Comparison of four criteria for potentially inappropriate medications in older patients with newly diagnosed non-small cell lung cancer.

BACKGROUND: Potentially inappropriate medication (PIM) use is a common problem among older patients. This study aimed to compare the prevalence of PIMs in older patients with newly diagnosed non-small cell lung cancer (NSCLC), and to identify the correlates of PIMs. RESEARCH DESIGN AND METHODS: A secondary analysis of a prospective cohort study was conducted. Patients were enrolled from January 2014 to December 2020 and information were extracted from patients' electronic medical records (EMRs). We evaluated the PIMs using four different PIM criteria. The concordance among the four PIM criteria was calculated using kappa tests. The possible risk factors associated with PIMs were analyzed by multivariate logistic regression. RESULTS: The prevalence of at least one PIM identified by the four criteria ranged from 25.1% to 48.2% among 514 patients. There was moderate consistency between the GO-PIM scale and the AGS/Beers criteria, while poor consistency with the other criteria (the STOPP criteria and the Chinese criteria). Polypharmacy was found to be significantly associated with the occurrence of PIMs in all criteria (p < 0.001). CONCLUSIONS: Our results showed a high prevalence of PIMs in older patients with NSCLC, which was significantly associated with polypharmacy, and the consistency across the four criteria was poor-to-moderate.

Immune checkpoint inhibitor related myositis: an observational, retrospective, pharmacovigilance study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) show promise in cancer treatment, but recent cases highlight myositis as a serious complication. RESEARCH DESIGN AND METHODS: We did a retrospective study on drug safety using FAERS data up to Q3 2022, focusing on immune checkpoint inhibitors (ICIs) and myositis. We used IC and ROR to assess the association. Logistic regression in R 3.2.5 helped identify factors linked to fatal outcomes. RESULTS: We identified 558 cases of ICIs-associated myositis. Our study found a significant link between ICIs and myositis (ROR 15.54 [14.23-16.96], IC 3.79 [3.66-3.92], see Figure 1). Notably, myositis was more common in patients on ICI combination therapy compared to monotherapy (ROR 1.72 [1.39-2.11], IC 0.63 [0.30-0.93]). Age increased the risk of ICI-associated myositis and was also a factor in fatality (p = 0.011). Common accompanying adverse events included myocarditis (21.33%), severe myasthenia gravis (16.49%), and malignant neoplasm progression (8.06%). Fatal cases were more common when myositis was accompanied by myocarditis, severe myasthenia gravis, or malignant neoplasm progression. CONCLUSIONS: Clinicians must note the risk of ICI-associated myositis, especially dangerous in older patients or when combined with other issues like myocarditis or severe myasthenia gravis.

Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue.

AIMS: To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms. MATERIALS AND METHODS: Insulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration. RESULTS: We found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine-induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine-induced adipose tissue macrophage infiltration and M1-like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine-induced insulin resistance at least in part through a GABAB receptor-dependent pathway. CONCLUSIONS: These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.

Prevalence of aggressive care among patients with cancer near the end of life: a systematic review and meta-analysis.

