The golden key to open mystery boxes of SMARCA4-deficient undifferentiated thoracic tumor: focusing immunotherapy, tumor microenvironment and epigenetic regulation.

SMARCA4-deficient undifferentiated thoracic tumor is extremely invasive. This tumor with poor prognosis is easily confused with SMARCA4-deficent non-small cell lung cancer or sarcoma. Standard and efficient treatment has not been established. In this review, we summarized the etiology, pathogenesis and diagnosis, reviewed current and proposed innovative strategies for treatment and improving prognosis. Immunotherapy, targeting tumor microenvironment and epigenetic regulator have improved the prognosis of cancer patients. We summarized clinicopathological features and immunotherapy strategies and analyzed the progression-free survival (PFS) and overall survival (OS) of patients with SMARCA4-UT who received immune checkpoint inhibitors (ICIs). In addition, we proposed the feasibility of epigenetic regulation in the treatment of SMARCA4-UT. To our knowledge, this is the first review that aims to explore innovative strategies for targeting tumor microenvironment and epigenetic regulation and identify potential benefit population for immunotherapy to improve the prognosis.

Efficacy and safety of pembrolizumab combined with albumin-bound paclitaxel and nedaplatin for advanced esophageal squamous cell carcinoma.

Objective: This research aimed to assess the efficacy and safety of pembrolizumab (PBL) combined with albumin-bound paclitaxel (ab-Pac) and nedaplatin (NDP) for advanced esophageal squamous cell carcinoma (ESCC). Methods: A total of 47 ESCC patients were administered PBL or NDP on day 1 and ab-Pac on days 1 and 8, every 21 days for one cycle. Tumor and toxicities were evaluated every two cycles and every cycle, respectively. Results: The objective response rate was 68.1% and the disease control rate was 100%. The median follow-up was 16.7 months; median progression-free and overall survival were 12.6 and 19.9 months, respectively. Conclusion: The combination of PBL with ab-Pac and NDP proved to be an effective and safe treatment regimen for advanced ESCC.

Temporal trends and barriers for inpatient palliative care referral in metastatic gynecologic cancer patients receiving specific critical care therapies.

Objective: Existing evidence suggests that palliative care (PC) is highly underutilized in metastatic gynecologic cancer (mGCa). This study aims to explore temporal trends and predictors for inpatient PC referral in mGCa patients who received specific critical care therapies (CCT). Methods: The National Inpatient Sample from 2003 to 2015 was used to identify mGCa patients receiving CCT. Basic characteristics were compared between patients with and without PC. Annual percentage change (APC) was estimated to reflect the temporal trend in the entire cohort and subgroups. Multivariable logistic regression was employed to explore potential predictors of inpatient PC referral. Results: In total, 122,981 mGCa patients were identified, of whom 10,380 received CCT. Among these, 1,208 (11.64%) received inpatient PC. Overall, the rate of PC referral increased from 1.81% in 2003 to 26.30% in 2015 (APC: 29.08%). A higher increase in PC usage was found in white patients (APC: 30.81%), medium-sized hospitals (APC: 31.43%), the Midwest region (APC: 33.84%), and among patients with ovarian cancer (APC: 31.35%). Multivariable analysis suggested that medium bedsize, large bedsize, Midwest region, West region, uterine cancer and cervical cancer were related to increased PC use, while metastatic sites from lymph nodes and genital organs were related to lower PC referral. Conclusion: Further studies are warranted to better illustrate the barriers for PC and finally improve the delivery of optimal end-of-life care for mGCa patients who receive inpatient CCT, especially for those diagnosed with ovarian cancer or admitted to small scale and Northeast hospitals.

ICOSL expressed in triple-negative breast cancer can induce Foxp3+ Treg cell differentiation and reverse p38 pathway activation.

