Correlation analysis between camrelizumab trough concentration levels and efficacy or safety in East Asian patients with advanced lung cancer.

BACKGROUND: Camrelizumab combined with chemotherapy is approved across tumor types. However, only a fraction of patients benefits from immunotherapy, and biomarkers such as the expression of PD-L1, tumor mutational burden, and CXCL11 are expensive and suboptimal specificity for cancer patients. An exposure-response (E-R) relationship has been reported in many immune checkpoint inhibitors (ICIs), and the trough concentrations and other drug exposure metrics are broadly used to guide dosing decisions, assess exposure-outcomes relationships, and ultimately predict outcomes based on those relationships. However, the potential use of trough concentration levels for camrelizumab is still not clear. METHODS: Blood samples were obtained at trough levels after doses 3 and 4 from 77 patients with advanced lung cancer who received camrelizumab (200 mg Q3 W) monotherapy or combined with chemotherapy. We optimized a competitive ELISA method to measure the trough concentration. RESULTS: We found that the trough concentration was steady after 3 dose cycles, and the trough concentration level of camrelizumab was higher in patients who developed immune-related adverse effects (irAEs) than in those who did not (P < 0.05) but was not observed in disease progression and PFS (P > 0.05). Age (< 65 years old), no smoking history, and efficacy evaluation after 4-dose treatment were associated with PFS (P < 0.05), but no significance was observed in other clinical characteristics. Total bilirubin and albumin had an influence on trough concentration, and monocytes and albumin were independent risk factors for PFS (P < 0.05). CONCLUSIONS: Our results suggest that the trough concentration level of camrelizumab might be a risk factor for the occurrence of irAEs in advanced lung cancer, and using the immunotherapy as early as possible may bring better clinical outcomes.

Efficacy and safety evaluation of albumin-bound paclitaxel chemotherapy in East Asian patients with gynecological tumors based on the degree of paclitaxel binding to patient plasma.

Nab-PTX is a special dosage form of antitumor drug that is different from other injections. In order to explore the efficacy and safety of albumin-bound paclitaxel, we developed an analytical method with UPLC-MS/MS to quantify the total and free paclitaxel in plasma, and prospectively evaluate the impact of unbound fraction fu (%) on the prognosis and adverse reactions of patients with gynecological tumors. From 2020.10 to 2021.10, a total of 116 patients with gynecological tumors were included, application of albumin-bound paclitaxel combined with platinum chemotherapy drugs, the blood collection time is 18-30 h after nab-PTX intravenous infusion. The collection time and the start (end) time of intravenous drip are recorded correctly, and a high-precision and sensitive UPLC-MS/MS method for the simultaneous determination of total and free paclitaxel was established. With fu (%) = Cunbound/Ctotal as the evaluation index, the concentration of total paclitaxel and free paclitaxel were determined by UPLC-MS/MS. The value of fu (%) was closely related to clinical adverse reactions, neutropenia, thrombocytopenia, leukopenia and bone marrow suppression. Neurotoxicity was statistically remarkable ( P up0.001), and fu (%) has a significant correlation with clinical efficacy ( P up0.001). We have developed a highly precise, highly sensitive and specific UPLC-MS/MS method for the simultaneous determination of binding and free albumin-bound paclitaxel concentrations in patients' serum. In addition, we found that fu (%) could be used as the detection index. The higher the fu (%) was, the more taxol could be free, the more adverse reactions related to toxic events occurred in patients.

Effect of concomitant antibiotics use on patient outcomes and adverse effects in patients treated with ICIs.

