Search

Background: The HIMALAYA trial found that durvalumab plus tremelimumab significantly prolonged progression-free survival and overall survival in patients with unresectable hepatocellular carcinoma (HCC) compared with sorafenib. Objective: This study aimed to investigate the cost-effectiveness of durvalumab plus tremelimumab compared with sorafenib in the first-line HCC setting. Design: A Markov model-based cost-effectiveness analysis. Methods: We created a Markov model to compare healthcare costs and clinical outcomes of HCC patients treated with durvalumab plus tremelimumab in the first-line setting compared with sorafenib. We estimated transition probabilities from randomized trials. Lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios were calculated for first-line durvalumab plus tremelimumab compared with sorafenib from a US payer's perspective. Results: In the base case, first-line durvalumab plus tremelimumab was associated with an improvement of 0.29 QALYs compared with sorafenib. While both treatment strategies were associated with considerable lifetime expenditures, first-line durvalumab plus tremelimumab was less expensive than sorafenib ($188,405 vs $218,584). The incremental net monetary benefit for durvalumab plus tremelimumab versus sorafenib was $72,762 (valuing QALYs at $150,000 each). The results of durvalumab plus tremelimumab were better in terms of costs and health outcomes in patients with HBV-related HCC and high alpha-fetoprotein levels. Conclusion: First-line durvalumab plus tremelimumab was estimated to be dominant for the treatment of unresectable HCC compared with sorafenib from a US payer's perspective. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death all over the world, and brings a heavy social economic burden especially in China. Several immuno‐combination therapies have shown promising efficacy in the first‐line treatment of unresectable HCC and are widely used in clinical practice. Nevertheless, which combination is the most affordable one is unknown. Our study assessed the cost‐effectiveness of the immuno‐combinations as first‐line treatment for patients with unresectable HCC from the perspective of Chinese payers. Methods: A Markov model was built according to five multicenter, phase III, open‐label, randomized trials (Himalaya, IMbrave150, ORIENT‐32, CARES‐310, LEAP‐002) to investigate the cost‐effectiveness of tremelimumab plus durvalumab (STRIDE), atezolizumab plus bevacizumab (A + B), sintilimab plus bevacizumab biosimilar (IBI305) (S + B), camrelizumab plus rivoceranib (C + R), and pembrolizumab plus lenvatinib (P + L). Three disease states were included: progression free survival (PFS), progressive disease (PD) as well as death. Medical costs were searched from West China Hospital, published literatures or the Red Book. Cost‐effectiveness ratios (CERs) and incremental cost‐effectiveness ratios (ICERs) were evaluated to compare costs among different combinations. Sensitivity analyses were performed to assess the robust of the model. Results: The total cost and quality‐adjusted life years (QALYs) of C + R, S + B, P + L, A + B and STRIDE were $12,109.27 and 0.91, $26,961.60 and 1.12, $55,382.53 and 0.83, $70,985.06 and 0.90, $84,589.01 and 0.73, respectively, resulting in the most cost‐effective strategy of C + R with CER of $13,306.89 per QALY followed by S + B with CER of $24,072.86 per QALY. Compared with C + R, the ICER of S + B strategy was $70,725.38 per QALY, which would become the most cost‐effective when the willing‐to‐pay threshold exceeded $73,500/QALY. In the subgroup analysis, with the application of Asia results in Leap‐002 trial, the model results were the same as global data. In the sensitivity analysis, with the variation of parameters, the results were robust. Conclusion: As one of the promising immuno‐combination therapies in the first‐line systemic treatment of HCC, camrelizumab plus rivoceranib demonstrated the potential to be the most cost‐effective strategy, which warranted further studies to best inform the real‐world clinical practices. [ABSTRACT FROM AUTHOR]

Background: The effect of whole-brain radiation therapy (WBRT) plus simultaneous integrated boost (SIB) in brain metastasis from breast cancers has not been demonstrated. Method: In this single-center retrospective study, we reviewed consecutive breast cancer patients who developed brain metastasis and were treated with hypofractionated radiation therapy plus WBRT using intensity-modulated radiation therapy (IMRT)-SIB approaches. We analyzed clinical outcomes, prognostic factors and patterns of treatment failure. Result: A total of 27 patients were eligible for analysis. Four (14.8%) patients achieved clinical complete response and 14 (51.9%) had partial response of brain lesions. The other nine patients were not evaluated for brain tumor response. The median brain progression-free survival was 8.60 (95% CI [6.43–13.33]) months and the median overall survival was 16.8 (95% CI [13.3–27.7]) months. Three patients had in-field failure, five had out-field failure and two had in-field and out-field failure. Conclusion: WBRT plus SIB led to improved tumor control and clinical outcome in breast cancer patients with brain metastasis. [ABSTRACT FROM AUTHOR]

