Accurately predicting the risk of unfavorable outcomes after endovascular coil therapy in patients with aneurysmal subarachnoid hemorrhage: an interpretable machine learning model.

BACKGROUND: Despite endovascular coiling as a valid modality in treatment of aneurysmal subarachnoid hemorrhage (aSAH), there is a risk of poor prognosis. However, the clinical utility of previously proposed early prediction tools remains limited. We aimed to develop a clinically generalizable machine learning (ML) models for accurately predicting unfavorable outcomes in aSAH patients after endovascular coiling. METHODS: Functional outcomes at 6 months after endovascular coiling were assessed via the modified Rankin Scale (mRS) and unfavorable outcomes were defined as mRS 3-6. Five ML algorithms (logistic regression, random forest, support vector machine, deep neural network, and extreme gradient boosting) were used for model development. The area under precision-recall curve (AUPRC) and receiver operating characteristic curve (AUROC) was used as main indices of model evaluation. SHapley Additive exPlanations (SHAP) method was applied to interpret the best-performing ML model. RESULTS: A total of 371 patients were eventually included into this study, and 85.4% of them had favorable outcomes. Among the five models, the DNN model had a better performance with AUPRC of 0.645 (AUROC of 0.905). Postoperative GCS score, size of aneurysm, and age were the top three powerful predictors. The further analysis of five random cases presented the good interpretability of the DNN model. CONCLUSION: Interpretable clinical prediction models based on different ML algorithms have been successfully constructed and validated, which would serve as reliable tools in optimizing the treatment decision-making of aSAH. Our DNN model had better performance to predict the unfavorable outcomes at 6 months in aSAH patients compared with Yan's nomogram model.

Incorporating preoperative frailty to assist in early prediction of postoperative pneumonia in elderly patients with hip fractures: an externally validated online interpretable machine learning model.

BACKGROUND: This study aims to implement a validated prediction model and application medium for postoperative pneumonia (POP) in elderly patients with hip fractures in order to facilitate individualized intervention by clinicians. METHODS: Employing clinical data from elderly patients with hip fractures, we derived and externally validated machine learning models for predicting POP. Model derivation utilized a registry from Nanjing First Hospital, and external validation was performed using data from patients at the Fourth Affiliated Hospital of Nanjing Medical University. The derivation cohort was divided into the training set and the testing set. The least absolute shrinkage and selection operator (LASSO) and multivariable logistic regression were used for feature screening. We compared the performance of models to select the optimized model and introduced SHapley Additive exPlanations (SHAP) to interpret the model. RESULTS: The derivation and validation cohorts comprised 498 and 124 patients, with 14.3% and 10.5% POP rates, respectively. Among these models, Categorical boosting (Catboost) demonstrated superior discrimination ability. AUROC was 0.895 (95%CI: 0.841-0.949) and 0.835 (95%CI: 0.740-0.930) on the training and testing sets, respectively. At external validation, the AUROC amounted to 0.894 (95% CI: 0.821-0.966). The SHAP method showed that CRP, the modified five-item frailty index (mFI-5), and ASA body status were among the top three important predicators of POP. CONCLUSION: Our model's good early prediction ability, combined with the implementation of a network risk calculator based on the Catboost model, was anticipated to effectively distinguish high-risk POP groups, facilitating timely intervention.

In vitro co-culture systems of hepatic and intestinal cells for cellular pharmacokinetic and pharmacodynamic studies of capecitabine against colorectal cancer.

