Chemotherapy最新文献

Background: Identifying the underlying mechanisms of immune checkpoint inhibitor resistance in patients with cachexia is a current challenge. Ghrelin is a peptide hormone that plays an important role in the metabolism of patients with cancer cachexia. Despite the importance of ghrelin in cancer cachexia, most previous studies on the subject have not distinguished between the forms of ghrelin.

Material and methods: We retrospectively screened patients with advanced or recurrent non-small cell lung cancer receiving PD-1/PD-L1 inhibitor monotherapy. Active and inactive ghrelin levels were measured in 100 patients with available plasma samples at immune checkpoint inhibitor initiation. Cancer cachexia was defined as weight loss of at least 5% during the past 6 months or weight loss of at least 2% with a BMI < 20. We analyzed the associations of the active and inactive ghrelin levels and active-to-inactive ghrelin ratio (AIR) with cancer cachexia. The prognostic impact of the active and inactive ghrelin levels and AIR were also analyzed.

Results: Among 100 patients, 35 were diagnosed with cancer cachexia. The active ghrelin level and AIR were significantly associated with cancer cachexia, whereas the inactive ghrelin level was not. The active and inactive ghrelin levels and AIR were not associated with patient prognosis.

Conclusions: The active ghrelin level and AIR were associated with cancer cachexia but not with patient prognosis. The function of the active and inactive forms of ghrelin may differ in cancer patients. The form of ghrelin should be clearly mentioned in relevant studies on cancer cachexia.

Introduction: Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) therapy is indicated as first-line or neoadjuvant chemotherapy (NAC) for patients with advanced or metastatic urothelial carcinoma (UC). However, no studies reported ddMVAC therapy with pegfilgrastim (3.6 mg) in Japanese patients. We investigated the safety and efficacy of ddMVAC therapy with pegfilgrastim in patients with advanced or metastatic UC.

Methods: A total of 43 patients received ddMVAC therapy with pegfilgrastim (3.6 mg) from February 2021 to December 2023. Among them, 25 and 18 patients received this regimen as first-line chemotherapy and NAC, respectively. We assessed toxicity and efficacy using Common Terminology Criteria for Adverse Events version 4.0 and Response Evaluation Criteria in Solid Tumors version 1.1, respectively.

Results: The median number of ddMVAC therapy cycles was 3 (range: 1-5), with a total of 131 cycles. Cisplatin at the full dose without reduction was administered to 24 (56%) patients. Grade ≥3 hematologic toxicity occurred in 15 (35%) patients. Among them, anemia, neutropenia, thrombocytopenia, and febrile neutropenia were 13.9%, 9.3%, 11.7%, and 7.0%, respectively. Regarding non-hematologic toxicity, grade 3 appetite loss was observed in 2 (5%) patients. Complete response was observed in 7 (16%) patients and partial response in 26 patients (60%), yielding an objective response rate of 76%. Pathologic complete response (pCR; ypT0pN0) was observed in 3 (16.7%) patients and downstaging occurred in 13 (72.2%) patients. The median progression-free survival and overall survival of first-line treatment with ddMVAC were 18.6 months and not reached, respectively.

Conclusion: The ddMVAC with pegfilgrastim (3.6 mg) reduced injection-related patient burden, caused fewer grade ≥3 adverse events, and demonstrated similar efficacy when compared to the original ddMVAC regimen that used granulocyte colony-stimulating factor for 7 consecutive days.

Introduction: High-dose methotrexate (MTX) is used to treat pediatric acute lymphoblastic leukemia (ALL). The drug has a low therapeutic index and a highly interindividual variability in systemic exposure. These characteristics necessitate dose adjustments and therapeutic drug monitoring protocols, while population pharmacokinetic (POP/PK) models may enable more precise drug dosing. Therefore, we assessed the performance of external POP/PK models in ALL children receiving high-dose MTX.

Methods: We retrospectively harvested clinical and laboratory data from ALL children during their first two cycles of chemotherapy. A POP/PK model was elaborated using the Monolix suite 2024R1. External models were selected from PUBMED based on strict inclusion/exclusion criteria, and their fit to the actual data was assessed by calculating bias (percentage prediction error [PE%]) and precision (percentage root mean squared error [RMSE%]).

