Cancer Chemotherapy and Pharmacology最新文献

Background: High-dose chemotherapy (HDCT) combined with autologous stem cell transplantation (ASCT) rescue is an effective treatment option for relapsed or refractory germ-cell tumors. The TI-CE regimen, consisting of paclitaxel and ifosfamide for stem cell mobilization followed by high dose carboplatin and etoposide with ASCT rescue, is frequently used in the treatment of refractory disease. This regimen is challenging in patients who have undergone unilateral nephrectomy, since potential nephrotoxicity of ifosfamide poses a serious risk for permanent damage of the preserved kidney. Currently, the literature lacks data on the substitution of ifosfamide in the TI-CE regimen for an alternative chemotherapeutic agent with equivalent potency while being less nephrotoxic.

Case presentation: We present a case of a patient with refractory progressive metastatic germ-cell tumor who underwent nephrectomy and was successfully treated with a modified chemo-mobilization strategy. In the TI-CE protocol, ifosfamide was replaced for cyclophosphamide (TC-CE), resulting in a sufficient stem cell harvest through a single apheresis session. Post chemo-mobilization, LDH and hCG + hCGβ levels were normalized. Renal function remained stable throughout the course of treatment. Two months after HDCT, the patient showed a complete metabolic response, with no detectable tumor remnants. Currently, one year post-therapy, there are no signs of disease recurrence.

Conclusion: An effective and potentially less nephrotoxic chemo-mobilization regimen, using paclitaxel and cyclophosphamide (TC-CE), was administered to a patient with refractory metastatic germ-cell tumor who underwent HDCT followed by ASCT rescue after unilateral nephrectomy. Cyclophosphamide demonstrated to be a viable substitute for ifosfamide within the TI-CE regimen.

Mirdametinib is an MEK1/2 inhibitor having therapeutic potential for the treatment of neurofibromatosis type 1 (NF1)-associated plexiform neurofibromas (PNs). NF1 is a rare and progressive genetic disorder. As a selective MAPK pathway modulator, it targets the dysregulated RAS (Rat Sarcoma viral oncogene homolog)/RAF (Rapidly Accelerated Fibrosarcoma)/MEK (Mitogen-activated protein kinase)/ (ERK) Extracellular signal-regulated kinase) signaling cascade, which plays a crucial role in NF1 tumor growth. PN, often progressive and disfiguring, significantly impairs quality of life (QOL), and it can transform into malignant peripheral nerve sheath tumors (MPNST). In February 2025, mirdametinib was FDA-approved under the brand name GOMEKLI for pediatric and adult patients with inoperable PNs.

Purpose: To evaluate the pharmacokinetic properties of UGN-102, a mitomycin-containing reverse thermal gel.

Methods: Twelve patients with NMIBC received 6 once-weekly intravesical instillations of UGN-102 (BL004: 120 mg mitomycin [n = 6]; BL005: 75 mg mitomycin [n = 6]). Plasma samples for determination of pharmacokinetic (PK) parameters were collected up to 6 h following instillation.

Results: In BL004, mean C_max was 20.39 ng/mL, and median was 16.10 ng/mL (range 4.00-40.40), 100-10-fold lower than reported myelosuppression toxic level (RMTL); and median T_max was 1.5 h. Mean AUC_0-6 was 56.23 ng·h/mL and mean apparent terminal half-life (t_1/2) was 49 min. The highest observed C_max (40.40 ng/mL) was 59-fold and 13-fold lower than C_max following IV 30 mg or 10 mg mitomycin, respectively, and 10-fold lower than the RMTL. Maximum measured urine concentration was 635 µg/mL. In BL005, mean C_max was 2.27 ng/mL, 181-fold lower than the RMTL; mean T_max was 1.95 h and mean AUC_0-6 was 5.69 ng·h/mL. At 4-6 h post intravesical instillation, mitomycin concentrations in urine were either below or approaching the lower level of quantification (< 0.250 µg/mL) in 5/6 patients. In the remaining patient, the measurable urine concentrations over the 6-hour period suggest dwell time was > 6 h post-instillation, possibly due to the tumor location restricting urine flow. However systemic exposure was < 4 ng/mL, 100-fold lower than the RMTL.

Conclusions: Intravesical instillation of UGN-102 results in low-level systemic absorption of mitomycin, with C_max values considerably lower than those following IV administration and those associated with myelosuppression.

Study registration: BL004: NCT02307487; BL005: NCT03558503.

Purpose: OX40 may stimulate T-cell activation, potentially enhanced with checkpointinhibition. Results are from the dose-escalation part of an ongoing, multicenter, open-label study (NCT04215978, registered 30 December 2019) investigating OX40 agonist BGB-A445 alone or with anti-PD-1 antibody tislelizumab in patients with advanced solid tumors.

