Pembrolizumab combined with chemotherapy versus placebo combined with chemotherapy for HER2-negative advanced gastric cancer in China: a cost-effectiveness analysis.

OBJECTIVE: This study aims to conduct a cost-effectiveness analysis of pembrolizumab in combination with chemotherapy for HER2-negative advanced gastric cancer in China. METHODS: A partitioned survival approach model was constructed to simulate the progression of HER2-negative advanced gastric cancer and evaluate the outcomes of different treatment strategies. We calculated incremental cost-effectiveness ratios (ICER) to assess the cost associated with each quality-adjusted life-year (QALY) gained. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess robustness and reliability. RESULTS: The analysis conducted in the base case demonstrated that the ICER associated with pembrolizumab was $177405.83/QALY gained in all population. In the subgroup analysis, it was found that individuals with a PD-L1 CPS ≥ 1 and those with a PD-L1 CPS ≥ 10 had ICERs of $152397.06/QALY and $109534.13/QALY, respectively. All ICER values for both the all population groups and the subgroups exceeded the WTP threshold in China. Our analysis shows the robustness of these results, as they remained consistent when input parameters were varied within a ± 25% range. CONCLUSION: The findings of this cost-effectiveness analysis suggest that pembrolizumab in combination with chemotherapy is not a cost-effective treatment option for HER2-negative advanced gastric cancer in China.

Design, synthesis and molecular modeling of novel D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives as anti-inflammatory agents by inhibition of COX-2/iNOS production and down-regulation of NF-κB/MAPKs in LPS-induced RAW264.7 macrophage cells.

It has been reported that 4,5-dihydropyrazole and thiazole derivatives have many biological functions, especially in the aspect of anti-inflammation. According to the strategy of pharmacophore combination, we introduced thiazolinone and dihydropyrazole moiety into steroid skeleton to design and synthesize a novel series of D-ring substituted steroidal 4,5-dihydropyrazole thiazolinone derivatives, and assessed their in vitro anti-inflammatory profiles against Lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. The anti-inflammatory activities assay demonstrated that compound 12e was considered as the most effective anti-inflammatory drug, which suppressed the expression of pro-inflammatory mediators including nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), it also dose-dependently inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 macrophage cells. Furthermore, the results of the Western blot analysis showed a correlation between the inhibition of the Nuclear factor-kappa B (NF-κB) and Mitogen-activated protein kinases (MAPKs) signaling pathways and the suppressive effects of compound 12e on pro-inflammatory cytokines. Molecular docking studies of compound 12e into the COX-2 protein receptor (PDB ID: 5IKQ) active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of dexamethasone (DXM), explaining their remarkable COX-2 inhibitory activity. The findings revealed that these candidates could be identified as potent anti-inflammatory agents, compound 12e could be a promising drug for the treatment of inflammatory diseases.

First-Line Tislelizumab for Advanced or Metastatic Esophageal Squamous Cell Carcinoma:A Cost-Effectiveness Analysis.

OBJECTIVE: The primary objective of this current study is to evaluate the cost-effectiveness of incorporating tislelizumab into the first-line treatment of metastatic or advanced esophageal squamous cell carcinoma (ESCC) in comparison to placebo with chemotherapy. METHOD: We conducted a partitioned survival model with a time horizon of 10 years from a Chinese perspective. The direct medical costs were collected from the local setting in China. To enhance the credibility and robustness of the findings, sensitivity analyses were also conducted. RESULTS: The inclusion of tislelizumab in conjunction with chemotherapy was shown to significantly enhance quality-adjusted life years (QALY) by 0.328 when compared to chemotherapy alone. This improvement comes at an additional cost of $9833.694. The incorporation of tislelizumab into the treatment regimen for advanced ESCC results in an incremental cost-effectiveness ratio (ICER) of $29980.774/QALY gained, which falls below the WTP threshold of $37304.346/QALY in China. One-way sensitivity analyses showed that no parameters were found to be adjustable within a specific range without altering the overall outcomes of our study. CONCLUSION: Tislelizumab plus chemotherapy as first-line treatment for advanced or metastatic ESCC is may be a cost-effective option compared to chemotherapy alone.