Background: Immune checkpoint inhibitors (ICIs) such as PD-1/PD-L1/CTLA-4 inhibitors have brought new opportunities for the cure of cancer patients and have been widely used and which are the most successful cancer immunotherapy drug in recent years. Gut microbiome and metabolites exert a critical regulatory function in cancer immunotherapy of ICIs, which can be affected by antibiotics intervention. However, inflammatory infections caused by impaired immune function in tumor patients often require antibiotic treatment.Objective: In this review, we briefly discussed the correlation between antibiotics and ICIs treatment to evaluate the impact of antibiotics on cancer progression.Methods: By searches of PubMed, we collected the data such as progression-free survival time (PFS) and overall survival time (OS) in patients with non-small cell lung cancer (NSCLC), kidney cancer, Melanoma, colorectal cancer, and other tumors.Results: Antibiotics have a negative effect on the prolongation of survival in cancer patients treated with ICIs. This may depend on the patient's cancer type and the type of ICIs and antibiotics they have used.Conclusions: Antibiotics may reduce the effectiveness of immunotherapy by depleting the body's microbiome. Therefore, paying attention to the changes in the level of microorganisms in cancer patients, while making more individualized and precise improvements in treatment regimens, may bring new opportunities to improve the efficacy of immunotherapy.

Biomarkers of related driver genes predict anti-tumor efficacy of immune checkpoint inhibitors.

Cancer is a disease with high morbidity and mortality in the world. In the past, the main treatment methods for cancer patients were surgery, radiotherapy and chemotherapy. However, with early treatment, the recurrence rate of cancer is higher, and the drug resistance of cancer cells is faster. In recent years, with the discovery of immune escape mechanism of cancer cells, Immunotherapy, especially Immune Checkpoint Inhibitors (ICIs), has made a breakthrough in the treatment of solid tumors, significantly prolonging the overall survival time and disease-free progression in some solid tumors, and its clinical benefits are more prominent than those of traditional anti-tumor drugs, which has become the hope of cancer patients after the failure of multi-line therapy. More and more studies have shown that there is a correlation between cancer driving genes and the clinical benefits of ICIs treatment, and the therapeutic effects and adverse reactions of ICIs can be predicted by the status of driving genes. Therefore, screening potential biomarkers of people who may benefit from immunotherapy in order to maximize the therapeutic benefits is a top priority. This review systematically summarizes the cancer driving genes that may affect the clinical benefits of immune checkpoint inhibitors, and provides accurate scientific basis for clinical practice.

The Ancient Town Residential Environment of the Elderly in Xiangxi Tujia: Survey, Questions, and Recommendations.

This study uses behavioral observation, interviews, and questionnaire research to investigate the residential environment. It also evaluates the elderly in four representative ancient towns of Xiangxi, namely, Liye Ancient Town, Furong Ancient Town, Liexi Ancient Town, and Xichehe Ancient Town. It includes indoor air (CO2, PM2.5, PM10) and light intensity monitoring for the residential environment. The results showed that the elderly had a significant sense of frustration and loneliness. Of the elderyly, 70% believed the current living environment had an impact on healthy living, and 45% believed the safety and convenience of the living environment should be improved. More than 80% of the elderly were dissatisfied with their indoor acoustic environment, and more than 70% were dissatisfied with their home transportation. More than 85% of the elderly considered traditional wooden components and spaces to be the source of cultural identity. Furthermore, the average indoor PM2.5 concentration during the fire pit fire was 350-600 µg/m3, about 4.7-8 times the Chinese standard value. The average concentration of PM10 in all rooms was more than 400 µg/m3, approximately three times the Chinese standard value. Also, targeted environmental improvement strategies were proposed. The study results provided actual information to develop a systematic approach and a targeted design based on the needs to improve the residential environment of the elderly in ancient cities.

Indoor Air Quality in Tujia Dwellings in Hunan, China: Field Tests, Numerical Simulations, and Mitigation Strategies.

Air pollution is a major health hazard. The traditional habits and unique ethnic fire culture in Hunan Tujia region result in the long-term exposure of residents, especially elderly people, to pollutants. In this study, we conducted field monitoring and assessment of indoor pollutants in the residential houses of Hunan Tujia families and subsequently visualised and simulated fire pollutants in representative residential houses by using fire-dynamic-simulator software. Pollutant-control strategies, using passive smoke collectors and resizing windows, were proposed and simulated for validation. The results revealed that passive smoke collectors reduced the pollutant concentration in the hall house by 43.96%. Furthermore, the optimal window size was 1500 mm × 1500 mm, and the most reasonable windowsill height of the firepit was 1800 mm. The results of the study can be used to improve the indoor air quality of Tujia dwellings and mitigate the adverse health effects of exposure to indoor air pollution without restricting ethnic beliefs and traditional customs.