Methods: Adults ≥18 years with previously treated advanced solid tumors, measurable by RECIST v1.1, enrolled. Dose-escalation A: 8 cohorts received increasing doses of IV BGB-A445 as monotherapy (20, 60, 150, 300, 600, 1200, 2400, 3600 mg); dose-escalation B: 6 cohorts received increasing doses of IV BGB-A445 (150, 300, 600, 1200, 2400, 3600 mg) + IV tislelizumab 200 mg. Primary objectives were safety and tolerability; secondary objectives included overall response rate (ORR) and pharmacokinetics.

Results: 112 patients were treated (A, n=63; B, n=49); 34/112 (30.4%) previously received checkpoint inhibitors. Treatment-related adverse events occurred in 36 (57.1%) (A) and 37 (75.5%) (B) patients, were grade ≥3 in 4 (6.3%) and 9 (18.4%), and caused treatment discontinuations in 1 (1.6%) and 1 (2.0%), respectively. Immune-mediated adverse events occurred in 8 (12.7%) (A) and 18 (36.7%) (B) patients, and infusion-related reactions in 9 (14.3%) (A) and 9 (18.4%) (B). No dose-limiting toxicities occurred. Unconfirmed ORR was 3.3% (unconfirmed partial response [PR], n=2) (A); confirmed was 21.3% (including PR, n=10) (B). BGB-A445 exposure increased dose-proportionally with a half-life of 8-13 days. OX40 receptor occupancy was saturated at ≥300 mg BGB-A445 in all cohorts.

Conclusion: BGB-A445 was well tolerated and demonstrated on-target immune activation at clinically relevant doses. Antitumor activity was observed across cohorts.

Purpose: Pediatric obesity is a growing public health concern, affecting drug pharmacokinetics, including chemotherapies. These challenges are amplified by the underrepresentation of children with obesity in clinical trials and the absence of clear dosing guidelines.

Methods: A retrospective, single-center cohort study was conducted at the Institute of Pediatric Hematology and Oncology (Lyon, France), including children with obesity (Body mass index > IOTF-30) treated with at least one intravenous chemotherapy between 2008 and 2022. Medical records were reviewed for patient characteristics, chemotherapy type, administered dose and adjustments. A literature review was performed using PubMed to evaluate chemotherapy dosing recommendations for children with obesity.

Results: A total of 248 chemotherapy courses for 113 children were analyzed, including 239 cytotoxic agents and 9 monoclonal antibodies. Most treatments were for hematological malignancies (n = 151), followed by solid tumors (n = 97). Only 45 chemotherapies (18%) were dose-adjusted in 19 patients (17%). Among these, 87% were capped at a body surface area (BSA) of 2 m², while 13% involved percentage-based reductions. Five adjustments were based on ideal body weight (IBW). Among the 25 patients with BSA > 2 m², 68% received adjusted doses, primarily through capping. In contrast, for patients with BSA < 2 m², dose reductions were rare and applied to avoid potential toxicity. The literature review revealed that total body weight (TBW) is generally used for dosing most chemotherapeutic agents, though certain drugs may require ideal body weight or adjusted body weight.

Conclusion: Heterogeneity in clinical practice reflects the absence of standardized pediatric guidelines. Therapeutic drug monitoring and further pharmacokinetic studies may further help optimize dosing. TBW is recommended based on the study results and literature review, with exceptions, and guidelines should be widely disseminated to improve clinical practice.

Background: Locally advanced oral squamous cell carcinoma (OSCC) is associated with poor survival outcomes, particularly in resource-limited settings, where treatment delays are prevalent. Oral metronomic chemotherapy (OMCT) utilising methotrexate and celecoxib is a potentially low-toxicity, cost-effective alternative in the neoadjuvant setting.

Methods: Thirteen patients diagnosed with stage 3 or 4 resectable OSCC were enrolled in this study. Each participant received one month of OMCT prior to surgical intervention and continued OMCT as maintenance therapy following treatment. The expression levels of PTGS2, VEGFA, VEGFB, KDR, CXCR1, and CXCR2 were analysed both before and after OMCT administration. Additionally, organ function and patient survival were evaluated to determine the efficacy and toxicity of treatment.

Results: PTGS2, VEGFA, VEGFB, and KDR were significantly upregulated in the tumour tissues at baseline. Post-OMCT, VEGFA, VEGFB, and KDR were significantly downregulated, whereas PTGS2 expression increased. No significant changes were observed in CXCR1 and CXCR2 expression. Liver, renal, and thyroid functions remained within normal limits. No adverse events were reported. The median overall survival was 22.1 months, and the median disease-free survival was 20 months. Upregulation of PTGS2, VEGFA, and VEGFB was correlated with improved outcomes.

Conclusion: OMCT has the potential to manage disease progression in patients with OSCC awaiting surgical intervention. It is characterised by low toxicity and may exert anti-angiogenic effects through modulation of the VEGF pathway. Further large-scale trials are necessary to substantiate these findings and to establish optimal treatment strategies.

Trial registration: The study was also registered in the Clinical Trials Registry of India (registration number: CTRI/2021/01/030256).