Background: Aggressive care near patients' end-of-life (EOL) entails limited therapeutic values, high costs, and compromised quality of life (QoL). In this study, we aimed to estimate the global prevalence of aggressive care in patients with cancer and explore potential subgroup differences. Methods: We searched PubMed, Embase, and the Cochrane Library from database inception to Feb 16, 2024. Eligible studies reported the prevalence of aggressive EOL care using at least one quantifiable measure. Random-effects models were used to derive the pooled prevalence and subgroup analyses were performed to investigate differences in the prevalence of aggressive care across regions, the country's level of economic development, tumor types, ages, and sample sizes. This review is registered with PROSPERO, number CRD42023467839. Findings: A total of 129 studies were included in this systematic review, of which 118 (91.5%) were from high-income countries. Studies were mostly conducted in the Americas (60, 46.5%), Europe (34, 26.4%), and Western Pacific (31, 24.0%). Measures of aggressive care were inconsistent across studies, with the most commonly used measure being the use of chemotherapy in the last 14 days of life (DOLs) (n = 87, 67.4%) and intensive care unit (ICU) stay in the last 30 DOLs (n = 87, 67.4%). The prevalence of the five claims-based measures of aggressive care, i.e., chemotherapy in the last 14 DOLs, ICU stay in the last 30 DOLs, repeated hospital admission in the last 30 DOLs, repeated emergency room (ER) visit in the last 30 DOLs, and hospice care <3 days before death were 11.6% (95% CI, 9.8%-13.4%), 14.4% (95% CI, 11.8%-17.0%), 17.9% (95% CI, 14.4%-21.4%), 14.8% (95% CI, 12.0%-17.6%), and 14.4% (95% CI, 11.2%-17.6%), respectively. Regional differences were statistically significant in the prevalence of ICU stay and repeated hospital admission in the last 30 DOLs (p < 0.01; p = 0.03). Patients with hematologic malignancies were more likely to receive aggressive care than those with solid tumors, as seen in their higher rates of chemotherapy in the last 14 DOLs (21.7% versus 11.6%; p = 0.03), ICU stay in the last 30 DOLs (25.5% versus 10.8%; p < 0.01), and hospice care <3 days before death (26.7% versus 14.2%; p < 0.01). In addition, the prevalence of chemotherapy in the last 14 DOLs (26.2%; p < 0.01) and repeated hospital admission in the last 30 DOLs (31.4%; p < 0.01) were highest among pediatric patients with cancer. Interpretation: This meta-analysis found that aggressive EOL care was common in patients with cancer, regardless of the definition used, and varied by regions and populations. It is necessary to be aware of the global burden of aggressive care for patients with cancer near their EOL and take prompt action to address it. Funding: National Natural Science Foundation of China (Grant No. 72274004).

Anticancer drug-induced interstitial lung disease: a critical appraisal of clinical practice guidelines and consensus statements.

Anticancer drug-induced interstitial lung disease (DIILD) has received increasing clinical attention, and the quality of relevant guidance documents has become critical. Our purpose was to assess the quality of documents for anticancer DIILD and summarize the recommendations. Clinical practice guidelines (CPGs) and consensus statements with recommendations were searched in electronic databases, websites of guideline organizations, and professional societies. The quality of documents was assessed using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) methodology, and the specific recommendations were aggregated and compared. A total of 11 documents were eligible, including 6 CPGs and 5 consensus statements, and the quality of AGREE II assessments differed greatly. The domains of scope and purpose and clarity of presentation received the highest median scores, while the stakeholder involvement domain received the lowest score. Recommendations were inconsistent between documents, particularly regarding the selection of steroid regimens. The methodological quality of the guidance documents needs to be enhanced, especially in the domain of stakeholder involvement. Inconsistencies exist in documents, and further discussions among multidisciplinary experts are needed. Particularly, differences in steroid regimens require attentions, and researches on the risks of adverse events and discovery of precise biomarkers are necessary.

Formaldehyde aggravates airway inflammation through induction of glycolysis in an experimental model of asthma exacerbated by lipopolysaccharide.

Formaldehyde (FA) exposure has been reported to induce or aggravate allergic asthma. Infection is also a potential risk factor for the onset and aggravation of asthma. However, no study has addressed the effects of FA exposure on asthmatic patients with respiratory infection. FA is ubiquitous in environment and respiratory infections are common in clinics. Therefore, it is necessary to explore whether FA exposure leads to the further worsening of symptoms in asthma patients with existing respiratory infection. In the present study, ovalbumin (OVA) was used to establish the murine asthma model. Lipopolysaccharide (LPS) was intratracheal administrated to mimic asthma with respiratory infection. The mice were exposed to 0.5 mg/m3 FA. FA exposure did not induce a significant aggravation on OVA induced allergic asthma. However, the lung function of specific airway resistance (sRaw), histological changes and cytokines production were greatly aggravated by FA exposure in OVA/LPS induced murine asthma model. Monocyte-derived macrophages (MDMs) were isolated from asthmatic patients. Exposure of MDMs to FA and LPS resulted in increased TNF-α, IL-6, IL-1ß, and nitric oxide (NO) production. Lactate produciton and lactate dehydrogenase A (LDHA) expression were found to be upregulated by FA in OVA/LPS induced asthmatic mice and LPS stimulated MDMs. Furthermore, glycolysis inhibitor 2-Deoxy-d-glucose attenuated FA and LPS induced TNF-α, IL-6, IL-1ß, and NO production. We conclude that FA exposure can lead to the aggravation of allergic asthma with infection through induction of glycolysis. This study could offer some new insight into how FA promotes asthma development.

Development and validation of a nomogram predictive model for colorectal adenoma with low-grade intraepithelial neoplasia using routine laboratory tests: A single-center case-control study in China.

