Cost-effectiveness analysis of durvalumab plus etoposide: platinum in the first-line therapy of extensive stage small-cell lung cancer from the Chinese payers' perspective.

INTRODUCTION: Results from the CASPIAN trial (Durvalumab ± Tremelimumab in Combination With Platinum Based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer) trial demonstrated the clinical benefit of durvalumab plus etoposide-platinum (EP) chemotherapy as first-line treatment for patients with extensive stage small-cell lung cancer (ES-SCLC). However, considering the high price of durvalumab, it is unclear whether addition of durvalumab to EP chemotherapy has economic value compared with EP alone. In this study, we aimed to evaluate the cost-effectiveness of durvalumab plus EP chemotherapy as a first-line treatment for patients with ES-SCLC. METHODS: A Markov model comprising three health states (stable, progressive, and dead) was developed to simulate the process of small-cell lung cancer. Utility and costs were obtained from published resources. Health outcomes were derived from the CASPIAN trial. Costs were calculated based on the standard medical fees in Zhejiang Province from Chinese patients' perspective. Utility values were obtained from published data. One-way and probabilistic sensitivity analyses were applied to verify model robustness. RESULTS: The addition of durvalumab to EP chemotherapy costs more than $32,220, with a gain of 0.14 quality-adjusted life years (QALYs) compared with EP alone. The incremental cost-effective ratio was $230,142.9 per QALY, which exceeds the willingness to pay threshold of $28,527 per QALY. In the sensitivity analysis, the utility values for the progressive state, costs of durvalumab and EP chemotherapy, and costs for the progressive state were considered to be the three most sensitive factors in the model. CONCLUSION: The addition of durvalumab to EP chemotherapy is not a cost-effective strategy in the first-line therapy of ES-SCLC from the Chinese payers' perspective.

High expression of monocarboxylate transporter 4 (MCT 4), but not MCT 1, predicts poor prognosis in patients with non-small cell lung cancer.

BACKGROUND: The monocarboxylate transporter (MCT) family especially MCT1 and MCT4 have been recognized to play an important role in lactate transport, a key glycolytic product. The expression of MCT1 and MCT4 expression was previously found to be related to poor outcome in various cancer types. In this study, we investigated the expression status of MCT1 and MCT4 and their relationship with prognosis in non-small cell lung cancer (NSCLC). METHODS: Expression of MCT4 and MCT1 in NSCLC tumor and adjacent lung tissues were detected by immunohistochemistry. Kaplan-Meier plots were used to evaluate two proteins' prognostic role, and the log-rank test obtained the P value. For multivariate analysis, the Cox proportional-hazards regression method was performed. RESULTS: High MCT4 and MCT1 expression was observed in cancer cells, with a rate of 45% for MCT4 versus 15% for MCT1 among all NSCLC patients. High expression of MCT4, and not MCT1, was associated with worse overall survival (OS) [hazard ratio (HR) =1.96 (1.06-3.75), P=0.032] and progression-free survival (PFS) [HR =1.72 (1.05-2.93), P=0.032] in NSCLC patients. In our multivariate analysis, advanced cancer stage and high MCT4 level were identified as independent predictive indicators for both PFS [HR(MCT4) =1.888 (1.114-3.199), P=0.018 and OS [HR (MCT4) =2.421 (1.271-4.610), P=0.007]. Subgroup and interaction analyses were also performed in different clinical characteristic groups and no significant differences were observed. CONCLUSIONS: High MCT4 expression is a predictive marker for worse outcome in NSCLC patients.

Multi-Omics Analysis of Acute Lymphoblastic Leukemia Identified the Methylation and Expression Differences Between BCP-ALL and T-ALL.

Acute lymphoblastic leukemia (ALL) as a common cancer is a heterogeneous disease which is mainly divided into BCP-ALL and T-ALL, accounting for 80-85% and 15-20%, respectively. There are many differences between BCP-ALL and T-ALL, including prognosis, treatment, drug screening, gene research and so on. In this study, starting with methylation and gene expression data, we analyzed the molecular differences between BCP-ALL and T-ALL and identified the multi-omics signatures using Boruta and Monte Carlo feature selection methods. There were 7 expression signature genes (CD3D, VPREB3, HLA-DRA, PAX5, BLNK, GALNT6, SLC4A8) and 168 methylation sites corresponding to 175 methylation signature genes. The overall accuracy, accuracy of BCP-ALL, accuracy of T-ALL of the RIPPER (Repeated Incremental Pruning to Produce Error Reduction) classifier using these signatures evaluated with 10-fold cross validation repeated 3 times were 0.973, 0.990, and 0.933, respectively. Two overlapped genes between 175 methylation signature genes and 7 expression signature genes were CD3D and VPREB3. The network analysis of the methylation and expression signature genes suggested that their common gene, CD3D, was not only different on both methylation and expression levels, but also played a key regulatory role as hub on the network. Our results provided insights of understanding the underlying molecular mechanisms of ALL and facilitated more precision diagnosis and treatment of ALL.