Preoperative Prognostic Nutritional Index Predict Survival in Patients with Resectable Adenocarcinoma of the Gastroesophageal Junction: A Retrospective Study Based on Propensity Score Matching Analyses.

Background: This study evaluated the value of PNI to predicting relapse-free survival (RFS) and overall survival (OS) in patients with resectable gastroesophageal junction adenocarcinoma (AGE). Methods: Between 2016 and 2020, there were 236 resectable AGE patients underwent a retrospective review via propensity score matched (PSM) analysis. The PNI values were computed for each patient prior to surgery [PNI= 10×albumin (gr/dL) + 0.005×total lymphocyte count (mm3)]. By using disease progression and mortality as the end points, a receiver operating characteristic(ROC) curve was plotted to identify the PNI cut-off value. Kaplan-Meier curves and Cox proportional hazard models were used for survival analysis. Results: The ROC curve indicated that the ideal cutoff value was 45.60. After propensity score matching, there were 143 patients in our retrospective study, which included 58 patients in the low-PNI group and 85 patients in the high-PNI group. When compared to the low PNI group, the high PNI group substantially increased RFS and OS (p<0.001, p=0.003, respectively) according to the Kaplan-Meier analysis and Log rank test. Advanced pathological N stage (p=0.011) and poor PNI (p=0.004) were also significant risk factors for a shorter OS, according to a univariate analysis. Multivariate analysis revealed that the N0 plus N1 group had an endpoint mortality risk that was 0.39 times lower than the N2 plus N3 group's (p=0.008). In comparison to the high PNI group, the hazard of endpoint mortality was 2.442 times greater in the low PNI group (p = 0.003). Conclusion: PNI is a simplistic and practical predictive predictor of the RFS and OS time in patients with resectable AGE.

Cost-effectiveness analysis of serplulimab as first-line treatment for advanced esophageal squamous cell carcinoma.

Objective: To evaluate the cost-effectiveness of serplulimab as first-line treatment for patients with advanced esophageal squamous cell carcinoma from the perspective of the Chinese healthcare system. Materials & methods: A partitioned survival model was created to evaluate costs and health outcomes. The model's robustness was evaluated using one-way and probabilistic sensitivity analyses. Results: Serplulimab demonstrated an incremental cost-effectiveness ratio of $104,537.375/quality-adjusted life-year in the overall population group. Subgroup analysis showed that serplulimab had incremental cost-effectiveness ratios of $261,750.496/quality-adjusted life-year and $68,107.997/quality-adjusted life-year in the populations with PD-L1 1 ≤ combined positive score <10 and PD-L1 combined positive score ≥10, respectively. Conclusion: Incremental cost-effectiveness ratios of serplulimab therapy were found to exceed the willingness-to-pay threshold of $37,304.34. Thus, serplulimab is not cost-effective compared with chemotherapy as a first-line treatment for esophageal squamous cell carcinoma patients.

Economic evaluation of toripalimab plus chemotherapy compared with chemotherapy as first-line treatment for advanced esophageal squamous cell carcinoma in China.

OBJECTIVES: The purpose of this study was to compare the cost-effectiveness of toripalimab versus Chemotherapy for patients with advanced esophageal squamous cell carcinoma (ESCC) from the perspective of the Chinese healthcare system. METHODS: A partitioned survival model was designed. Clinical data on survival was taken from the JUPITER-06 trials. Direct medical expenditures and utilities were gathered from published literature and a local database. One-way and probability sensitivity methods were used to evaluate the model's robustness. RESULTS: Compared with chemotherapy alone, toripalimab offered an incremental cost of $8950.427 with an additional 0.294 QALYs, yielding an ICER of 30,443.629$/QALYs first-line therapy for advanced ESCC. The ICER was below the threshold of willingness to pay in China, indicating that the toripalimab group had a cost-effective advantage. Sensitivity analysis showed that the ICERs were most sensitive to the utility of PD, but all the parameters had no significant impact on the model's outcomes. CONCLUSION: Toripalimab may be a cost-effective first-line treatment choice in our research when compared to chemotherapy alone for patients with advanced ESCC.