BACKGROUND: As a prodrug of 5-fluorouracil (5-FU), orally administrated capecitabine (CAP) undergoes preliminary conversion into active metabolites in the liver and then releases 5-FU in the gut to exert the anti-tumor activity. Since metabolic changes of CAP play a key role in its activation, a single kind of intestinal or hepatic cell can never be used in vitro to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) nature. Hence, we aimed to establish a novel in vitro system to effectively assess the PK and PD of these kinds of prodrugs. METHODS: Co-culture cellular models were established by simultaneously using colorectal cancer (CRC) and hepatocarcinoma cell lines in one system. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis were used to evaluate cell viability and apoptosis, respectively. Apoptosis-related protein expression levels were measured using western blot analysis. A selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for cellular PK in co-culture models. RESULTS: CAP had little anti-proliferative effect on the five monolayer CRC cell lines (SW480, LoVo, HCT-8, HCT-116 and SW620) or the hepatocarcinoma cell line (HepG2). However, CAP exerted marked anti-tumor activities on each of the CRC cell lines in the co-culture models containing both CRC and hepatocarcinoma cell lines, although its effect on the five CRC cell lines varied. Moreover, after pre-incubation of CAP with HepG2 cells, the culture media containing the active metabolites of CAP also showed an anti-tumor effect on the five CRC cell lines, indicating the crucial role of hepatic cells in the activation of CAP. CONCLUSION: The simple and cost­effective co-culture models with both CRC and hepatocarcinoma cells could mimic the in vivo process of a prodrug dependent on metabolic conversion to active metabolites in the liver, providing a valuable strategy for evaluating the PK and PD characteristics of CAP-like prodrugs in vitro at the early stage of drug development.

A visualized MAC nomogram online predicts the risk of three-month mortality in Chinese elderly aneurysmal subarachnoid hemorrhage patients undergoing endovascular coiling.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is an aggressive disease with higher mortality rate in the elderly population. Unfortunately, the previous models for predicting clinical prognosis are still not accurate enough. Therefore, we aimed to construct and validate a visualized nomogram model to predict online the 3-month mortality in elderly aSAH patients undergoing endovascular coiling. METHOD: We conducted a retrospective analysis of 209 elderly aSAH patients at People's Hospital of Hunan Province, China. A nomogram was developed based on multivariate logistic regression and forward stepwise regression analysis, then validated using the bootstrap validation method (n = 1000). In addition, the performance of the nomogram was evaluated by various indicators to prove its clinical value. RESULT: Morbid pupillary reflex, age, and using a breathing machine were independent predictors of 3-month mortality. The AUC of the nomogram was 0.901 (95% CI: 0.853-0.950), and the Hosmer-Lemeshow goodness-of-fit test showed good calibration of the nomogram (p = 0.4328). Besides, the bootstrap validation method internally validated the nomogram with an area under the curve of the receiver operator characteristic (AUROC) of 0.896 (95% CI: 0.846-0.945). Decision curve analysis (DCA) and clinical impact curve (CIC) indicated the nomogram's excellent clinical utility and applicability. CONCLUSION: An easily applied visualized nomogram model named MAC (morbid pupillary reflex-age-breathing machine) based on three accessible factors has been successfully developed. The MAC nomogram is an accurate and complementary tool to support individualized decision-making and emphasizes that patients with higher risk of mortality may require closer monitoring. Furthermore, a web-based online version of the risk calculator would greatly contribute to the spread of the model in this field.

A risk prediction model based on machine learning for postoperative cognitive dysfunction in elderly patients with non-cardiac surgery.

BACKGROUND: Early identification of elderly patients undergoing non-cardiac surgery who may be at high risk for postoperative cognitive dysfunction (POCD) can increase the chances of prevention for them, as extra attention and limited resources can be allocated more to these patients. AIM: We performed this analysis with the aim of developing a simple, clinically useful machine learning (ML) model to predict the probability of POCD at 3 months in elderly patients after non-cardiac surgery. METHODS: We collected information on patients who received surgical treatment at Nanjing First Hospital from May 2020 to May 2021. We used LASSO regression to select key features and built 5 ML models to assess the risk of POCD at 3 months in elderly patients after non-cardiac surgery. The Shapley Additive exPlanations (SHAP) and methods were introduced to interpret the best model. RESULTS: A total of 415 patients with non-cardiac surgery were included. The support vector machine (SVM) was the best-performing model of the five ML models. The model showed excellent performance compared to the other four models. The SHAP results showed that VAS score, age, intraoperative hypotension, and preoperative hemoglobin were the four most important features, indicating that the SVM model had good interpretability and reliability. The website of the web-based calculator was https://modricreagan-non-3-pocd-9w2q78.streamlit.app/ . CONCLUSION: Based on six important perioperative variables, we successfully established a series of ML models for predicting POCD occurrence at 3 months after surgery in elderly non-cardiac patients, with SVM model being the best-performing model. Our models are expected to serve as decision aids for clinicians to monitor screened high-risk patients more closely or to consider further interventions.

Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial.

BACKGROUND: Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients. METHODS: We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes. RESULTS: CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival. CONCLUSION: This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.

On-treatment blood TMB as predictors for camrelizumab plus chemotherapy in advanced lung squamous cell carcinoma: biomarker analysis of a phase III trial.

BACKGROUND: Camrelizumab plus chemotherapy significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone as first-line treatment in advanced lung squamous cell carcinoma (LUSC) in the phase III trial (CameL-sq), which has become an option of standard-of-cares for Chinese patients with advanced LUSC. However, the predictive biomarkers remain unknown. METHODS: Tumor tissue samples at baseline, and peripheral blood samples at baseline (pretreatment) and after two cycles of treatment (on-treatment) were prospectively collected from 270 LUSC patients from the CameL-sq study. Blood tumor mutation burden (bTMB) and its dynamics were analyzed to explore their predictive values. RESULTS: Pretreatment bTMB was not associated with objective response, PFS and OS in camrelizumab or placebo plus chemotherapy groups. Low on-treatment bTMB was associated with significantly better objective response (73.8% vs 27.8%, P < 0.001), PFS (median, 9.1 vs 4.1 months; P < 0.001) and OS (median, not reached vs 8.0 months; P < 0.001) in camrelizumab plus chemotherapy group whereas it did not correlate with objective response and PFS in chemotherapy alone group. Importantly, on-treatment bTMB level could discriminate patients of initially radiological stable disease who would long-term benefit from camrelizumab plus chemotherapy (low vs high, median OS, 18.2 vs 7.8 months; P = 0.001). Combing on-treatment bTMB and its dynamics improved the ability for predicting the efficacy of camrelizumab plus chemotherapy. CONCLUSION: On-treatment bTMB together with its dynamics could serve as a predictive biomarker for camrelizumab plus chemotherapy in patients with advanced LUSC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03668496.

Identification of Biomarkers Associated with Hepatocellular Carcinoma Stem Cell Characteristics Based on Co-Expression Network Analysis of Transcriptome Data and Stemness Index.

Mounting evidence has revealed the key role of cancer stem cells in hepatocellular carcinoma (HCC) metastasis and therapy resistance, yet the genes maintaining HCC stem cell features remain to be explored. This study aimed to identify and validate the key biomarkers associated with HCC stemness. mRNA expression-based stemness index (mRNAsi) was calculating using one-class logistic regression algorithm. RNA-sequencing data and clinical information of HCC samples were downloaded from the cancer genome atlas (TCGA) and merged with the corresponding mRNAsi. We investigated the correlation between mRNAsi and HCC clinical characteristics, including tumor grades, pathologic stages, vascular invasion, and survival outcomes. Significant genes associated HCC stemness features were screened through weighted gene co-expression network analysis (WGCNA) and were functionally annotated using enrichment analysis. Protein-protein interaction network was constructed among significant genes and the key biomarkers were finally identified based on the maximal clique centrality (MCC) method. The expression of key biomarkers and its correlation with HCC clinical outcomes were validated using oncomine and gene expression omnibus (GEO) database. mR-NAsi was significantly higher in HCC tissues and gradually increased according to tumor grades and pathologic stages. Patients with vascular invasion or poor survival exhibited higher mRNAsi. Forty-four highly-correlated significant gens were screened through WGCNA and functionally related to cell cycle, cellular senescence, p53 signaling pathway, DNA replication, and mismatch repair. Four different GEO datasets confirmed that the expression levels of these 44 genes were notably higher in HCC tissues. We finally identified 15 key biomarkers (KIF4A, TTK, CCNB1, CDC20, NCAPG, CCNB2, CDC45, UBE2C, CENPA, AURKB, RRM2, CDCA8, BIRC5, TPX2, and KIF2C) through MCC method. The expression of these biomarkers was up-regulated in multiple types of cancers and showed a gradually increasing trend with HCC tumor grades. Furthermore, high expression levels of these biomarkers were also correlated with HCC metastasis, recurrence, sorafenib resistance, and poor overall survival. We identified 15 key biomarkers associated with HCC stemness features and these genes might serve as promising therapeutic targets for HCC.