Background: Colorectal cancer (CRC) is the third most common cancer in the world and has a high mortality rate. Colorectal adenoma (CRA) is precancerous lesions of CRC. The purpose of the present study was to construct a nomogram predictive model for CRA with low-grade intraepithelial neoplasia (LGIN) in order to identify high-risk individuals, facilitating early diagnosis and treatment, and ultimately reducing the incidence of CRC. Methods: We conducted a single-center case-control study. Based on the results of colonoscopy and pathology, 320 participants were divided into the CRA group and the control group, the demographic and laboratory test data were collected. A development cohort (n = 223) was used for identifying the risk factors for CRA with LGIN and to develop a predictive model, followed by an internal validation. An independent validation cohort (n = 97) was used for external validation. Receiver operating characteristic curve, calibration plot and decision curve analysis were used to evaluate discrimination ability, accuracy and clinical practicability of the model. Results: Four predictors, namely sex, age, albumin and monocyte count, were included in the predictive model. In the development cohort, internal validation and external validation cohort, the area under the curve (AUC) of this risk predictive model were 0.946 (95%CI: 0.919-0.973), 0.909 (95 % CI: 0.869-0.940) and 0.928 (95%CI: 0.876-0.980), respectively, which demonstrated the model had a good discrimination ability. The calibration plots showed a good agreement and the decision curve analysis (DCA) suggested the predictive model had a high clinical net benefit. Conclusion: The nomogram model exhibited good performance in predicting CRA with LGIN, which can aid in the early detection of high-risk patients, improve early treatment, and ultimately reduce the incidence of CRC.

Safety analysis of pemigatinib leveraging the US Food and Drug administration adverse event reporting system.

Background: Cholangiocarcinoma (CCA) is a highly lethal and aggressive epithelial tumor of the hepatobiliary system. A poor prognosis, propensity for relapse, low chance of cure and survival are some of its hallmarks. Pemigatinib, the first targeted treatment for CCA in the United States, has been demonstrated to have a significant response rate and encouraging survival data in early-phase trials. The adverse events (AEs) of pemigatinib must also be determined. Objective: To understand more deeply the safety of pemigatinib in the real world through data-mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: Disproportionality analysis was employed in a retrospective pharmacovigilance investigation to identify the AEs linked to pemigatinib use as signals. Data were collected between 1 January 2020 to 30 June 2022. Four data-mining methods (proportional reporting odds ratio; proportional reporting ratio; Bayesian confidence propagation neural networks of information components; empirical Bayes geometric means) were used to calculate disproportionality. Results: A total of 203 cases using pemigatinib as the prime-suspect medication were found in our search, which involved 99 preferred terms (PTs). Thirteen signals of pemigatinib-induced AEs in seven System Organ Classes were detected after confirming the four algorithms simultaneously. Nephrolithiasis was an unexpected significant AE not listed on the drug label found in our data-mining. Comparison of the differences between pemigatinib and platinum drugs in terms of 33 PTs revealed that 13 PTs also met the criteria of the four algorithms. Ten of these PTs were identical to those compared with all other drugs, in which (excluding a reduction in phosphorus in blood) other PT signal values were higher than those of all other drugs tested. However, comparison of the differences between pemigatinib and infigratinib in terms of the 33 PTs revealed no significant signals in each algorithm method. Conclusion: Some significant signals were detected between pemigatinib use and AEs. PTs with apparently strong signals and PTs not mentioned in the label should be taken seriously.

Interstitial pneumonitis associated with EGFR/ ALK tyrosine kinase inhibitors used in non-small cell lung cancer: an observational, retrospective, pharmacovigilance study.

BACKGROUND: Epidermal Growth Factor Receptor/ Anaplastic Lymphoma Kinase Tyrosine kinase inhibitors (EGFR/ALK TKIs) may provoke fatal interstitial pneumonitis (IP). The study was conducted to characterize the main characteristics of EGFR/ALK TKI-induced IP and identify factors associated with death. RESEARCH DESIGN AND METHODS: A disproportionality analysis was conducted using Vigibase, the World Health Organization pharmacovigilance database. Clinical features of patients with EGFR/ALK-TKI-related IP were compared between the fatal and non-fatal groups. RESULTS: A total of 3355 EGFR/ALK-TKI-IP events were identified, over half of them from Asia (57.47%) and mostly the aged (63.21%). Osimertinib appeared the strongest IP association. The median time to onset (TTO) was 40 (interquartile range [IQR] 16-84) days. There were significant differences between the fatal and non-fatal groups in terms of reporting year and TKI regimens (P < 0.05). The fatality rate of erlotinib-induced IP was the highest (35.54%). CONCLUSION: Our study showed that EGFR/ALK TKIs were associated with IP that had a high fatality rate and tended to occur earlier in fatal cases. It is necessary to raise awareness of IP surveillance when EGFR/ALK TKIs were administered.

