Cost-effectiveness of neoadjuvant pembrolizumab plus chemotherapy with adjuvant pembrolizumab for early-stage non-small cell lung cancer in the United States.

Introduction: Perioperative (neoadjuvant and adjuvant) pembrolizumab has shown favorable efficacy in patients with early-stage non-small cell lung cancer (NSCLC). This study aims to evaluate the cost-effectiveness of this treatment from the perspective of the United States healthcare payers. Methods: We established a Markov model to compare the cost-effectiveness of perioperative pembrolizumab with that of neoadjuvant chemotherapy in 21-day cycles, utilizing data from the phase 3 KEYNOTE-671 trial. Additional data were extracted from other publications or online sources. Sensitivity analyses were conducted to evaluate the robustness of the findings. A willingness-to-pay threshold of $150,000 per quality-adjusted life-years (QALYs) gained was established. The main outcomes of this study were the measurement of QALYs, overall costs, incremental cost-effectiveness ratio (ICER), and net monetary benefit (NMB). Results: During a 10-year time horizon, the total costs of perioperative pembrolizumab and the control treatment were $224,779.1 and $110,026.3, respectively. The QALYs were 4.19 and 2.97 for the two treatments, respectively, which led to an ICER of $94,222.29 per QALY gained. The NMB at the WTP threshold at $150,000 per QALY gained was $67,931.3. One-way sensitivity analysis identified the cost of pembrolizumab as the primary factor influencing cost-effectiveness. Probabilistic sensitivity analysis indicated a 97.7% probability of perioperative pembrolizumab being cost-effective at the WTP threshold. Conclusions: From the perspective of the United States healthcare payers, perioperative pembrolizumab is a cost-effective treatment for patients with early-stage NSCLC.

Development of a nomogram model for the early prediction of sepsis-associated acute kidney injury in critically ill patients.

Sepsis-associated acute kidney injury is a common complication of sepsis, but it is difficult to predict sepsis-associated acute kidney injury. In this retrospective observational study, adult septic patients were recruited from the MIMIC-III database as the training cohort (n = 4764) and from Xiangya Hospital (n = 1568) and Zhang's database as validation cohorts. We identified eleven predictors with seven independent risk predictors of sepsis-associated acute kidney injury [fluid input_day1 ≥ 3390 ml (HR hazard ratio 1.42), fluid input_day2 ≥ 2734 ml (HR 1.64), platelet_min_day5 ≤ 224.2 × 109/l (HR 0.86), length of ICU stay ≥ 2.5 days (HR 1.24), length of hospital stay ≥ 5.8 days (HR 1.18), Bun_max_day1 ≥ 20 mmol/l (HR 1.20), and mechanical ventilation time ≥ 96 h (HR 1.11)] by multivariate Cox regression analysis, and the eleven predictors were entered into the nomogram. The nomogram model showed a discriminative ability for estimating sepsis-associated acute kidney injury. These results indicated that clinical parameters such as excess input fluid on the first and second days after admission and longer mechanical ventilation time could increase the risk of developing sepsis-associated acute kidney injury. With our study, we built a real-time prediction model for potentially forecasting acute kidney injury in septic patients that can help clinicians make decisions as early as possible to avoid sepsis-associated acute kidney injury.

MRI radiomics for brain metastasis sub-pathology classification from non-small cell lung cancer: a machine learning, multicenter study.

The objective of this study is to develop a machine-learning model that can accurately distinguish between different histologic types of brain lesions in patients with non-small cell lung cancer (NSCLC) when it is not safe or feasible to perform a biopsy. To achieve this goal, the study utilized data from two patient cohorts: 116 patients from Xiangya Hospital and 35 patients from Yueyang Central Hospital. A total of eight machine learning algorithms, including Xgboost, were compared. Additionally, a 3-dimensional convolutional neural network was trained using transfer learning to further evaluate the performance of these models. The SHapley Additive exPlanations (SHAP) method was developed to determine the most important features in the best-performing model after hyperparameter optimization. The results showed that the area under the curve (AUC) for the classification of brain lesions as either lung adenocarcinoma or squamous carcinoma ranged from 0.60 to 0.87. The model based on single radiomics features extracted from contrast-enhanced T1 MRI and utilizing the Xgboost algorithm demonstrated the highest performance (AUC: 0.85) in the internal validation set and adequate performance (AUC: 0.80) in the independent external validation set. The SHAP values also revealed the impact of individual features on the classification results. In conclusion, the use of a radiomics model incorporating contrast-enhanced T1 MRI, Xgboost, and SHAP algorithms shows promise in accurately and interpretably identifying brain lesions in patients with NSCLC.

A multiomics approach-based prediction of radiation pneumonia in lung cancer patients: impact on survival outcome.