Camrelizumab in different PD-L1 expression cohorts of pre-treated advanced or metastatic non-small cell lung cancer: a phase II study.

BACKGROUND: This phase II study evaluated camrelizumab in different PD-L1 expression cohorts of patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC; NCT03085069, registered March 21, 2017). METHODS: Patients who progressed during/after chemotherapy were enrolled and divided into four cohorts based on PD-L1 tumor proportion score (TPS). Patients with EGFR/ALK alterations and PD-L1 TPS ≥ 50% were also eligible. All enrolled patients received camrelizumab at 200 mg IV Q2W. The primary endpoint was objective response rate. RESULTS: A total of 146 patients were enrolled. As of data cutoff on Aug 20, 2020, the median follow-up was 29.5 months (95% CI 27.4-30.8). Objective response rate was 17.8% (95% CI 12.0-25.0) and improved with the increasing PD-L1 TPS (TPS < 1%, 12.2% [95% CI 5.7-21.8]; ≥ 1-< 25%, 19.4% [95% CI 7.5-37.5]; ≥ 25-< 50%, 36.4% [95% CI 10.9-69.2]; ≥ 50%, 23.3% [95% CI 9.9-42.3]). No response was observed in the five patients harboring EGFR mutations. Median progression-free survival was 3.2 months (95% CI 2.0-3.4), and patients with positive PD-L1 TPS had longer progression-free survival. Median overall survival was 14.8 months (95% CI 10.2-18.7). Treatment-related adverse events (TRAEs) of any grade occurred in 87.7% of patients, and 21.2% had grade ≥ 3 TRAEs. CONCLUSION: Camrelizumab showed improved efficacy compared with historical data of the second-line chemotherapy in pre-treated advanced/metastatic NSCLC. Patients with positive PD-L1 expression derived greater benefit from camrelizumab. Camrelizumab has a manageable safety profile.

Activity and safety of SHR3680, a novel antiandrogen, in patients with metastatic castration-resistant prostate cancer: a phase I/II trial.

BACKGROUND: Antagonizing the androgen-receptor (AR) pathway is an effective treatment strategy for patients with metastatic castration-resistant prostate cancer (CRPC). Here, we report the results of a first-in-human phase 1/2 study which assessed the safety, pharmacokinetics, and activity of SHR3680 (a novel AR antagonist) in patients with metastatic CRPC. METHODS: This phase 1/2 study enrolled patients with progressive metastatic CRPC who had not been previously treated with novel AR-targeted agents. In the phase 1 dose-escalation portion, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg per day. In phase 2 dose-expansion portion, patients were randomized to receive daily dose of 80 mg, 160 mg, or 240 mg of SHR3680. The primary endpoint in phase 1 was safety and tolerability and in phase 2 was the proportion of patients with a prostate-specific antigen (PSA) response (≥ 50% decrease of PSA level) at week 12. RESULTS: A total of 197 eligible patients were enrolled and received SHR3680 treatment, including 18 patients in phase 1 and 179 patients in phase 2. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 116 (58.9%) patients, with the most common one being proteinuria (13.7%). TRAEs of grade ≥ 3 occurred in only 23 (11.7%) patients, and no treatment-related deaths occurred. Antitumor activities were evident at all doses, including PSA response at week 12 in 134 (68.0%; 95% CI, 61.0-74.5) patients, stabilized bone disease at week 12 in 174 (88.3%; 95% CI, 87.2-95.5) patients, and responses in soft tissue lesions in 21 (34.4%, 95% CI, 22.7-47.7) of 61 patients. CONCLUSION: SHR3680 was well tolerated and safe, with promising anti-tumor activity across all doses tested in patients with metastatic CRPC. The dose of 240 mg daily was recommended for further phase 3 study. TRIAL REGISTRATION: Clinical trials.gov NCT02691975; registered February 25, 2016.