Risk of cutaneous adverse events in cancer patients treated with phosphatidylinositol-3-kinase inhibitors: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Cutaneous adverse effects (AEs) are common following the phosphoinositide-3-kinase (PI3K) inhibitors treatment. We aim to estimate the incidence and risk of PI3K inhibitor-related cutaneous AEs. METHODS: The protocol was submitted to the PROSPERO registry. We searched ClinicalTrials.gov and international databases up to July 29, 2022. Meta-analysis was conducted by using risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: Fourteen randomized controlled trials (RCTs) comprising 3877 patients were analyzed in this study. Compared with control arms, PI3K inhibitors showed a significant increase in the risk of all-grade rash, high-grade rash, and serious rash events (RR 2.29, 95% CI 1.58-3.31, p < 0.00001; RR 9.34, 95% CI 4.21-20.69, p < 0.00001; RR 5.11, 95% CI 2.11-12.36, p = 0.0003). The overall incidences of all-grade rash and high-grade rash were 26.2% (592/2257) and 4.4% (66/1487). Subgroup analyses of all-grade rash according to cancer types and PI3K inhibitor assignations identified the significant associations. PI3K inhibitors also significantly increased the risk of pruritus and dry skin (RR 1.63, 95% CI 1.14-2.33, p = 0.007; RR 3.34, 95% CI 2.30-4.85, p < 0.00001), with incidences of 13.4% (284/2115) and 9.8% (141/1436) in the treatment group. CONCLUSION: There is a significantly increased risk of some cutaneous AEs in patients using PI3K inhibitors. Advance intervention is recommended in case of severe and life-threatening events. Further research is required to investigate the risk factors and pathogenesis.

Interstitial lung disease associated with anti-HER2 anti-body drug conjugates: results from clinical trials and the WHO's pharmacovigilance database.

BACKGROUND: Interstitial lung disease (ILD) events associated with anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates (ADCs) have aroused wide attention. RESEARCH DESIGN AND METHODS: In meta-analysis, we systematically reviewed literatures, and the outcomes were the proportion and risk of ILD related to anti-HER2 ADCs. A disproportionality analysis based on data from VigiBase was conducted to characterize the main features of anti-HER2 ADC-related ILD/pneumonitis. RESULTS: Two hundred and forty-five all-grade and 47 grade ≥ 3 ILD events with the proportion of 4.4% (95% confidence interval (CI) [2.0%, 6.8%]) and 0.5% (95% CI [0.3%, 0.8%]) were observed for anti-HER2 ADCs, respectively. Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine significantly increased the risk of all-grade and grade ≥ 3 ILD events with Peto odd ratios of 2.62 (95% CI [1.71, 4.04], P < 0.0001) and 2.82 (95% CI [1.07, 7.42], P = 0.04), respectively. In VigiBase, 271 cases of ILD/pneumonitis related to trastuzumab emtansine and trastuzumab deruxtecan were extracted. The median time to the onset of event was 86 days and 54.95% of events occurred within 3 months. CONCLUSIONS: Trastuzumab emtansine, trastuzumab deruxtecan and trastuzumab duocarmazine increased the risk of ILD, which can lead to serious outcomes and tends to occur early.

Urinary incontinence as a possible signal of neuromuscular toxicity during immune checkpoint inhibitor treatment: Case report and retrospective pharmacovigilance study.