PURPOSE: To predict the risk of radiation pneumonitis (RP), a multiomics model was built to stratify lung cancer patients. Our study also investigated the impact of RP on survival. METHODS: This study retrospectively collected 100 RP and 99 matched non-RP lung cancer patients treated with radiotherapy from two independent centres. They were divided into training (n = 175) and validation cohorts (n = 24). The radiomics, dosiomics and clinical features were extracted from planning CT and electronic medical records and were analysed by LASSO Cox regression. A multiomics prediction model was developed by the optimal algorithm. Overall survival (OS) between the RP, non-RP, mild RP, and severe RP groups was analysed by the Kaplan‒Meier method. RESULTS: Sixteen radiomics features, two dosiomics features, and one clinical feature were selected to build the best multiomics model. The optimal performance for predicting RP was the area under the receiver operating characteristic curve (AUC) of the testing set (0.94) and validation set (0.92). The RP patients were divided into mild (≤ 2 grade) and severe (> 2 grade) RP groups. The median OS was 31 months for the non-RP group compared with 49 months for the RP group (HR = 0.53, p = 0.0022). Among the RP subgroup, the median OS was 57 months for the mild RP group and 25 months for the severe RP group (HR = 3.72, p < 0.0001). CONCLUSIONS: The multiomics model contributed to improving the accuracy of RP prediction. Compared with the non-RP patients, the RP patients displayed longer OS, especially the mild RP patients.

The value of postoperative radiotherapy in thymoma patients with myasthenia gravis.

INTRODUCTION: Surgery is the first-line treatment for patients with thymoma associated with myasthenia gravis (MG); however, the value of radiotherapy among these patients remains debatable. Herein, we examined the impact of postoperative radiotherapy (PORT) on the efficacy and prognosis of patients with thymoma and MG. METHODS: This retrospective cohort study included 126 patients with thymoma and MG who were enrolled in the Xiangya Hospital clinical database between 2011 and 2021. Demographic and clinical data were collected including sex, age, histologic subtype, Masaoka-Koga staging, primary tumor, lymph node, metastasis (TNM) staging, and therapeutic modalities. To evaluate short-term MG symptom improvement following PORT, we examined changes in the quantitative myasthenia gravis (QMG) scores within 3 months post-treatment. Minimal manifestation status (MMS) was the main endpoint for assessing long-term improvement in MG symptoms. Overall survival (OS) and disease-free survival (DFS) were primary endpoints to determine the impact of PORT on prognosis. RESULTS: Effects of PORT on MG symptoms: QMG scores significantly differed between the non-PORT and PORT groups (χ2 = 6.300, p = 0.012). The median time to achieve MMS was significantly shorter in the PORT group than that in the non-PORT group (2.0 years vs. 4.4 years; p = 0.031). Multivariate analysis revealed that radiotherapy was associated with a reduced time to achieve MMS (hazard ratio [HR] 1.971, 95% confidence interval [CI]:1.102-3.525, p = 0.022). Effects of PORT on DFS and OS: The 10-year OS rate of the entire cohort was 90.5%, whereas OS rates for the PORT and non-PORT groups were 94.4 and 85.1%, respectively. The 5-year DFS rates for the whole cohort, PORT group, and non-PORT group were 89.7, 95.8, and 81.5%, respectively. PORT was associated with improved DFS (HR 0.139, 95% CI: 0.037-0.533, p = 0.004). In the high-risk histologic subgroup (type B2, B3), patients who received PORT had better OS (p = 0.015) and DFS (p = 0.0053) than those who did not receive PORT. PORT was associated with improved DFS (HR 0.232, 95% CI: 0.069-0.782, p = 0.018) in Masaoka-Koga stages II, III, and IV disease. CONCLUSIONS: Overall, our findings indicate that PORT positively impacts thymoma patients with MG, particularly those with a higher histologic subtype and Masaoka-Koga staging.

The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis.

Background: Although immunotherapy has been widely used, there is currently no research comparing immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). This meta-analysis addresses a gap in the comparison of immunotherapy efficacy, including immune checkpoint inhibitors (ICIs), chemotherapy (CT), radiotherapy (RT), and ICI combined CT or RT. Methods: A search of Pubmed, Cochrane, EMBASE, and ClinicalTrial.gov was conducted to identify studies which enrolled NSCLC patients with BM treated with ICIs. The outcomes consisted of intracerebral overall response rate (iORR), intracerebral disease control rate (iDCR), extracranial overall response rate (EORR), distant brain failure (DBF), local control (LC), progression-free survival (PFS), and overall survival (OS). Results: A total of 3160 participants from 46 trials were included in the final analysis. Patients treated with immunotherapy were associated with a longer PFS (0.48, 95%CI: 0.41-0.56), and a longer OS (0.64, 95%CI: 0.60-0.69) compared with immunotherapy-naive patients. In prospective studies, dual ICI combined CT and ICI combined CT achieved a better OS. The hazard ratio (HR) of dual ICI combined CT versus dual ICI was 0.61, and the HR of ICI combined CT versus ICI monotherapy was 0.58. Moreover, no statistical difference in PFS, OS, EORR, iORR, iDCR, and EDCR was found between patients with ICI monotherapy and ICI combined cranial radiotherapy. Concurrent ICI combined RT was shown to decrease the rate of DBF (OR = 0.15, 95% CI: 0.03-0.73) compared with RT after ICI. Patients treated with WBRT might have an inferior efficacy than those with SRS because the iORR of SRS was 0.75 (0.70, 0.80) and WBRT was 0. Furthermore, no obvious difference in PFS and OS was observed among the three different types of ICI, which targets PD-1, PD-L1, and CTLA-4, respectively. Conclusions: Patients treated with ICI got superior efficacy to those without ICI. Furthermore, dual ICI combined CT and ICI combined CT seemed to be optimal for NSCLC patients with BM. In terms of response and survival, concurrent administration of SRS and ICI led to better outcomes for patients with BMs than non-concurrent or non-SRS. Importance of the Study: In the new era of immunotherapy, our meta-analysis validated the importance of immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). By comparing the long-term and short-term impacts of various regimens, all immunotherapy treatments had superior efficacy to immunotherapy-naive. At the same time, through pairwise comparison in immunotherapy, our findings can help clinicians to make treatment decisions for NSCLC patients with BMs. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=269621, identifier CRD42021269621.