PCSK9 inhibitor recaticimab for hypercholesterolemia on stable statin dose: a randomized, double-blind, placebo-controlled phase 1b/2 study.

BACKGROUND: Recaticimab (SHR-1209, a humanized monoclonal antibody against PCSK9) showed robust LDL-C reduction in healthy volunteers. This study aimed to further assess the efficacy and safety of recaticimab in patients with hypercholesterolemia. METHODS: In this randomized, double-blind, placebo-controlled phase 1b/2 trial, patients receiving stable dose of atorvastatin with an LDL-C level of 2.6 mmol/L or higher were randomized in a ratio of 5:1 to subcutaneous injections of recaticimab or placebo at different doses and schedules. Patients were recruited in the order of 75 mg every 4 weeks (75Q4W), 150Q8W, 300Q12W, 150Q4W, 300Q8W, and 450Q12W. The primary endpoint was percentage change in LDL-C from the baseline to end of treatment (i.e., at week 16 for Q4W and Q8W schedule and at week 24 for Q12W schedule). RESULTS: A total of 91 patients were enrolled and received recaticimab and 19 received placebo. The dose of background atorvastatin in all 110 patients was 10 or 20 mg/day. The main baseline LDL-C ranged from 3.360 to 3.759 mmol/L. The least-squares mean percentage reductions in LDL-C from baseline to end of treatment relative to placebo for recaticimab groups at different doses and schedules ranged from -48.37 to -59.51%. No serious treatment-emergent adverse events (TEAEs) occurred. The most common TEAEs included upper respiratory tract infection, increased alanine aminotransferase, increased blood glucose, and increased gamma-glutamyltransferase. CONCLUSION: Recaticimab as add-on to moderate-intensity statin therapy significantly and substantially reduced the LDL-C level with an infrequent administration schedule (even given once every 12 weeks), compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov , number NCT03944109.

Neoadjuvant pyrotinib, trastuzumab, and docetaxel for HER2-positive breast cancer (PHEDRA): a double-blind, randomized phase 3 trial.

BACKGROUND: Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine has survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer. We further assessed addition of pyrotinib to trastuzumab and docetaxel in the neoadjuvant setting. METHODS: In this multicenter, double-blind, phase 3 study (PHEDRA), treatment-naive women with HER2-positive early or locally advanced breast cancer were randomly assigned (1:1) to receive four neoadjuvant cycles of oral pyrotinib or placebo (400 mg) once daily, plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and docetaxel (100 mg/m2) every 3 weeks. The primary endpoint was the total pathological complete response (tpCR; ypT0/is and ypN0) rate per independent central review. RESULTS: Between Jul 23, 2018, and Jan 8, 2021, 355 patients were randomly assigned, 178 to the pyrotinib group and 177 to the placebo group. The majority of patients completed four cycles of neoadjuvant treatment as planned (92.7% and 97.7% in the pyrotinib and placebo groups, respectively). The tpCR rate was 41.0% (95% CI 34.0 to 48.4) in the pyrotinib group compared with 22.0% (95% CI 16.6 to 28.7) in the placebo group (difference, 19.0% [95% CI 9.5 to 28.4]; one-sided P < 0.0001). The objective response rate per investigator was 91.6% (95% CI 86.6 to 94.8) in the pyrotinib group and 81.9% (95% CI 75.6 to 86.9) in the placebo group after the neoadjuvant treatment, resulting in an increase of 9.7% (95% CI 2.7 to 16.6). The most common grade 3 or worse adverse events were diarrhea (79 [44.4%] in the pyrotinib group and nine [5.1%] in the placebo group), neutropenia (33 [18.5%] and 36 [20.3%]), and decreased white blood cell count (29 [16.3%] and 24 [13.6%]). No deaths were reported during neoadjuvant treatment. CONCLUSIONS: The primary endpoint of the study was met. Neoadjuvant pyrotinib, trastuzumab, and docetaxel significantly improved the tpCR rate compared with placebo, trastuzumab, and docetaxel, with manageable toxicity, providing a new option for HER2-positive early or locally advanced breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03588091.