Background: Growing evidence has shown that atopic dermatitis (AD) may decrease lung cancer (LC) risk. However, the causality between the two diseases is inconsistent and controversial. Therefore, we explored the causal relationship between AD and different histological subtypes of LC by using the Mendelian randomization (MR) method. Materials and methods: We conducted the MR study based on summary statistics from the genome‐wide association studies (GWAS) of AD (10,788 cases and 30,047 controls) and LC (29,266 cases and 56,450 controls). Instrumental variables (IVs) were obtained after removing SNPs associated with potential confounders. We employed inverse‐variance weighted (IVW), MR‐Egger, and weighted median methods to pool estimates, and performed a comprehensive sensitivity analysis. Results: The results of the IVW method suggested that AD may decrease the risk of developing lung adenocarcinoma (LUAD) (OR = 0.91, 95% CI: 0.85‐0.97, P = 0.007). Moreover, no causality was identified between AD and overall LC (OR = 0.96, 95% CI: 0.91–1.01, P = 0.101), lung squamous cell carcinoma (LUSC) (OR = 1.04, 95% CI: 0.96–1.036, P = 0.324), and small cell lung carcinoma (SCLC) (OR = 0.95, 95% CI: 0.82–1.10, P = 0.512). A comprehensive sensitivity test showed the robustness of our results. Conclusion: The present study indicates that AD may decrease the risk of LUAD in the European population, which needs additional investigations to identify the potential molecular mechanisms. [ABSTRACT FROM AUTHOR]

It is unclear how telomere-binding protein TPP1 interacts with human telomerase reverse transcriptase (hTERT) and influences cervical cancer development and progression. This study included all eligible 156 cervical cancers diagnosed during 2003–2008 and followed up through 2014, 102 cervical intraepithelial neoplasia (CIN) patients, and 16 participants with normal cervix identified at the same period. Correlation of expression of TPP1 and hTERT in these lesions was assessed using Kappa statistics. TPP1 was knocked down by siRNA in three cervical cancer cell lines. We assessed mRNA expression using quantitative real-time polymerase chain reaction and protein expression using tissue microarray-based immunohistochemical staining. We further analyzed the impact of TPP1 expression on the overall survival of cervical cancer patients by calculating the hazard ratio (HR) with 95% confidence intervals (CIs) using the multivariable-adjusted Cox regression model. Compared to the normal cervix, high TPP1expression was significantly associated with CIN 3 and cervical cancers (P<0.001 for both). Expressions of TPP1 and hTERT were highly correlated in CIN 3 (Kappa statistics = 0.50, P = 0.005), squamous cell carcinoma (Kappa statistics = 0.22, P = 0.011), and adenocarcinoma/adenosquamous carcinoma (Kappa statistics = 0.77, P = 0.001). Mechanistically, knockdown of TPP1 inhibited the expression of hTERT in both mRNA and protein levels. High expression of TPP1 (HR = 2.61, 95% CI 1.23–5.51) and co-high expression of TPP1 and hTERT (HR = 2.38, 95% CI 1.28–4.43) were independently associated with worse survival in cervical cancer patients. TPP1 and hTERT expression was correlated and high expression of TPP1 was associated with high risk of CIN 3 and cervical cancer and could predict a worse survival in cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Head and neck soft-tissue sarcomas are rare but aggressive malignancies. Definitive radiotherapy might be an alternative treatment choice in patients unfit for surgery with preservation of organ function and facial morphology. Whether definitive radiotherapy is comparable with surgery has not been fully demonstrated. In this study, we compared the prognosis of patients with radiotherapy-based treatment and with surgery-based treatment. Methods: From May 2014 to February 2021, patients with locally advanced head and neck soft-tissue sarcoma treated with either definitive radiotherapy-based treatment or radical surgery-based treatment were retrospectively enrolled. Clinical outcomes including tumor response, patients' survival and acute treatment-related toxicities were evaluated. Kaplan–Meier curves with log-rank test were used to compare survival data. Cox regression analysis was used to explore prognostic factors. Results: A total of 24 patients (12 males and 12 females, 3 to 61 years old) were eligible for analysis. The median follow-up time was 49 (range: 6–96) months. In 16 patients receiving definitive radiotherapy-based treatment, 6 reached complete response. The survival curve showed that there was no statistically significant difference in overall survival (OS), distant metastasis-free survival (DMFS), loco-regional relapse-free survival (LRRFS) and progression-free survival (PFS) between the two groups of patients (p = 0.35, p = 0.24, p = 0.48, p = 0.1, respectively). COX regression analysis showed that older age was associated with poor DMFS. There was no significant difference in grade 3–4 toxicities between the two groups. Conclusions: In cases of contradictions to surgery, refusal to surgery or failure to complete resection, chemoradiotherapy might be an alternative treatment option. [ABSTRACT FROM AUTHOR]