Background: Sacituzumab govitecan (SG) is approved for metastatic triple-negative breast cancer in ≥ 2 line setting at 10 mg/kg IV on Days 1 and 8 (21-day cycle). Trials confirmed its superiority over 8 mg/kg with manageable safety. In practice, precautionary dose reductions are used despite no formal guidance. In Poland, fixed 200 mg vials and unreimbursed drug waste lead to early dose adjustments.

Methods: This retrospective study evaluated the impact of initial SG dose reduction on treatment outcomes and tolerability in Polish patients. Medical records provided data on baseline features, treatment, survival, and safety. Kaplan-Meier and chi-square tests were used for survival and group comparisons. A multivariate Cox model assessed the independent effect of dose reduction on overall survival (OS) and progression-free survival (PFS). Significance was set at p < 0.05.

Results: Among 83 patients (median age 55, range 30-86), initial dose reductions ≥ 10% were observed in 16 patients (19.3%), including 9 (10.8%) with dose reduced ≥ 20%. Administrative adjustments (reductions > 10% to flat doses of 200 mg multiplications) accounted for 18.1% of the entire cohort. Grade ≥ 2 and ≥ 3 adverse events occurred in 83.1% and 56.6%, respectively. In a multivariate analysis, a ≥ 20% initial dose reduction remained an independent predictor of shorter PFS (HR: 2.6; 95% CI: 1.1-6.6; p = 0.04) and OS (HR: 6; 95% CI: 2-17.5; p = 0.001). Initial dose reduction did not affect toxicity.

Conclusions: In this preliminary report initial dose reduction of SG negatively impacted PFS and OS without reducing toxicity, highlighting the need for further studies and dosing policy adjustments.

Purpose: Cyclophosphamide is a widely used anticancer agent, though its clinical application is often constrained by myelotoxicity. Infliximab, a monoclonal antibody targeting TNF-α, may alleviate this toxicity by mitigating oxidative stress. This study aimed to assess the protective effects of infliximab against cyclophosphamide-induced myelotoxicity, focusing on bone marrow and spleen-related parameters.

Methods: Male Wistar rats (260 ± 20 g) were randomly divided into four groups (n = 5 each): Control (normal saline), Infliximab (7 mg/kg, IP), Cyclophosphamide (200 mg/kg, IP), and Infliximab + Cyclophosphamide (same respective doses with a four-day interval between administrations). Nine days after the initiation of the experiment, bone marrow and spleen histopathology, bone marrow cellularity, spleen index, and levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in bone marrow tissue, along with serum TNF-α and G-CSF concentrations, were evaluated.

Results: Infliximab prevented myelofibrosis in bone marrow tissue; however, it did not mitigate cellularity depletion. It failed to counteract the effects of cyclophosphamide on spleen histology and the spleen index. Additionally, infliximab enhanced antioxidant activity in the bone marrow. Moreover, inhibition of TNF-α was associated with an increase in G-CSF levels.

Conclusion: Although infliximab improved molecular pathways associated with cyclophosphamide-induced bone marrow and hematologic toxicity in the rat model, it did not lead to significant improvements in clinical manifestations.

Background: In glioblastoma, the heterogeneity of tumors often complicates treatment outcomes, particularly resistance to temozolomide (TMZ). This study aimed to investigate the expression characteristics of MCM10 in gliomas and its potential role in TMZ resistance.

Methods: Analyze the expression of MCM10 in glioma cells within the datasets Glioma_GSE102130, Glioma_GSE130224, Glioma_GSE131928_10X, and Glioma_GSE131928_Smartseq2 using the TISCH2 single-cell database.Subsequently, the expression level of MCM10 was evaluated using the TMZ-resistant cell lines U251-TR and LN229-TR. Glioma cells with reduced MCM10 expression were constructed through lentiviral interference.Construct glioma cells with MCM10 knockdown through lentiviral interference. Additionally, this study conducts an association analysis between MCM10 expression and patterns of DNA methylation and RNA methylation.Finally, the function of MCM10 was validated in a heterotopic mouse model.

Results: MCM10 mRNA is highly expressed in osteoclast-like malignant cells (OC-likemalignant cells) and oligodendrocyte progenitor-like malignant cells (OPC-like malignant cells). After treatment with TMZ, the levels of MCM10 protein and mRNA significantly increased. Knocking down MCM10 significantly reduced the migration and invasion of U251 and LN229 cells, while altering the expression of molecular markers associated with epithelial-mesenchymal transition (EMT). Weighted gene co-expression network analysis (WGCNA) revealed signaling pathways associated with drug resistance and identified overlapping differentially expressed mRNAs between resistant cells and MCM10 knockdown cells. High expression of MCM10 is associated with low DNA methylation, and MCM10 methylation is positively correlated with patient survival rates. Furthermore, inhibition of MCM10 significantly slowed tumor growth, indicating its potential as a therapeutic target for gliomas.

Conclusion: MCM 10 is a key mediator of TMZ resistance in glioblastoma.