Results: Thirty-seven ALL children participated in the study (18 males, median age 5.1 years, range 1.7-15.2 years), and six external POP/PK models were chosen. Except for one model (median PE% value, -97.45%), all models exhibited acceptable bias (median PE% values, -4.17%-2.67%), despite none of them demonstrating good precision (median RMSE% values, 89.19%-120.40%).

Conclusion: External models should be accurately evaluated before they are implemented in clinical practice, even when patients share very similar characteristics.

Introduction: This study investigates the efficacy of fucoidan combination with antibiotics, against single-species biofilms and mixed-species, individual planktonic, and coculture planktonic conditions of Methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii by time-kill curve analysis.

Materials and methods: Fucoidan, a sulfated polysaccharide, was purchased from Sigma-Aldrich, USA. Clinical isolates of MRSA and A. baumannii from diabetic foot ulcers (DFUs) were used, and single-species biofilms and mixed-species biofilms were developed to assess susceptibility to the treatments using MIC, MBC, minimum biofilm inhibitory concentration, minimum biofilm eradication concentration, and time-kill kinetics assays. Cytotoxicity was assessed using MTT assays on human skin fibroblast cells (HSF-PI 16).

Results: The study determined the geometric mean MIC and MBC values for gentamicin, imipenem, and fucoidan in MRSA and A. baumannii cultures, both individually and in co-cultures. The MIC and MBC values were significantly lower under co-culture conditions, indicating enhanced antimicrobial efficacy. Synergy between fucoidan, gentamicin, and imipenem was confirmed through time-kill assays, which showed complete inhibition of bacterial growth and effective biofilm eradication, particularly in mixed-species biofilms. Fucoidan demonstrated low cytotoxicity at optimal concentrations, highlighting their potential as a therapeutic strategy against biofilm-associated infections in DFUs.

Conclusion: The study concludes that fucoidan, in combination with gentamicin and imipenem, effectively disrupts mixed-species biofilms of MRSA and A. baumannii, suggesting fucoidan-based therapies could improve outcomes for DFU patients, warranting further clinical investigation.

Introduction: We report the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of a multi-kinase inhibitor (TG02 capsule) as a new therapy for patients with recurrent high-grade gliomas in China.

Methods: This is a single-center, dose-escalation, open-label phase I study, which enrolled patients with recurrent high-grade gliomas who failed to temozolomide. Patients were assigned sequentially into different dose groups and received TG02 every 4 weeks. The dose was increased in a traditional 3 + 3 design. Primary endpoints were the dose-limited toxicity (DLT) and the maximum tolerated dose (MTD).

Results: Twelve patients (8 glioblastomas, 4 diffuse astrocytoma) were enrolled between May 2019 and November 2021. Three patients received 100 mg and 9 received 150 mg TG02 twice a week. The plasma concentration of TG02 reached the maximum at 2 h after administration, and the elimination half-life was about 7 h. No DLT occurred and MTD was not defined in this study. Eleven patients had one or more investigator-assessed treatment-related adverse events (TRAEs). The most frequent TRAEs were vomiting (91.7%) and diarrhea (75.0%), and 50% of the patients had grade 3 or 4 adverse events. There were no treatment-related deaths. The median progression-free survival and overall survival were 1.77 (95% confidence interval [CI]: 0.82-4.24) and 9.63 (95% CI: 2.66-not estimated) months, respectively.

Conclusions: TG02 capsule 150 mg twice a week is safe and tolerable in Chinese patients with recurrent high-grade gliomas. Patients who failed to temozolomide showed obvious tumor reduction when switching to TG02 capsule. The efficacy of recurrent gliomas warrants further investigation.

Introduction: Duodenal squamous cell carcinoma is an exceedingly rare occurrence among gastrointestinal malignancies, and its diagnosis and treatment are not well understood.

Case presentation: In this report, we present a case of duodenal squamous cell carcinoma with liver and adrenal metastasis. The patient was treated with gemcitabine and S-1, achieving a progression-free survival of 7 months and an overall survival of 9 months. Additionally, we review the features and treatment approaches reported in previous cases of primary duodenal carcinoma.

Conclusion: Clearly, further case reports, such as ours, can contribute to a deeper understanding that is essential for characterizing this entity and establishing management guidelines.

