Cancer Chemotherapy and Pharmacology最新文献

Purpose: The high-dose methotrexate (MTX) regimen is a first-line treatment for primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL). However, MTX-related kidney injury is a severe treatment complication. No cases of capillary leak syndrome (CLS) causing delayed MTX metabolism-associated renal failure have been reported.

Case presentation: A 48-year-old female presented to Zibo Central Hospital in April 2024 with headaches. Contrast-enhanced magnetic resonance imaging (MRI) of the brain revealed a space-occupying lesion in the right occipital lobe. A stereotactic biopsy was performed to determine the nature of the lesion. Postoperative pathology confirmed DLBCL. The patient underwent a TZM regimen, which included Tislelizumab, MTX, and Zanubrutinib. On the first day following MTX, the patient developed generalized edema, shortness of breath, and reduced urine output. Laboratory tests revealed hypoxemia, low albumin levels, and acute kidney injury. Based on these findings, the patient was diagnosed with CLS. To quickly lower the blood MTX concentration, pleural effusion drainage and continuous renal replacement therapy (CRRT) were performed. The treatment was successful, and the patient recovered and was discharged.

Conclusion: CLS is a serious complication for DLBCL patients receiving high-dose MTX therapy.

Background: Hand-foot syndrome (HFS) is the most common adverse effect of capecitabine.

Objective: We aimed at evaluating the protective effect of celecoxib against capecitabine induced hand and foot syndrome in patients with colorectal cancer (CRC).

Methods: In this randomized controlled parallel study, 44 newly diagnosed patients with stage II CRC were randomly allocated into two groups; Group 1(control group; n = 22) which received 6 cycles of capecitabine-based chemotherapy (cycle is every 3 weeks) and group 2 (celecoxib group; n = 22) which received 6 cycles of capecitabine-based chemotherapy (cycle is every 3 weeks) in addition to 200 mg of oral celecoxib twice daily for 14 days of the 3-week cycle. At baseline and after the 6th chemotherapy cycle the patients' quality of life (QOL) was assessed using hand and foot syndrome (HFS) specific QOL questionnaire (HFS-14). Moreover, blood samples were collected in order to evaluate the serum levels of cyclooxygenase-2 (COX-2), tumour necrosis factor-alpha (TNF-α) and malondialdehyde (MDA). Data was analysed using paired and un-paired t-tests.

Results: At the end of the study and as compared to control group, celecoxib treated group showed significantly lower incidence of HFS (P = 0.015). Additionally, celecoxib treated group showed significant decline in the serum levels of TNF-α (P = 0.016) and MDA (P = 0.014) which was associated with non-significant difference in the serum level of COX-2 between the two groups (P = 0.476). Celecoxib was safe and well-tolerated throughout the study period.

Conclusion: Celecoxib may represent a potential protective agent against capecitabine induced hand and foot syndrome in patients with colorectal cancer.

Purpose: Antiangiogenic tyrosine kinase inhibitors (TKIs) are associated with elevated hemoglobin [Hb] levels, potentially influencing prognosis in advanced hepatocellular carcinoma (HCC) patients. However, the impact of altitude on Hb dynamics and its prognostic significance remains underexplored. This study aimed to assess altitude-related Hb changes and their relationship with treatment outcomes in patients following TKI treatment.

Methods: In this retrospective cohort study, medical data from two institutions in Tibet and Beijing were analyzed. Between 2016 and 2022, 128 advanced HCC patients treated with antiangiogenic TKIs were divided into high- and low-altitude groups based on their city of residence. Hematological parameters were retrieved at baseline and every 3 months for 9 months post-treatment initiation. Propensity score matching (PSM) was used to adjust for demographic and baseline differences. Hb percentage changes from baseline (no increase, increase < 15%, increase ≥ 15%) were evaluated at each time point as predictors of time to treatment failure (TTTF) using the Cox proportional hazards model.

