrexate-induced hepatotoxicity, vincristine-induced neurotoxicity, paclitaxel-induced peripheral neuropathy, and irinotecan, which elicits severe diarrhea. Currently, specific treatments beyond dose reduction are lacking for most toxicities. Further research on cellular and molecular pathways is imperative to improve their management. This review synthesizes preclinical and clinical data on the pharmacological mechanisms underlying DLTs and explores possible treatment approaches. A comprehensive perspective reveals knowledge gaps and emphasizes the need for future studies to develop more targeted strategies for mitigating these dose-dependent adverse effects. This could allow the safer administration of fully efficacious doses to maximize patient survival.