A cost-effectiveness analysis of first-line toripalimab plus chemotherapy in advanced nonsquamous non-small cell lung cancer in China.

BACKGROUND: This study compares first-line toripalimab with chemotherapy for advanced nonsquamous non-small cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. RESEARCH DESIGN AND METHODS: A three-state Markov model was established to compare the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) of first-line toripalimab plus chemotherapy versus chemotherapy. Clinical outcomes data were acquired from the CHOICE-01 clinical trials. Costs and utilities were gathered from regional databases or published publications. One-way sensitivity and probability sensitivity analyses were used to investigate the stability of the model parameters. RESULTS: First-line toripalimab treatment for advanced nonsquamous NSCLC resulted in an incremental cost of $16,214.03 and added 0.77 QALYs compared to chemotherapy, which had an ICER of $21,057.18 per QALY gained. The ICER was substantially lower than the willingness to pay (WTP) threshold in China, which was $37,663.26 per QALY. The toripalimab cycle used was shown to have the greatest impact on the ICERs, according to sensitivity analysis, although none of the factors significantly affected the model's outcomes. CONCLUSIONS: Toripalimab plus chemotherapy is likely to be a cost-effective option compared with chemotherapy alone for patients with advanced nonsquamous NSCLC from the perspective of the Chinese healthcare system.

Cost-effectiveness analysis of lenvatinib plus pembrolizumab compared with chemotherapy for patients with previously treated mismatch repair proficient advanced endometrial cancer in China.

Aims: This study aimed to evaluate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) vs. chemotherapy for patients with previously treated mismatch repair proficient advanced endometrial cancer in China. Methods: A lifetime of partitioned survival Markov was used to evaluate the overall lifetime, total costs, quality adjusted life years (QALYs), and incremental cost effectiveness ratio (ICER) across a 10-years time horizon in the study 309-KEYNOTE-775 clinical trial. Direct costs and utility values were gathered from available literature. The willingness to pay (WTP) was defined at $37,663.26 per QALY. Sensitivity analyses were carried out to determine the model's uncertainty. Results: According to the baseline analysis, the LP group gained 4.02 total life years and 3.13 QALYs for $93,496.69, whereas the chemotherapy group gained 2.86 total life years and 2.24 QALYs for $30,578.04. LP versus chemotherapy resulted in an incremental cost of $62,918.65, with an ICER of $70,962.09/QALY, which was higher than China's WTP threshold ($37,663.26/QALY). The ICERs were most sensitive to the cost of pembrolizumab and the cycle of LP delivered, according to the sensitivity analysis. However, changing the range of those parameters has no influence on the model's results. Conclusion: Our present analysis suggests that LP treatment is not cost-effective for patients with previously treated mismatch repair proficient advanced endometrial cancer. However, LP treatment may be a cost-effective treatment option if the price is reduced.

Cost-effectiveness analysis of sugemalimab vs. chemotherapy as first-line treatment of metastatic nonsquamous non-small cell lung cancer.