Influence of tirofiban on stroke outcome after mechanical thrombectomy in acute vertebrobasilar artery occlusion.

BACKGROUND: Even undergoing mechanical thrombectomy (MT), patients with acute vertebrobasilar artery occlusion (AVBAO) still have a high rate of mortality. Tirofiban is a novel antiplatelet agent which is now widely empirically used in acute ischemic stroke (AIS). In this study, we aimed to evaluate the safety and efficacy of tirofiban as adjunctive therapy for MT in AVBAO. METHODS: From October 2016 to July 2021, consecutive AVBAO patients receiving MT were included in the prospective stroke registry. The short-term outcomes were (1) symptomatic intracerebral hemorrhage (sICH); (2) in-hospital death; (3) National Institute of Health Stroke Scale (NIHSS) at discharge. The Long-term outcomes were: (1) modified Rankin Scale (mRS) at 3 months; (2) death at 3 months. RESULTS: A total of 130 eligible patients were included in the study, 64 (49.2%) patients received tirofiban. In multivariate regression analysis, no significant differences were observed in all outcomes between the tirofiban and non-tirofiban group [sICH (adjusted OR 0.96; 95% CI, 0.12-7.82, p = 0.97), in-hospital death (adjusted OR 0.57; 95% CI, 0.17-1.89, p = 0.36), NIHSS at discharge (95% CI, -2.14-8.63, p = 0.24), mRS (adjusted OR 1.20; 95% CI, 0.40-3.62, p = 0.75), and death at 3 months (adjusted OR 0.83; 95% CI, 0.24-2.90, p = 0.77)]. CONCLUSIONS: In AVBAO, tirofiban adjunctive to MT was not associated with an increased risk of sICH. Short-term (in-hospital death, NIHSS at discharge) and long-term outcomes (mRS and death at 3 months) seem not to be influenced by tirofiban use.

Interpretable machine learning model to predict rupture of small intracranial aneurysms and facilitate clinical decision.

Estimating whether to treat the rupture risk of small intracranial aneurysms (IAs) with size ≤ 7 mm in diameter is difficult but crucial. We aimed to construct and externally validate a convenient machine learning (ML) model for assessing the rupture risk of small IAs. One thousand four patients with small IAs recruited from two hospitals were included in our retrospective research. The patients at hospital 1 were stratified into training (70%) and internal validation set (30%) randomly, and the patients at hospital 2 were used for external validation. We selected predictive features using the least absolute shrinkage and selection operator (LASSO) method and constructed five ML models applying diverse algorithms including random forest classifier (RFC), categorical boosting (CatBoost), support vector machine (SVM) with linear kernel, light gradient boosting machine (LightGBM), and extreme gradient boosting (XGBoost). The Shapley Additive Explanations (SHAP) analysis provided interpretation for the best ML model. The training, internal, and external validation cohorts included 658, 282, and 64 IAs, respectively. The best performance was presented by SVM as AUC of 0.817 in the internal [95% confidence interval (CI), 0.769-0.866] and 0.893 in the external (95% CI, 0.808-0.979) validation cohorts, which overperformed compared with the PHASES score significantly (all P < 0.001). SHAP analysis showed maximum size, location, and irregular shape were the top three important features to predict rupture. Our SVM model based on readily accessible features presented satisfying ability of discrimination in predicting the rupture IAs with small size. Morphological parameters made important contributions to prediction result.

Development and validation of a liquid chromatography-tandem mass spectrometry method for CPUL1, a novel antitumor candidate compound, and its application to pharmacokinetic studies.

An active substance of pyrano[3,2-a]phenazine, also called CPUL1, is a synthesized phenazine derivative and displays broad-spectrum anticancer activities. Quantitative assessment of CPUL1 in biological samples has not been well established, hindering pharmaceutical development and application. According to international guidelines, a sensitive and selective liquid chromatography-tandem mass spectrometry method in negative ion mode was developed and validated for quantification of CPUL1 in human plasma, colorectal cancer cell lines, and rat plasma, whereby linearity and accuracy were demonstrated for the range of 1-1000 ng/ml. The validated liquid chromatography-tandem mass spectrometry method was successfully employed in pharmacokinetic studies of CPUL1 in vitro and in vivo. Notably, the cellular pharmacokinetic behavior of CPUL1 varies in colorectal cancer cell lines. Regarding the pharmacokinetic processes in vivo, oral absorption was less effective than an injection, with a bioavailability of 23.66%. CPUL1 was linearly eliminated after a single administration; however, it could accumulate in tissues (heart, liver, spleen, lung, and kidney) after multiple injections. In summary, this study established a capable bioanalytical method for CPUL1 and provided exploratory pharmacokinetic data, paving the way for use of this promising derivative in disease models.