Background: Immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), but there is limited evidence regarding the association between urinary incontinence and ICIs. Methods: We described the case of a patient experiencing urinary incontinence who later experienced a series of irAEs such as myocarditis, myositis, and neurologic diseases while on ICI treatment in our hospital. In addition, we queried the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from the third quarter of 2010 to the third quarter of 2020 to perform a retrospective study to characterize the clinical features of urinary incontinence associated with ICIs. Result: In the FAERS study, 59 cases of ICI-related urinary incontinence were retrieved, and approximately 32.2% of the cases were fatal. Combination therapy with nervous system drugs and age >80 years old were the significant risk factors for fatal outcomes. Among these cases of ICI-related urinary incontinence, 40.7% (n = 24) occurred concomitantly with other adverse events, especially, neurological (fifteen cases), cardiovascular (seven cases), musculoskeletal (six cases), and urological disorders (five cases). Five cases had an overlapping syndrome similar to our case report, including one case of myasthenia gravis with myocarditis and another of myasthenic syndrome with polymyositis. Conclusion: ICI-related urinary incontinence might be a signal of fatal neuromuscular irAEs, especially when it occurs concomitantly with ICI-associated neuromuscular-cardiovascular syndrome. Clinicians should be aware of the occurrence of urinary incontinence to identify potentially lethal irAEs in the early phase.

Effect of bariatric surgery on long-term cardiovascular outcomes: a systematic review and meta-analysis of population-based cohort studies.

This meta-analysis aimed to compare the effects of bariatric surgery and nonsurgery on cardiovascular outcomes in patients with obesity. A systematic literature search of the Medline (via PubMed), Embase, and Cochrane Central Register of Controlled Trials databases was performed until August 18th, 2021. Population-based cohort studies comparing long-term cardiovascular outcomes for patients with obesity undergoing bariatric surgery or not were included. A meta-analysis of relative risks (RRs) was performed for all outcomes. We conducted subgroup analyses and meta-regression to explore sources of heterogeneity and the stability of the results. Twenty-one population-based cohort studies involving 2,857,016 participants were identified. The major adverse cardiovascular event (MACE) RR in the bariatric surgery group was .53 (95% confidence interval [CI] = .45-.62, P < .001) relative to the nonsurgical group. Relative to the nonsurgical group, the risk of myocardial infarction (MI) (RR = .40, 95% CI = .30-.52, P < .001), stroke (RR = .60, 95% CI = .46-.79, P < .001), cardiovascular death (RR = .43, 95% CI = .35-.54, P < .001), and all-cause death (RR = .44, 95% CI = .32-.59, P < .001) was significantly reduced for patients who underwent bariatric surgery. In subgroup analyses, as the proportion of patients with diabetes mellitus increased, lower RRs for MACE, MI, and stroke were observed in the surgery group relative to the nonsurgical group. The decreased risk of MACE was also observed in the subgroup with median follow-up duration ≥5 years.Bariatric surgery improves cardiovascular outcomes in patients with obesity, especially providing long-term benefits, and this effect is more pronounced in patients with comorbid diabetes.

Risk of Thromboembolic Events in Cancer Patients Treated with Immune Checkpoint Inhibitors: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The association between immune checkpoint inhibitors (ICIs) and thromboembolic events (TEEs) remains controversial. OBJECTIVE: The goal of this study was to assess the risk of major TEEs associated with ICIs. METHODS: We explored ICI-related TEEs in randomized controlled trials available in ClinicalTrials.gov and electronic databases up to June 30, 2021. Meta-analysis was performed by using Peto odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of 61 studies were included. Patients treated with ICIs had a similar risk of venous thromboembolism (VTE) but a significantly increased risk of arterial thromboembolism (ATE) (Peto OR: 1.58 [95% CI: 1.21-2.06]) compared with non-ICI regimens. Stratified by different regimens, only PD-L1 (programmed cell death ligand 1) inhibitors showed a significant increase in ATE (Peto OR: 2.07 [95% CI: 1.26-3.38]). The incidence of VTE was higher in PD-1/PD-L1 inhibitor and CTLA-4 (cytotoxic T lymphocyte antigen 4) inhibitor combination therapies compared with monotherapies (Peto OR: 2.23 [95% CI: 1.47-3.37]). Stratified by tumor, for pulmonary embolism (PE) and cerebral ATE, the statistically significant results were only seen in lung cancer patients (Peto OR: 1.42 [95% CI: 1.02-1.97]; Peto OR: 2.10 [1.07-4.12]), and for myocardial infarction, the statistically significant result was only seen in other tumor types (Peto OR: 2.66 [95% CI: 1.68-4.20], p < 0.0001). CONCLUSION: There was no significant increase in the overall risk of VTE in patients treated with ICIs; however, special attention should be given to the risk of VTE in PD-1/PD-L1 inhibitor and CTLA-4 inhibitor combination therapy and PE in lung cancer patients. PD-L1 inhibitors were associated with a significant increase in ATE.