The Hyperbilirubinemia and Potential Predictors Influence on Long-Term Outcomes in Sepsis: A Population-Based Propensity Score-Matched Study.

Objective: Although hyperbilirubinemia has been associated with mortality in patients who are critically ill, yet no clinical studies dissect the effect of dynamic change of hyperbilirubinemia on long-term septic prognosis. The study aims to investigate the specific stages of hyperbilirubinemia and potential risk factors on long-term outcomes in patients with sepsis. Methods: In this retrospective observational cohort study, patients with sepsis, without previous chronic liver diseases, were identified from the Medical Information Mart for the Intensive Care III MIMIC-III database. We used propensity scores (PS) to adjust the baseline differences in septic patients with hyperbilirubinemia or not. The multivariate Cox was employed to investigate the predictors that influence a clinical outcome in sepsis. Results: Of 2,784 patients with sepsis, hyperbilirubinemia occurred in 544 patients (19.5%). After PS matching, a survival curve demonstrated that patients with sepsis with the new onset of total bilirubin (TBIL) levels more than or equal to 5 mg/dl survived at significantly lower rates than those with TBIL levels <5 mg/dl. Multivariate Cox hazard analysis showed that patients with TBIL at more than or equal to 5 mg/dl during sepsis exhibit 1.608 times (95% CI: 1.228-2.106) higher risk of 1-year mortality than those with TBIL levels <5 mg/dl. Also, age above 65 years old, preexisting malignancy, a respiratory rate above 30 beats/min at admission, serum parameters levels within 24-h admission, containing international normalized ratio (INR) above 1.5, platelet <50*10∧9/L, lactate above 4 mmol/L, and bicarbonate <22 or above 29 mmol/L are the independent risk factors for long-term mortality of patients with sepsis. Conclusions: After PS matching, serum TBIL levels at more than or equal to 5 mg/dl during hospitality are associated with increased long-term mortality for patients with sepsis. This study may provide clinicians with some cutoff values for early intervention, which may improve the prognosis of patients with sepsis.

Protective effect and mechanisms of exogenous neutrophil gelatinase-associated lipocalin on lipopolysaccharide-induced injury of renal tubular epithelial cell.

PURPOSES: To investigate the protective effect of exogenous neutrophil gelatinase-associated lipocalin (NGAL) on the lipopolysaccharide-induced injury of renal tubular epithelial cells and its regulation of autophagy. METHODS: Renal tubular epithelial cells were treated with lipopolysaccharide (LPS) at different concentrations (0-100 µg/mL) and at different times (0-24 h), the expression of NGAL was detected to determine the optimal time and concentration of LPS treatment. The NGAL gene knockdown lentivirus (NGAL-RNAi) was constructed and verified its knockdown rate and inhibition effect. Renal tubular epithelial cells were randomly divided into Control group, LPS group, LPS + NGAL group, NGAL-RNAi + LPS group, and NGAL-RNAi + LPS + NGAL group. Western blot and immunofluorescence tested the expression of autophagy-associated proteins, the changes in the number of autophagosomes were observed by electron microscopy, analyzed the role of exogenous NGAL. RESULTS: The study showed the expression of autophagy-associated proteins (LC3-II and Beclin-1) in NGAL-RNAi + LPS group was significantly lower than the LPS group (P < 0.0100). The expression of LC3-II and Beclin-1 in the NGAL-RNAi + LPS + NGAL group was significantly higher than the NGAL-RNAi + LPS group (P < 0.0100). After the addition of exogenous NGAL, the autophagosomes in the LPS + NGAL group and the NGAL-RNAi + LPS + NGAL group were significantly increased under the electron microscope compared with the LPS group and the NGAL-RNAi + LPS group, and the cell proliferation rate and cell viability was significantly higher than unjoined groups (P < 0.0500). CONCLUSION: NGAL knockdown can significantly reduce the level of autophagy and decrease the proliferation rate and viability of cells.The addition of exogenous NGAL can increase the level of autophagy. This suggests that NGAL may play a protective role in the LPS-induced injury of renal tubular epithelial cells by promoting autophagy.