Effects of Concomitant Antibiotics Use on Immune Checkpoint Inhibitor Efficacy in Cancer Patients.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have changed the outcomes of a variety of cancers in an unprecedented manner. Gut microbiome plays a crucial regulatory role in the antineoplastic therapy of ICIs, which can be influenced by antibiotic (ABX) administration. In this efficacy evaluation, we aimed to clarify the correlations of ABX administration with the survival of cancer patients receiving ICIs treatment. METHOD: The eligible literatures were searched using PubMed, Cochrane Library, Web of Science, and Clinical trials.gov databases before Nov 2021. The correlations of ABX administration with progression-free survival (PFS) and overall survival (OS) were determined using Hazard ratios (HRs) coupled with 95% confidence intervals (CIs). RESULTS: A total of 12 studies enrolling 6010 cancer patients receiving ICIs treatment were included in this efficacy evaluation. ABX administration was significantly correlated worse PFS (HR=1.60, 95%CI=1.33-1.92, P<0.00001) and OS (HR=1.46, 95%CI=1.32-1.61, P<0.00001). Similar results were found in the subgroup analysis of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and melanoma. CONCLUSIONS: ABX use during ICIs treatment of cancer may significantly shorten PFS and OS. ABX should be used cautiously in cancer patients receiving ICIs. However, further validations are still essential due to existing publication bias.

Correlation between pharmacokinetic parameters of 5-fluorouracil and related metabolites and adverse reactions in East-Asian patients with advanced colorectal cancer.

BACKGROUND AND OBJECTIVE: To examine the range of the area under the concentration-time curve (AUC) calculated using plasma 5-FU concentration at steady-state plasma concentration-time of 5-fluorouracil (5-FU) and correlation between 5-FU metabolites (5,6-dihydro-5-fluorouracil, 5-FUH2 and α-fluoro-ß-Alanine, FBAL) plasma concentration and adverse reactions when patients with advanced colorectal cancer (CRC) received 5-FU-based chemotherapy. METHODS: 74 patients with advanced CRC receiving 5-FU-based chemotherapy from Aug. 2017 to Nov. 2020 in Harbin Medical University Cancer Hospital were involved in this study, the dosage of 5-FU being determined according to the patient's body surface area (BSA). Using an ultra-high performance liquid chromatography-tandem mass spectrum (UPLC-MS/MS) to determine the 5-FU steady-state plasma concentration (CSS) and plasma concentration of 5-FUH2 and FBAL in CRC patients receiving 5-FU in continuous intravenous infusion for 18-30 h, the start time and end time of 5-FU infusion in patients were accurately recorded and the continuous infusion time (TCI) was calculated. The AUC value was calculated according to AUC = CSS × TCI. At the same time, the treatment effects and adverse drug reactions of patients were evaluated, to analyze the relationship between 5-FU AUC, 5-FUH2 and FBAL plasma concentration and clinical efficacy and adverse reactions in CRC patients, and explore the ideal AUC range of 5-FU in the treatment of colorectal cancer. RESULTS: The AUC of 5-FU was not normally distributed and ranged from 3.13 to 41.12mgh/L, with an average value of 14.81 ± 8.62 mg·h /L, and the AUC values had obvious inter-individual differences up to 13 times. 5-FUH2 ranged from 131.98 to 987.93 ng/mL, with an average of 550.58 ± 260.60 ng/mL; FBAL ranged from 23.58 to 262.48 ng/mL, with an average of 89.79 ± 58.47 ng/mL. Correlation analysis results revealed a significant correlation between 5-FU AUC, 5-FUH2 and FABL plasma concentration and adverse reactions, 5-FU AUC and clinical efficacy. CONCLUSIONS: There are obvious individual differences in AUC values in CRC patients receiving different dosages of 5-FU based on BSA. The ideal AUC range of 5-FU is 18.23-29.17 mg·h/L. There was a significant correlation between 5-FUH2 and FABL plasma concentration and adverse reactions.