Integrative Analysis of Pharmacokinetic and Metabolomic Profiles for Predicting Metabolic Phenotype and Drug Exposure Caused by Sotorasib in Rats.

Sotorasib is a novel targeted inhibitor of Kirsten rat sarcoma (KRAS) (G12C) that has shown exciting tumor-suppressing effects not only for single targeted agents but also for combination with immune checkpoint inhibitors. However, no integrative analysis of the pharmacokinetics (PK) and pharmacometabolomics (PM) of sotorasib has been reported to date. In the present study, a sensitive and robust high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was firstly developed and fully validated for the quantitation of sotorasib in rat plasma. After one-step protein precipitation, sotorasib and an internal standard (carbamazepine) were separated on a Waters XBrige C18 column (50 mm × 2.1 mm, 3.5 µm) and analyzed in electrospray ionization positive ion (ESI+) mode. The optimized method was fully validated according to guidance and was successfully applied for the PK study of sotorasib at a dose of 10 mg/kg. In addition, a longitudinal and transversal PM was employed and correlated with PK using partial least squares model and Pearson's analysis. With multivariate statistical analysis, the selected six (AUC model) and nine (C max model) metabolites completely distinguished the high- and low-exposure groups after sotorasib treatment, which indicates that these potential biomarkers can predict drug exposure or toxicity. The results of this study will not only shed light on how sotorasib disturbs the metabolic profiles and the relationship between PK and PM but also offer meaningful references for precision therapy in patients with the KRAS (G12C) mutation.

Serum Eicosanoids Metabolomics Profile in a Mouse Model of Renal Cell Carcinoma: Predicting the Antitumor Efficacy of Anlotinib.

Anlotinib (ANL) shows promising efficacy in patients with renal cell cancer (RCC). Here, for the first time, a serum eicosanoid metabolomics profile and pharmacodynamics in Renca syngeneic mice treated with ANL was performed and integrated using our previous HPLC-MS/MS method and multivariate statistical analysis. The tumor growth inhibition rates of ANL were 39% and 52% at low (3 mg/kg) and high (6 mg/kg) dose levels, without obvious toxicity. A total of 15 disturbed metabolites were observed between the normal group and the model group, and the intrinsic metabolic phenotype alterations had occurred due to the treatment of ANL. A total of eight potential metabolites from the refined partial least squares (PLS) model were considered as potential predictive biomarkers for the efficacy of ANL, and the DHA held the most outstanding sensitivity and specificity with an area under the receiver operating characteristic curve of 0.88. Collectively, the results of this exploratory study not only provide a powerful reference for understanding eicosanoid metabolic reprogramming of ANL but also offer an innovative perspective for the development of therapeutic targets and strategies, the discovery of predictive biomarkers, and the determination of effective tumor monitoring approaches.

Interstitial lung disease in patients treated with Cyclin-Dependent Kinase 4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Cyclin-Dependent Kinase (CDK) 4/6 inhibitors have shown significant clinical activity in cancer patients. However, some concerns regarding rare adverse events (AEs) have occurred including interstitial lung disease (ILD)/pneumonitis, for which data are deficient. The aim of this study was to evaluate the overall incidence and risk of ILD/pneumonitis related to CDK4/6 inhibitors in randomized controlled trials (RCTs). METHODS: Electronic databases and ClinicalTrials.gov were searched from inception to October 1, 2021 for RCTs reporting the occurrence of LD/pneumonitis in cancer patients treated with CDK4/6 inhibitors. Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs) were used to pool the study. RESULTS: 12 RCTs with a total of 16,060 patients were eligible. The overall incidence of all-grade ILD/pneumonitis was 1.6% (131/8407) in the treatment group compared with 0.7% (50/7349) in the control group. CDK4/6 inhibitors significantly increased the risk of all-grade ILD/pneumonitis with a pooled Peto OR of 2.12 (95% CI [1.57, 2.86], P < 0.00001) with no heterogeneity (I2 = 0%, χ2 P = 0.98). A higher incidence of grade 3 or higher ILD/pneumonitis was also observed in the treatment group (0.2%, 16/7087) compared with the control group (0.05%, 3/6617) with a Peto OR of 3.22 (95% CI [1.28, 8.09], P = 0.01) with no heterogeneity (I2 = 0%, χ2 P = 0.62). Two grade 5 pneumonitis were reported in the included studies. Subgroup analyses did not show any significant difference. CONCLUSIONS: The risk of all-grade and grade 3 or higher ILD/pneumonitis was higher in patients treated with CDK4/6 inhibitors compared to controls. The awareness for these rare AEs in the application of CDK4/6 inhibitors should be enhanced. Further studies are required to validate the mechanisms and the risk factors of ILD/pneumonitis with CDK4/6 inhibitors.