Tumour‐associated macrophages (TAMs) are one of the primary sources of PD‐L1 expression in the tumour microenvironment (TME). Ionizing radiation (IR) promotes PD‐L1 expression in tumour cells. However, the effect of IR on macrophage PD‐L1 expression and the underlying mechanisms remain unclear. ATM kinase, as the key kinase for initiating DNA damage repair (DDR) process, is associated with innate immune STING axis activation. Here, we explored the molecular mechanism implicated in macrophage PD‐L1 expression regulated by IR as well as the role of ATM kinase in this process. IR‐regulated PD‐L1 expression in macrophages and associated signalling pathways were explored by in vitro studies using murine and human macrophage cell lines. A colorectal xenograft murine model was employed to demonstrate the impact of targeting ATM and PD‐L1 expression in TAMs following IR on growth of tumour in vivo. IR up‐regulated PD‐L1 expression in macrophages, which was further augmented by ATM kinase inhibition. ATM inhibition increased IR‐induced DNA damage, which activated STING/interferon regulatory factor 3 (IRF3) signalling pathway and up‐regulated type I interferon (IFN‐I) expression in macrophages. IFN‐I bound to the IFN α receptor 1 on macrophages, activated the downstream JAK1 and STAT1/3 signalling and eventually led to PD‐L1 up‐expression. ATM inhibition augmented IR‐induced PD‐L1 expression in macrophages and CD8+ T cell infiltration, and promoted anti‐tumour efficacy in vivo. These results suggested that ATM inhibition promoted IR‐induced PD‐L1 expression through the activation of innate immunity in TAMs, which provided a novel approach to enhance the anti‐tumour efficacy of RT. [ABSTRACT FROM AUTHOR]