Objective: Sugemalimab is approved in China as a first-line treatment in combination with chemotherapy for metastatic nonsquamous non-small cell lung cancer (NSCLC). This study aims to evaluate the cost-effectiveness of first-line additional sugemalimab in combination with chemotherapy vs. chemotherapy from the perspective of the Chinese healthcare system. Materials and methods: A three-state Markov model was designed to evaluate the costs and quality-adjusted life years (QALYs) of first-line sugemalimab combination with chemotherapy vs. chemotherapy over a 10-year period. Data on clinical outcomes were obtained from GEMSTONE-302 clinical trials. Costs and health utilities were collected from local databases and published literature. The uncertainty of the model parameters was explored through sensitivity analysis. Results: Compared to chemotherapy, sugemalimab treatment for NSCLC resulted in an extra 0.50 QALYs at an additional cost of $73627.99, with an incremental cost-effectiveness ratio (ICER) of 148354.07/QALY at the willingness-to-pay (WTP) threshold of $37663.26/QALY. One-way sensitivity analysis indicated that the primary motivator in this model was the cost of sugemalimab. However, none of the parameters significantly affected the model's results. Conclusion: Sugemalimab combination therapy is not economically advantageous for the first-line management of metastatic non-squamous NSCLC, according to the Chinese healthcare system.

Cost-Effectiveness Analysis of Pembrolizumab Plus Chemotherapy vs. Chemotherapy Alone as First-Line Treatment in Patients With Esophageal Squamous Cell Carcinoma and PD-L1 CPS of 10 or More.

Background: This study aimed to analyze the economics of pembrolizumab plus chemotherapy as first-line treatment in patients with esophageal squamous cell carcinoma (ESCC) and programmed cell death-Ligand 1 (PD-L1) combined positive score (CPS) of 10 or more in China. Methods: Based on the advanced ESCC of the KEYNOTE-590 clinical trial data, a Markov model was performed to simulate the clinical course and evaluate the patient's total lifetime, total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) for pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil) vs. chemotherapy alone in first-line treatment of ESCC and PD-L1 CPS of 10 or more. Utility values and direct costs related to the treatments were gathered from the published literature data. One-way and probabilistic sensitivity analyses were conducted to check the stability of the model. Results: The baseline analysis indicated that the incremental effectiveness and cost of pembrolizumab plus chemotherapy vs. chemotherapy alone added 1.23 QALYs and resulted in an incremental cost of $51,320.22, which had an ICER of $41,805.12/QALY, higher than the willingness-to-pay (WTP) threshold of China ($37,663.26/QALY). The sensitivity analysis demonstrated that the ICERs were most sensitive to the cycle of pembrolizumab used and the cost of pembrolizumab. Conclusion: The result of our present analysis suggests that the addition of pembrolizumab plus chemotherapy as first-line treatment might not be cost-effective for patients with ESCC and PD-L1 CPS of 10 or more in China.

Preoperative Prognostic Nutritional Index Predict Survival in Patients With Resectable Esophageal Squamous Cell Carcinoma.

Background: Prognostic nutritional index (PNI) is one of the most important factors related to prognosis in many types of cancer. This study aimed to evaluate the PNI on predicting the overall survival (OS) in resectable esophageal squamous cell carcinoma (ESCC). Methods: A total of 165 patients with resectable ESCC were included in our retrospective study. PNI values before surgery were calculated for each patient [PNI = 10 × albumin (gr/dL) + 0.005 × total lymphocyte count (mm3)]. PNI cutoff value was selected by drawing receiver operating characteristics (ROC) curve, which used OS time as the endpoint. The Kaplan-Meier method and the Cox regression model of multivariate analysis were used to analyze the prognostic relationship between PNI and OS. Results: Among the 165 patients, 34 (20.6%) were women and 131 (79.4%) were men. The mean age was 62.67 ± 7.95 years, with the age range from 44 to 85 years. The average PNI was 46.68 ± 8.66. ROC curve showed that the best cutoff value was 43.85. All patients were divided into two groups: 72 patients (43.6%) were in the low PNI group (<43.85), while 93 patients (56.4%) were in the high PNI group (≥ 43.85). Univariate analysis demonstrated that PNI, tumor length, and T-stage and pathological stage were related to the prognosis of patients with ESCC (P <0.05). The Kaplan-Meier curve showed that the high PNI group has significantly increased OS compared to low PNI group (p = 0.01). Three-year OS rates were 57.5% in the low PNI group while 77.7% in the high PNI group. Univariate analysis showed that advanced pathological stage, large tumor length, and low PNI (separately, p < 0.05) were significant risk factors for shorter OS. Multivariate analysis showed that tumor length (P = 0.008) and PNI (P = 0.017) were independent prognostic factors in patients with resectable ESCC. Conclusion: PNI is a simple and useful predictive marker for the OS time in patients with radical esophagectomy.