Prognostic value of myosteatosis in patients with lung cancer: a systematic review and meta-analysis.

The prognostic value of myosteatosis has been widely investigated in lung cancer, yet conclusions remain controversial. The purpose of this meta-analysis was to illuminate this issue. Medline, Embase, Cochrane Library and Web of Science Core Collection online databases were systematically searched from inception to 24 September 2021. Newcastle-Ottawa Scale tool was applied to evaluate the quality of included studies. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were used to examine prognostic value of myosteatosis. Subgroup analysis and sensitivity analysis were conducted to assess heterogeneity and stability of results. A total of 484 articles were screened from which 9 eligible studies involving 1667 patients were enrolled in this meta-analysis. Lung cancer patients with myosteatosis had significantly worse OS than patients without myosteatosis (HR 1.10, 95% CI 1.05-1.16, P < 0.001), both in six multivariate analysis (HR 1.46, 95% CI 1.16-1.85, P = 0.001) and in three univariate analysis (HR 1.08, 95% CI 1.03-1.14, P = 0.003). Pooled data from five studies using multivariate survival analysis also showed that patients with myosteatosis had a statistically significant unfavorable PFS (HR = 1.27, 95% CI 1.00-1.62, P = 0.049). Sensitivity analysis showed the result for OS was stable. But for PFS, the result was not robust. Myosteatosis might serve as an independent indicator of unfavorable survival outcomes for OS and PFS in lung cancer patients. Further studies are needed to confirm our results.

Development and assessment of machine learning models for predicting recurrence risk after endovascular treatment in patients with intracranial aneurysms.

Intracranial aneurysms (IAs) remain a major public health concern and endovascular treatment (EVT) has become a major tool for managing IAs. However, the recurrence rate of IAs after EVT is relatively high, which may lead to the risk for aneurysm re-rupture and re-bleed. Thus, we aimed to develop and assess prediction models based on machine learning (ML) algorithms to predict recurrence risk among patients with IAs after EVT in 6 months. Patient population included patients with IAs after EVT between January 2016 and August 2019 in Hunan Provincial People's Hospital, and an adaptive synthetic (ADASYN) sampling approach was applied for the entire imbalanced dataset. We developed five ML models and assessed the models. In addition, we used SHapley Additive exPlanations (SHAP) and local interpretable model-agnostic explanation (LIME) algorithms to determine the importance of the selected features and interpret the ML models. A total of 425 IAs were enrolled into this study, and 66 (15.5%) of which recurred in 6 months. Among the five ML models, gradient boosting decision tree (GBDT) model performed best. The area under curve (AUC) of the GBDT model on the testing set was 0.842 (sensitivity: 81.2%; specificity: 70.4%). Our study firstly demonstrated that ML-based models can serve as a reliable tool for predicting recurrence risk in patients with IAs after EVT in 6 months, and the GBDT model showed the optimal prediction performance.

Cordycepin, a major bioactive component of Cordyceps militaris, ameliorates diabetes-induced testicular damage through the Sirt1/Foxo3a pathway.