Development and validation of a robust and sensitive HPLC-MS/MS method for the quantitation of MRTX849 in plasma and its application in pharmacokinetics.

MRTX849 is a novel, highly selective, targeted inhibitor of KRAS (G12C), which significantly improves the objective response rate in patients with advanced solid tumors. However, neither an analytical HPLC-MS/MS assay nor pharmacokinetics has been reported for MRTX849 in plasma. In the present study, chromatography was accomplished on a reversed phase C18 column (50 × 2.1 mm, 3.5 µm). The limit of detection of MRTX849 was 0.02 ng mL-1 at S/N ≥ 3. Only 20 µL of plasma was utilized for accurate quantitation. The optimized analytical assay was fully validated and verified in accordance with guidelines. The calibration curve for MRTX849 was linear with a correlation coefficient >0.99 in the range of 0.05-200 ng mL-1. The intra- and inter-day accuracy and precision were all within ±10%. The matrix effect and recovery were consistent and acceptable under several quality control concentrations. This HPLC-MS/MS method was successfully applied for a pharmacokinetic study of MRTX849 at a dose of 15 mg kg-1.

Clinical practice guidelines for management of dual antiplatelet therapy in patients with noncardiac surgery: A critical appraisal using the AGREE II instrument.

WHAT IS KNOWN AND OBJECTIVE: Despite the availability of clinical practice guidelines (CPGs), there are considerable differences in their recommendations in the perioperative management of stented patients who need elective noncardiac surgery. Our aim was to systematically review the quality of CPGs for perioperative management of dual antiplatelet therapy (DAPT) and summarize the recommendations. METHODS: A systematic search for perioperative DAPT guidelines was conducted on PubMed, Embase and websites of guideline organizations and professional societies until 4 February 2021. Independently, two assessors appraised the quality of CPGs using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument and extracted the data. Recommendations were summarized, and a comparative study was conducted to analyse the consistency among guidelines. RESULTS AND DISCUSSION: A total of 10 guidelines fulfilled our inclusion criteria. The domain of scope and purpose and clarity of presentation obtained the highest median scores, while the domain of stakeholder involvement and rigour of development obtained the lowest median scores. Three guidelines (ACCP, ESC/ESA and ACC/AHA) with a score of at least 60% in most AGREE II domains were recommended. Recommendations across perioperative management of DAPT guidelines were inconsistent. WHAT IS NEW AND CONCLUSION: The ACCP, ESC/ESA and ACC/AHA CPGs were recommended. There is a need for high-quality prospective studies assessing different management strategies on this issue. Given the lack of consensus, the results of this study will help to guide perioperative dual antiplatelet management strategies for patients with coronary stents who are undergoing noncardiac surgery.

The impact of pharmacist intervention on prophylactic antibiotics use in orthopedic surgery at a hospital in China.

ABSTRACT: This study aimed to assess the impact of the pharmacist-led intervention on perioperative antibiotic prophylaxis by standardizing the cephalosporin intradermal skin test in the orthopedic department.A pre-and postintervention study was conducted among patients in the Orthopedics Department at the Beijing Chao-Yang Hospital in China. Use of intradermal skin test, perioperative antibacterial prophylaxis, and cost of care were compared between the preintervention population (admitted from 6/1/2018 to 8/31/2018) and postintervention population (admitted from 1/1/2019 to 3/31/2019). Logistic regression and generalized linear regression were used to assess the intervention impact.425 patients from the preintervention period and 448 patients from the postintervention period were included in the study. After the implementation of the pharmacist intervention program, there was a decrease in the utilization of intradermal skin tests, from 95.8% to 16.5% (P < .001). Patients were more likely to have cephalosporin as prophylactic antimicrobials (OR = 5.28, P < .001) after the implementation. The cost of antimicrobials was significantly reduced by $150.21 (P < .001) for each patient.Pharmacist-involved intervention can reduce the utilization of cephalosporins skin tests and decrease the prescription of unnecessary high-cost antimicrobials.