Background: N6-methyladenosine (m6A) is the most abundant internal modification pattern in mammals that a plays critical role in tumorigenesis and immune regulations. However, the effect of m6A modification on head and neck squamous cell carcinoma (HNSCC) has not been clearly studied. Methods: We screened m6A regulators that were significantly correlated with tumor immune status indicated by ImmuneScore using The Cancer Genome Atlas (TCGA) dataset and obtained distinct patient clusters based on the expression of these m6A regulators with the R package "CensusClusterPlus." We then performed gene set enrichment analysis (GSEA), CIBERSORT, and single-sample gene set enrichment analysis (ssGSEA) to assess the differences in gene function enrichment and tumor immune microenvironment (TIME) among these clusters. We further conducted differently expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) and constructed a protein–protein interaction (PPI) network to determine hub genes among these clusters. Finally, we used the GSE65858 dataset as an external validation cohort to confirm the immune profiles related to the expression of m6A regulators. Results: Two m6A readers, YTHDF1 and IGF2BP2 , were found to be significantly associated with distinct immune status in HNSCC. Accordingly, patients were divided into two clusters with Cluster 1 showing high expression of YTHDF1 and IGF2BP2 and Cluster 2 showing low expression levels of both genes. Clinicopathologically, patients from Cluster 1 had more advanced T stage and pathological grades than those from Cluster 2. GSEA showed that Cluster 1 was closely related to the RNA modification process and Cluster 2 was significantly correlated with immune regulations. Cluster 2 had a more active TIME characterized by a more relative abundance of CD8+ T cells and CD4+ T cells and higher levels of MHC I and MHC II molecules. We constructed a PPI network composed of 16 hub genes between the two clusters, which participated in the T-cell receptor signaling pathway. These results were externally validated in the GSE65858 dataset. Conclusions: The m6A readers, YTHDF1 and IGF2BP2, were potential immune biomarkers in HNSCC and could be potential treatment targets for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy has become the new standard of care for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC), and PD-L1 is a widely used biomarker for immunotherapeutic response. However, PD-L1 expression in most cancer patients is low, and alternative biomarkers used to screen the population benefiting from immunotherapy are still being explored. Tumor microenvironment (TME), especially tumor immune-infiltrating cells, regulates the body's immunity, affects the tumor growth, and is expected to be a promising biomarker for immunotherapy. Purpose: This article mainly discussed how the immune-infiltrating cell patterns impacted immunity, thereby affecting HNSCC patients' prognosis. Method: The immune-infiltrating cell profile was generated by the CIBERSORT algorithm based on the transcriptomic data of HNSCC. Consensus clustering was used to divide groups with different immune cell infiltration patterns. Differentially expressed genes (DEGs) obtained from the high and low immune cell infiltration (ICI) groups were subjected to Kaplan–Meier and univariate Cox analysis. Significant prognosis-related DEGs were involved in the construction of a prognostic signature using multivariate Cox analysis. Results: In our study, 408 DEGs were obtained from high- and low-ICI groups, and 59 of them were significantly associated with overall survival (OS). Stepwise multivariate Cox analysis developed a 16-gene prognostic signature, which could distinguish favorable and poor prognosis of HNSCC patients. An ROC curve and nomogram verified the sensitivity and accuracy of the prognostic signature. The AUC values for 1 year, 2 years, and 3 years were 0.712, 0.703, and 0.700, respectively. TCGA-HNSCC cohort, GSE65858 cohort, and an independent GSE41613 cohort proved a similar prognostic significance. Notably, the prognostic signature distinguished the expression of promising immune inhibitory receptors (IRs) well and could predict the response to immunotherapy. Conclusion: We established a tumor immune cell infiltration (TICI)-based 16-gene signature, which could distinguish patients with different prognosis and help predict the response to immunotherapy. [ABSTRACT FROM AUTHOR]

Background: The expression of long non‐coding RNA (lncRNA) prostate cancer‐associated ncRNA transcripts 1 (PCAT1) is increased in non‐small cell lung cancer (NSCLC). It stimulates tumour growth and metastasis, but its role in the radioimmune responses remain unknown. We aimed to explore the impacts of PCAT1 on tumorigenesis and radioimmune responses and the underlying molecular mechanisms in NSCLC. Methods: Comprehensive bioinformatics analysis was performed to identify immunosuppressive lncRNAs involved with tumour invasion in NSCLC. The expression levels of PCAT1 were analysed by in situ hybridisation in 55 paired NSCLC tissues and adjacent normal tissues. Both loss‐ and gain‐of‐function assays were performed to examine the effects of PCAT1 and SOX2 on NSCLC cell behaviours in vivo and in vitro. Bioinformatic analyses, chromatin isolation by RNA purification (ChIRP) and dual‐luciferase reporter assays were applied to validate the regulatory effects of PCAT1 on SOX2 expression. Chromatin immunoprecipitation, luciferase and rescue assays were utilised to identify the relationship between SOX2 and the cGAS/stimulator of interferon genes (STING) signalling. Results: PCAT1 was immunosuppressive and related with NSCLC invasion. Increased PCAT1 was negatively correlated with immune cell infiltration in NSCLC. PCAT1 knockdown restrained proliferation, increased apoptosis, and repressed cell metastasis in vivo and in vitro. PCAT1 activated SOX2 that accelerated tumorigenesis and immunosuppression. SOX2 promoted tumour growth through inhibiting cytotoxic T‐cell immunity. Moreover, SOX2 restrained cGAS transcription and hampered downstream type I interferon (IFN)‐induced immune responses. Inhibition of PCAT1/SOX2 in collaboration with radiation further inhibited tumour growth, and initiated the cGAS/STING signalling pathway, which enhanced the immune responses of radiotherapy in NSCLC. Conclusions: PCAT1/SOX2 axis promoted tumorigenesis and immunosuppression through inhibition of cGAS/STING signalling‐mediated T‐cell activation. Inhibition of PCAT1 and SOX2 synergised with radiotherapy to activate the immune response and could serve as potential therapeutic targets. [ABSTRACT FROM AUTHOR]