Tyrosine Kinase Inhibitors-Induced Arrhythmias: From Molecular Mechanisms, Pharmacokinetics to Therapeutic Strategies.

With the development of anti-tumor drugs, tyrosine kinase inhibitors (TKIs) are an indispensable part of targeted therapy. They can be superior to traditional chemotherapeutic drugs in selectivity, safety, and efficacy. However, they have been found to be associated with serious adverse effects in use, such as myocardial infarction, fluid retention, hypertension, and rash. Although TKIs induced arrhythmia with a lower incidence than other cardiovascular diseases, much clinical evidence indicated that adequate attention and management should be provided to patients. This review focuses on QT interval prolongation and atrial fibrillation (AF) which are conveniently monitored in clinical practice. We collected data about TKIs, and analyzed the molecule mechanism, discussed the actual clinical evidence and drug-drug interaction, and provided countermeasures to QT interval prolongation and AF. We also pooled data to show that both QT prolongation and AF are related to their multi-target effects. Furthermore, more than 30 TKIs were approved by the FDA, but most of the novel drugs had a small sample size in the preclinical trial and risk/benefit assessments were not perfect, which led to a suspension after listing, like nilotinib. Similarly, vandetanib exhibits the most significant QT prolongation and ibrutinib exhibits the highest incidence in AF, but does not receive enough attention during treatment.

131I-radioisotope modified in PEGylation metal organic frameworks for sensitization in refractory differentiated thyroid cancer treatment.

Radiation therapy for cancer can lead to off-target toxicity and can be ineffective against refractory differentiated thyroid cancer. The nanoscale metal organic frameworks (NMOFs) have shown great potential in cancer diagnostic and treatment due to their advantages in the aspect of structural diversities, high intrinsic biodegradability and drug-loading capacities. Here, we provide that intratumoral injection, in mouse of refractory differentiated thyroid cancer.In this work, we used the therapeutic 131I radioisotope modified Zr-MOF (Zr-MOF@131I) with aim to enable long-term relief of tumour therapy, which has successfully eliminated tumour at ralatively low radioactivity doses. Polyethylene glycol (PEG) was coated into Zr-MOF and, as a result, circulation time was significantly improved by intratumoral injection. These findings therefore suggest that nanoparticles could be used in vivo combined therapy. On injection, while it is a highly effective drug for radioisotope, Zr-MOF with attenuation ability could apply for a radio-sensitizer to enhance inner radiotherapy (RT). The local therapy, which uses only biocompatible components, might enable new strategies for local tumour treatments. These could be further combined with systemic therapeutic responses for the inhibition of refractory differentiated thyroid cancer and the prevention of tumour recurrence in patients.

Evaluating the efficacy and safety of immune checkpoint inhibitors by detecting the exposure-response: An inductive review.

Immune checkpoint inhibitors (ICIs) have been demonstrated an effective treatment in multiple tumor type, which restore the immune response to against cancer cell. Currently, approved ICIs include anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4); anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) monoclonal antibodies (mAbs). In most these drugs, unique pharmacokinetic (PK) and pharmacodynamics (PD) have shown significant influence on clinical outcomes, which occurred by target-mediated drug concentration and time-varying drug clearance. An exposure-response (E-R) relationship has been used to describe the safety and efficacy of ICIs, and shown a plateaued E-R and time dependent changes in exposure. Using an enzyme linked immunosorbent assay (ELISA) or LC-MS/MS method to measure the peak concentration, trough concentration or area under the curve (AUC) of ICIs to assess the drug exposure. There are lots of covariates that have an influence on exposure, such as sex, clearance, body weight and tumor burden. In this review, we pooled data from studies of concentration or other pharmacokinetics parameter of mAbs to assess E-R in efficacy and safety.