Results: After PSM, Hb trajectories differed between the altitude groups. The high-altitude patients exhibited progressive increases, while the low-altitude patients experienced a transient rise followed by a decline. We found no significant TTTF differences between the matched altitude groups (P = 0.33). However, in the high-altitude unmatched cohort, a ≥ 15% increase in Hb at 9 months was linked to a significantly lower risk of treatment failure (HR = 0.22 [95% CI = 0.06-0.83]; P = 0.03). Patients with increases < 15% showed a numerical trend toward prolonged TTTF (HR = 0.30 [0.08-1.15]).

Conclusion: Antiangiogenic TKIs induce altitude-dependent Hb changes, with sustained increases at high altitudes and transient reversibility at low altitudes. A ≥ 15% increase in Hb at 9 months after TKI therapy may serve as a potential biomarker for identifying high-altitude populations likely to benefit more from TKI therapy. Future studies should validate these findings in larger cohorts.

The BRN2 transcription factor controls the protein expression involved in cell motility and is overexpressed in melanoma. Gene mutations involved in cell signaling pathways lead to BRN2 overexpression, tumor formation and metastasis. Peptides derived from the DNA binding domain of transcription factors can compete for the transcription binding and regulate protein expression. In this work, the antitumor activity in vitro and in vivo of the peptide E24G, derived from the DNA-binding POU domain of the BRN2 transcription factor was investigated. This peptide was fragmented into two smaller peptides E12F and A12G, their antitumor activities were characterized and compared with E24G. The E24G at 1 mM significantly reduced cell motility in vitro of B16F10-Nex2 melanoma cells. E12F peptide also inhibited cell motility at a concentration eight times smaller than E24G in murine and human melanoma cells. We observed that the antitumor activity of both E24G and E12F peptides depends on the macropinocytosis displayed by tumor cells. Also, the E24G and E12F peptides induced an increase of the CDH13 expression in 50%, however the treatment with E12F increased the expression already after 12 h by 100%. In vivo assays showed that both peptides reduced the development of metastatic lung nodules without presenting toxicity to normal organs. Our results indicate that E12F and E24G peptides can restore normal expression of BRN2 target genes at the molecular level, inhibiting the cell motility. In addition, we confirmed that the peptide binds to the DNA binding site of the BRN2 transcription factor. Further studies will elucidate their mechanisms of antitumor activity, so far our results pointed out the potential application of E12F and E24G peptides as innovative treatments for metastatic melanoma.

Purpose: While imatinib is effective for treating Gastrointestinal Stromal Tumors (GISTs), significant variability in patient outcomes exists, highlighting the need for reliable prognostic biomarkers. ETV1, a key transcription factor involved in GIST progression, is implicated in disease biology, but the role of ETV1-related single nucleotide polymorphisms (SNPs) in predicting prognosis remains unclear.

Methods: This study included 75 GIST patients. We focused on identifying tag SNPs in the ETV1 gene and examined their association with clinical outcomes. Patient characteristics, somatic mutations, and imatinib concentration were also analyzed in a multivariate model. ETV1 expression was assessed using immunohistochemistry, and miRNA interactions with ETV1 transcripts were investigated via the dual-luciferase reporter assay system.

Results: We found that the rs3735343 SNP, located in the 3' untranslated region of ETV1, was significantly associated with progression-free survival (PFS) in GIST patients receiving imatinib (P = 0.008). Multivariate analysis identified tumor size (P = 0.032, Hazard Ratio [HR] = 4.173, 95% CI: 1.127-15.454) and rs3735343 (P = 0.009, HR = 8.995, 95% CI: 1.712-47.255) as independent predictors of PFS. The rs3735343 risk allele also correlated with elevated ETV1 expression in GIST tissue (P = 0.04). Additionally, miR-4311 was found to specifically and negatively regulate ETV1 mRNA levels associated with the rs3735343 risk allele in vitro.