The Preoperative Neutrophil Lymphocyte Ratio and Platelet Lymphocyte Ratio Predicts Disease-Free Survival in Resectable Esophageal Squamous Cell Carcinoma.

BACKGROUND: Recent studies have revealed that the presence of systemic inflammation is associated with poor survival for esophageal squamous cell carcinoma. We aimed to investigate prognostic values of preoperative neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in resectable esophageal squamous cell carcinoma. METHODS: A cohort of 167 resectable ESCC patients was retrospectively reviewed between January 2017 and September 2020. The best cut-off value of NLR and PLR was selected by plotting the receiver operating characteristic curve. All reviewed patients were divided into high NLR/PLR or low NLR/PLR group to evaluate prognostic factors. RESULTS: Among the 167 patients, 34 (20.36%) were women and 133 (79.64%) were men. The mean age was 62.64 ±7.91 years, with an age range from 44 to 85 years. All patients were divided into low NLR (<2.20) or high NLR (≥2.20) group (AUC=62.5% with the sensitivity of 61.8% and specificity 60.9%, P=0.025), low PLR (<110) or high PLR (≥110) group (AUC=59.6% with the sensitivity of 82.4% and specificity 35.3%, P=0.083). High NLR and PLR were associated with a larger tumor diameter (P<0.05), while high NLR was also associated with poor tumor classification (P=0.022). There was a positive correlation between NLR and PLR (r = 0.614, P < 0.001). High NLR and PLR were significantly associated with poor disease-free survival. Multivariate analyses identified NLR as a prognostic factor in resectable ESCC. CONCLUSION: The NLR and PLR predict disease-free survival in resectable esophageal squamous cell carcinoma.

Synthesis and anti-inflammatory activity of novel steroidal chalcones with 3ß-pregnenolone ester derivatives in RAW 264.7 cells in vitro.

To identify new potential anti-inflammatory agents, we herein report the synthesis of novel steroidal chalcones with 3ß-pregnenolone esters of cinnamic acid derivatives using pregnenolone as the starting material. The structures of the newly synthesised compounds were confirmed by 1H NMR, 13C NMR, HRMS and infrared imaging. All the derivatives were examined to determine their in vitro anti-inflammatory profiles against LPS-induced inflammation in RAW 264.7 cells; the derivates were evaluated by the quantification of the pro-inflammatory mediator nitric oxide (NO) in the cell culture supernatant based on the Griess reaction, which measures nitrite levels, followed by an in vitro cytotoxicity study. Among these novel derivatives, compound 11e [3ß-3-phenyl acrylate-pregn-5-en-17ß-yl-3' -(p-fluoro)-phenylprop-2'-en-1'-one] was identified as the most potent anti-inflammatory agent, which showed significant anti-inflammatory activity by inhibiting the LPS-induced pro-inflammatory mediator NO in a dose-dependent manner without any cytotoxicity. Moreover, compound 11e markedly inhibited the expression of pro-inflammatory cytokines, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2), in LPS-induced RAW 264.7 cells. Further studies confirmed that compound 11e significantly suppressed the transcriptional activity of NF-κB in activated RAW 264.7 cells. Molecular docking study revealed the strong binding affinity of compound 11e to the active site of the pro-inflammatory proteins, which confirmed that compound 11e acted as an anti-inflammatory mediator. These results indicated that steroidal chalcones with 3ß-pregnenolone esters of cinnamic acid derivatives might be considered for further research in the design of anti-inflammatory drugs, and compound 11e might be a promising therapeutic anti-inflammatory drug candidate.