Diabetes-induced male dysfunction is considered as a worldwide challenge, and testicular damage mainly caused by oxidative stress is its most common manifestation. Cordycepin, a natural antioxidant, has been used in the treatment of diabetic complications. However, the protective action and underlying mechanism of cordycepin on hyperglycaemia-induced testicular damage are unclear. This study aimed to investigate the protective effects and molecular mechanisms of cordycepin against diabetes-induced testicular damage. The type 2 diabetes model was established in C57BL/6 male mice via high-fat diet for 4 weeks and injected intraperitoneally with 50 mg/kg/day streptozotocin for five consecutive days. Then mice were treated with cordycepin (10 and 20 mg/kg, respectively) for 8 weeks. At the end of experiment, biochemical indicators, microstructure of testicular tissue, sperm morphology, TUNEL staining and protein expressions were evaluated. In the present study, cordycepin alleviated the testicular damage, restored disruption of the blood-testis barrier, and improved spermatogenic function via the antiapoptotic and antioxidant capacity. Mechanistically, cordycepin significantly enhanced SIRT1 expression and triggered the activity of Foxo3a, further to induce the expression of its downstream antioxidant enzymes, including Mn-SOD and CAT. These findings indicated that cordycepin could improve hyperglycaemia-induced testicular damage by regulating downstream antioxidant enzymes activity through the SIRT1/Foxo3a signalling pathway.

Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. METHODS: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. FINDINGS: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. INTERPRETATION: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. FUNDING: Jiangsu Hengrui Medicine and National Key R&D Program of China. TRANSLATIONS: For the Chinese translation of the abstract see Supplementary Materials section.

Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: The addition of camrelizumab to gemcitabine and cisplatin showed promising activity as first-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma in a phase 1 trial. We therefore compared camrelizumab plus gemcitabine and cisplatin with placebo plus gemcitabine and cisplatin in a randomised phase 3 trial. METHODS: In this randomised, double-blind, phase 3 trial done at 28 hospitals in China, patients were eligible if they were aged 18-75 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and had previously untreated recurrent or metastatic nasopharyngeal carcinoma. Patients were randomly assigned (1:1; using an interactive web-response system with a block size of four) to receive either camrelizumab (200 mg on day 1) or matching placebo intravenously, plus gemcitabine and cisplatin (gemcitabine 1000 mg/m2 on days 1 and 8; cisplatin 80 mg/m2 on day 1) intravenously every 3 weeks for four to six cycles, followed by maintenance therapy with camrelizumab or placebo, until radiographic progression, unacceptable toxicity, start of new anticancer treatment, investigator decision, or withdrawal of consent. Stratification factors used in randomisation were liver metastases, previous radical concurrent chemoradiotherapy, and ECOG performance status. The allocation sequence was generated by an independent randomisation group. The primary endpoint was progression-free survival per independent review committee. The significance threshold for independent review committee-assessed progression-free survival was p=0·0086 (one-sided) at the interim analysis. Efficacy and safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03707509, and is closed for enrolment but is ongoing. FINDINGS: Between Nov 13, 2018, and Nov 29, 2019, 343 patients were screened and 263 were eligible and were randomly assigned to the camrelizumab group (n=134) or placebo group (n=129). At the prespecified interim analysis (June 15, 2020), independent review committee-assessed progression-free survival was significantly longer in the camrelizumab group (median 9·7 months [95% CI 8·3-11·4]) than in the placebo group (median 6·9 months [5·9-7·3]; hazard ratio 0·54 [95% CI 0·39-0·76]; one-sided p=0·0002). As of Dec 31, 2020, the most common grade 3 or worse adverse events of any cause were decreased white blood cell count (89 [66%] of 134 patients in the camrelizumab group vs 90 [70%] of 129 patients in the placebo group), decreased neutrophil count (86 [64%] vs 85 [66%]), anaemia (53 [40%] vs 57 [44%]), and decreased platelet count (53 [40%] vs 52 [40%]). Serious adverse events were reported in 59 (44%) of 134 patients in the camrelizumab group and 48 (37%) of 129 patients in the placebo group. Treatment-related deaths occurred in five (4%) patients in the camrelizumab group (two unknown cause of death, one multiple organ dysfunction syndrome, one pharyngeal haemorrhage, and one arrhythmia) and one (<1%) patient in the placebo group (unknown cause of death). INTERPRETATION: Our findings suggest that camrelizumab plus gemcitabine and cisplatin could be a new standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma in the first-line setting. Longer follow-up is needed to confirm this conclusion. FUNDING: Jiangsu Hengrui Pharmaceuticals (formerly Jiangsu Hengrui Medicine). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.