Elevated proportion of collapsed microvessels indicate poor survival outcome in patients with non-small cell lung cancer.

BACKGROUND: An integral and well-functioning vascular system is essential for tumor progression and chemotherapy infusion. However, the lumen integrity of the microvessels and its significance in prognosis has not been studied. In this study, we found that the proportion of collapsed microvessels is suggested to be a novel biomarker for predicting prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: In this study, immunohistochemical CD31 staining was performed to identify the microvessels in tumor specimens. Proportions of collapsed vessels were estimated in CD31-stained tumor specimens from 100 patients with NSCLC. The correlation between collapsed microvessel proportion and survival time were evaluated by univariate and multivariate analysis. RESULTS: Data from 99 patients were analyzed and a wide range of collapse-microvessel fraction was observed in 96 patients (1.4%-70%). Elevated collapse proportion (⩾6.5%) indicated poor overall survival in both univariate analysis (p = 0.042) and multivariate analysis (p = 0.014). CONCLUSIONS: Elevated proportion of collapsed microvessels indicted poor survival outcome in patients with NSCLC.

Dual-negative expression of Nrf2 and NQO1 predicts superior outcomes in patients with non-small cell lung cancer.

Functional studies in non-small cell lung cancer (NSCLC) patients revealed that hyperactivation of the NF-E2-related factor 2 (Nrf2) pathway facilitates tumor growth. We examined the usefulness of Nrf2 and NQO1 as indicators of prognosis in NSCLC. Tumor and adjacent non-tumor tissue samples were collected from 215 NSCLC patients who had tumor resections between 2006 and 2011. Immunohistochemistry was performed to detect Nrf2 or NQO1 expression. The correlation between Nrf2 or NQO1 expression and survival outcomes was evaluated using the Kaplan-Meier method and Cox proportional hazards regression model. Levels of Nrf2 and NQO1 were elevated in tumor tissues. In particular, Nrf2 was elevated in nearly all tumor cells. NQO1 expression positively correlated with Nrf2 expression (P = 0.039). Nrf2 expression positively correlated with lymph node metastasis (P = 0.001) and negatively correlated with tumor differentiation (P = 0.032). As compared with either Nrf2 or NQO1 alone, dual-negative expression of Nrf2 and NQO1 was more predictive of superior overall survival (P = 0.020) and disease free survival (P = 0.037). Subgroup analyses showed that females, nonsmokers, and patients with advanced-stage NSCLC were suitable populations in which to evaluate prognosis based on Nrf2 and NQO1 co-expression. These results indicate that dual-negative expression of Nrf2 and NQO1 is predictive of a better prognosis in NSCLC patients.

Keap1-Nrf2 pathway: A promising target towards lung cancer prevention and therapeutics.

OBJECTIVES: Drugs for targeted therapy have become a new strategy of adjuvant therapy for treatment of lung cancer. The Keap1 (kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2) pathway is recognized to be critical in regulating genes related to the cellular protective response and protecting cells from oxidative damages and toxic insult. METHODS: Pubmed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication. Search terms were "Nrf2" or "Keap1" and "Lung cancer". RESULTS: The upregulation of Nrf2 had been closely related to tumor protection and drug resistance. The aberrant state of Keap1 or Nrf2 that were frequently found in lung cancer conferred a poor prognosis. Nrf2 could prevent cells from undergoing oncogenesis as a tumor suppressor, while it could also promote cancer progression and resistance to chemotherapeutic drugs as an oncogene, depending on the different stages of tumor progression. Target Nrf2 signaling by specific chemicals showed it could prevent tumor growth or combat chemoresistance. CONCLUSIONS: Increasing evidence has demonstrated the dual roles of the Keap1-Nrf2 pathway in tumor initiation and progression. In this paper, we provide a comprehensive overview of the potency of the Keap1-Nrf2 pathway as an antitumor target, and the current status of Nrf2 activators or inhibitors for therapeutic approaches. Further studies are required to clarify the role of Nrf2 in lung cancer at different tumor stages, in order to maximize the efficacy of Keap1-Nrf2 targeting agents.