Synthesis and evaluation of novel D-ring substituted steroidal pyrazolines as potential anti-inflammatory agents.

To identify new potential anti-inflammatory agents, a number of novel steroidal derivatives with nitrogen heterocyclic side chains 4a-4l were synthesized and evaluated for their anti-inflammatory effects in activated RAW 264.7 macrophage cells. The synthesis scheme involves two steps, Claisen-Schmidt condensation with the corresponding pregnenolone and aromatic aldehydes as the first step followed by nucleophilic addition of thiosemicarbazide across an α, ß-unsaturated carbonyl as a later step. Compound structures were confirmed by 1H NMR, 13C NMR, HRMS, and IR. The compounds were assayed to test their anti-inflammatory effects in activated RAW 264.7 cells. Compound 4g, 3ß-hydroxy-pregn-5-en-17ß-yl-5'-(m-fluorophenyl)-4', 5'-dihydro-1'-carbothioic acid amido pyrazole, was identified as the most potent anti-inflammatory agent of the analysed compounds, with an IC50 value of 0.86 µM on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cells for 24 h compared to dexamethasone (IC50 = 0.62 µM) and low cytotoxicity against RAW 264.7 cells. Compound 4g significantly inhibited NO produced by LPS-induced RAW 264.7 cells. Further studies showed that compound 4g markedly inhibited the expression of pro-inflammatory factors, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) in LPS-induced RAW 264.7 cells. These results indicate that derivatives bearing pyrazoline structure might be considered for further research and scaffold optimization in designing anti-inflammatory drugs and compound 4g might be a promising therapeutic anti-inflammatory drug candidate.

Chemically modified dansyl probes: a fluorescent diagnostic for ion and proton detection in solution and in polymers.

[reaction: see text] The fluorescence emission intensity of the dansyl group is significantly diminished upon appending an ethyldimethylamino group to the N1 nitrogen substituent. Addition of acids and metal ions (i.e., Zn(2+)) to solutions of trimethylethylenediamine naphthalene sulfonamide (trinsyl) 2 produces a >25-fold increase in fluorescence intensity. Trinsyl probe 2 has been used as a diagnostic for the diffusion of protons and metal ions in a network polymer as well as an optical reporter for the glass transition temperature.

The boron-catalyzed polymerization of dimethylsulfoxonium methylide. A living polymethylene synthesis.

Trialkyl and aryl organoboranes catalyze the polymerization of dimethylsulfoxonium methylide (1). The product of the polymerization is a tris-polymethylene organoborane. Oxidation affords linear telechelic alpha-hydroxy polymethylene. The polymer molecular weight was found to be directly proportional to the stoichiometric ratio of ylide/borane, and polydispersities as low as 1.01-1.03 have been realized. Although oligomeric polymethylene has been the most frequent synthetic target of this method, polymeric star organoboranes with molecular weights of 1.5 million have been produced. The average turnover frequency at 120 degrees C in 1,2,4,5-tetrachlorobenzene/toluene is estimated at >6 x 10(6) g of polymethylene (mol boron)(-1) h(-1). The mechanism of the polyhomologation reaction involves initial formation of a zwitterionic organoborane.ylide complex which breaks down in a rate-limiting 1,2-alkyl group migration with concomitant expulsion of a molecule of DMSO. The reaction was found to be first order in the borane catalyst and zero order in ylide. DMSO does not interfere with the reaction. The temperature dependence of the reaction rate yielded the following activation energy parameters (toluene, DeltaH(++) = 23.2 kcal/mol, DeltaS(++) = 12.6 cal deg/mol, DeltaG(++) = 19.5 kcal/mol; THF, DeltaH(++) = 26.5 kcal/mol, DeltaS(++) = 21.5 cal deg/mol, DeltaG(++) = 20.1 kcal/mol).