Conclusion: This study reported ETV1 rs3735343 as a novel prognostic candidate biomarker for GISTs treated with Imatinib, providing a potential biomarker for risk assessment of GIST. Additionally, our findings suggest that rs3735343 may act as a miRNA-regulated SNP, with miR-4311 playing a key role in its regulation.

Purpose: The FEDR-CP-001 (NCT03983161) trial evaluated the pharmacokinetics (PK) and safety of a single dose of fedratinib in adults with moderate or severe hepatic impairment (HI) compared with matched healthy participants with normal hepatic function.

Methods: This was a non-randomized, open-label, multicenter, phase 1 trial. Participants were aged 18-75 years and had a BMI of 18-40 kg/m². HI was determined by Child-Pugh score. Participants were placed into 1 of the following groups: group 1, moderate HI; group 2, healthy participants matched to group 1; group 3, severe HI; and group 4, healthy participants matched to group 3. Participants received a single dose of fedratinib 300 mg (groups 1 and 2) or 200 mg (groups 3 and 4) and were followed for 21 days.

Results: All participants (N = 38; groups 1, 3, and 4 [n = 8 each], group 2 [n = 14]) completed the trial. Peak and total fedratinib exposures (C_max, AUC_0-∞) were similar between moderate HI versus matched healthy participants. In participants with severe HI, there were lower total exposures compared to the matched healthy participants where the ratios of geometric means for C_max, and AUC_0-∞ were 0.897 and 0.660, respectively, and with large inter-participant variability. Ten participants experienced a treatment-emergent adverse event (all were considered mild), which were evenly distributed across groups.

Conclusion: These data indicate that reducing fedratinib starting doses is not necessary for patients with moderate or severe HI, and support clinicians in regular monitoring of patients with HI taking fedratinib.

Background: Vascular endothelial growth factor (VEGF) inhibitors are associated with a high incidence of proteinuria. In patients with diabetes, increased proteinuria is closely associated with decreased renal function; however, the impact of increased proteinuria on renal function in patients with cancer and diabetes mellitus undergoing VEGF inhibitor therapy remains unknown.

Methods: The incidence of proteinuria and renal function in patients with cancer and a history of diabetes who were treated with VEGF inhibitors at the National Cancer Center Hospital East between January 2018 and December 2019 was retrospectively investigated.

Results: Among the 49 patients included, 21 (43%) developed proteinuria ≥ 3 + after VEGF inhibitor treatment. In all patients, a decreasing trend in the estimated glomerular filtration rate (eGFR) was observed beginning 2 years after treatment initiation. The decrease in eGFR from baseline was - 6.6% at 1 year, -11% at 2 years, and - 13% at 4 years. Patients who developed proteinuria ≤ 2 + showed no significant decrease in eGFR from baseline to either the end of treatment (p = 0.91) or the latest value during the observation period (p = 0.64). Similarly, no significant decrease in eGFR was observed in those with proteinuria ≥ 3+ (end of treatment, p = 0.91; latest value during the observation period, p = 0.18).

Conclusions: In patients with cancer and diabetes mellitus, increased proteinuria after VEGF inhibitor therapy suggested that it was not associated with a significant decline in renal function.

Pazopanib, a multi-targeted tyrosine kinase inhibitor, is used for advanced renal cell carcinoma and soft tissue sarcoma. However, it is associated with dose-dependent adverse events (AEs), including hypertension, and gastrointestinal issues. Antacids like proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) are often co-administered, raising concerns about potential drug interactions. Pazopanib's solubility and absorption are pH-dependent, with increased gastric pH potentially reducing its bioavailability. In this study, we analyzed VigiBase^® data using multivariate logistic regression models and found significant interactions between pazopanib and antacids (PPIs, H2RAs, and others), suggesting reduced serious AE reporting, possibly due to lower pazopanib exposure. A secondary analysis of CYP3A4 inhibitors showed a non-significant trend for higher serious AEs, aligning with expected pharmacokinetic effects. These findings emphasize the need for caution when combining antacids with pazopanib, as it may reduce both toxicity and efficacy.