Introduction: Our study aimed to identify relevant features associated with the reprisal of antineoplastic treatment in patients with solid cancers after unplanned admittance to the intensive care unit (ICU) and to assess 60th-month survival in patients with solid neoplasms admitted to the ICU.

Methods: This single-centre retrospective study of critically ill patients with active cancers was performed over a 13-year period (2005-2018). Patients' characteristics, overall survival, and antineoplastic treatment reprisal were extracted from digital medical files and compared.

Results: 134 patients were included in the study. Solid neoplasms were mostly localised to the head and neck (n = 53) followed by lung cancers (n = 29). Sepsis was the leading cause of ICU admission (62.1%) with 41/82 patients presenting with septic shock. Antineoplastic treatments were resumed in 40 patients. An age ≤60 years and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1 were found to be predictors for treatment reprisal, with odd ratios of, respectively, 2.83 (95% CI, 1.15-6.99) and 5.45 (95% CI, 2.01-14.82); area under the ROC curve of 72% (95% CI, 63-81%). Survival after the immediate discharge from the ICU was 101/134 (75%) and the 60-month survival rate was 29% and significantly higher in the treatment-reprisal group.

Conclusions: Age and ECOG PS were found to be predictors for treatment reprisal in patients with solid neoplasms admitted to the ICU. The latter benefits from better long-term survival.

Background: Despite major advances in cancer treatment in the past years, there is a need to optimize chemotherapeutic drug dosing strategies to reduce toxicities, suboptimal responses, and the risk of relapse. Most cancer drugs have a narrow therapeutic index with substantial pharmacokinetics variability. Yet, current dosing approaches do not fully account for the complex pathophysiological characteristics of the patients. In this regard, the effect of sex on anticancer chemotherapeutic drugs' disposition is still underexplored. In this article, we review sex differences in chemotherapeutic drug pharmacokinetics; we suggest a novel approach that integrates sex into the traditional a priori body surface area (BSA) dosing selection model, and finally, we provide an overview of the potential benefits of a broader use of therapeutic drug monitoring (TDM) in oncology.

Summary: To date, anticancer chemotherapeutic drug dosing is most often determined by BSA, a method widely used for its ease of practice, despite criticism for not accounting for individual factors, notably sex. Anatomical, physiological, and biological differences between males and females can affect pharmacokinetics, including drug metabolism and clearance. At equivalent doses, females tend to display higher circulating exposure and more organ toxicities, which has been formally demonstrated at present for about 20% of chemotherapeutic drugs. An alternative could be the sex-adjusted BSA (SABSA), incorporating a 10% increase in dosing for males and a 10% decrease for females, though this approach still lacks formal clinical validation. Another strategy to reduce treatment-related toxicity and potentially enhance clinical outcomes could be a more widespread use of TDM, for which a benefit has been demonstrated for 5-fluorouracil, busulfan, methotrexate, or thiopurines.

Key messages: The inclusion of sex besides BSA in an easy-to-implement formula such as SABSA could improve a priori chemotherapy dosing selection, even though it still requires clinical validation. The a posteriori use of TDM could further enhance treatment efficacy and safety in oncology.

Introduction: Therapeutic drug monitoring of imatinib is widely performed to individualize imatinib dosage. While N-desmethyl imatinib is an active metabolite of imatinib, its concentrations are not routinely determined.

Methods: Imatinib and N-desmethyl imatinib trough plasma concentrations at steady-state were obtained from 295 patients with either chronic myeloid leukemia or gastrointestinal stromal tumor to see whether N-desmethyl imatinib provided additional information. Pharmacokinetic data were analyzed using a nonlinear mixed effect approach. Correlations between several pharmacokinetic metrics of drug exposure were evaluated.

Results: The mean value of the N-desmethyl imatinib/imatinib ratio of trough concentrations was 0.31 with half of the values between 0.23 and 0.37. N-desmethyl imatinib and total (i.e., N-desmethyl imatinib plus imatinib) trough plasma concentrations or area under the curve values were closely correlated with imatinib values. The distribution of imatinib or total concentrations between patients requiring imatinib dosage adjustment, or not, was similar.

Conclusion: These results do not clearly support routine N-desmethyl monitoring since it does not provide additional information to imatinib data.