Inducible costimulator ligand (ICOSL) expressed on cancer cells has immunoregulatory functions in various malignancies. However, the role of ICOSL in triple-negative breast cancer (TNBC) remains unclear. In this study, the role and expression of ICOSL in TNBC were analyzed using the cBioPortal and GEPIA databases. Then the role of ICOSL in Foxp3+ Treg cell differentiation, reversal of p38 pathway activation and cell proliferation, migration and apoptosis was determined in vitro. Finally, the effect of ICOSL expression on TNBC progression was verified in a nude mouse model of TNBC. We here observed that ICOSL expression in TNBC was found to be related to relapse-free survival, and Treg abundance was positively correlated with ICOSL expression, as demonstrated by database analyses. In vitro experiments showed that ICOSL overexpression (OE) in MDA-MB-231 cells induced cocultured T cells to differentiate into Foxp3+ Treg cells and promoted secretion of the tumor-promoting factors IL-10 and IL-4. Furthermore, in vitro experiments showed that ICOSL reversed p38 phosphorylation and promoted the proliferation, invasion, and metastasis of MDA-MB-231 ICOSL-OE cells. Finally, tumor progression was found to be promoted by ICOSL expression in a TNBC nude mouse model. Together, ICOSL expression can enhance tumor cell growth by inducing Foxp3+ Treg cell differentiation and reversing p38 pathway activation in TNBC.

Prevalence, trends, and outcomes of atrial fibrillation in hospitalized patients with metastatic cancer: findings from a national sample.

BACKGROUND: Epidemiological evidence regarding the link between cancer and atrial fibrillation (AF) are limited and outcomes of metastatic cancer comorbid with AF need to be elucidated. OBJECTIVE: This study aims to evaluate the prevalence, temporal trends, and outcomes of AF in hospitalized metastatic cancer patients. METHODS: The National Inpatient Sample (NIS) database was used to identify adult patients with metastatic tumors from 2003 to 2014. We analyzed the trends in AF prevalence, in-hospital mortality, total cost, length of stay (LOS), and comorbidities pertaining to metastatic cancer. Multivariable-adjusted models were used to evaluate the association of AF with clinical factors, in-hospital mortality, total cost, and LOS. RESULTS: Among 2,478,598 patients with metastatic cancer, 8.74% (216,737) were diagnosed with AF. The proportion of comorbid AF increased from 8.28% in 2003 to 10.06% in 2014 (p < 0.0001). Older age, white race, male, Medicare, higher income, larger hospital bed size, and urban teaching hospital were associated with higher AF occurrence. Among primary tumor sites, lung cancer experienced the highest odds of AF compared to other cancers. Patients with metastasis to lymph node and respiratory organ had higher odds of AF. In metastatic cancer, AF was associated with higher in-hospital mortality (odds ratio: 1.48; 95% confidence interval: 1.43-1.54), 18% longer LOS, and 19% higher cost. CONCLUSIONS: AF prevalence in metastatic cancer continues to increase from 2003 to 2014. AF is linked to poorer prognosis and higher healthcare resource utilization. As the population ages, optimal preventive and treatment management strategies are needed for metastatic cancer comorbid with AF.

Chimeric antigen receptor-natural killer cells: Novel insight into immunotherapy for solid tumors (Review).

The chimeric antigen receptor (CAR) is an artificially modified fusion protein consisting of an extracellular antigen-binding domain, transmembrane domain and intracellular signalling domain. CAR-T therapy has demonstrated remarkable clinical efficacy in hematological malignancies. However, cytokine release syndrome and other side effects have hindered its application in solid tumors. CAR-natural killer (NK) cells have attracted broad attention due to their safety in clinical applications, their mechanism in recognising cancer cells and the abundance of its clinical specimens. Preclinical and clinical trials of human primary NK cells and NK-92 cell lines demonstrated that CAR-NK cells are able to fight haematological malignancies and solid tumors. However, the implication of CAR-NK cell therapy also has certain challenges, including the expansion and activation of primary NK cells in vitro, selection of CAR targets, survival time of CAR-NK cells in vivo, storage and transportation of NK cells, and efficiency of NK cell transduction. This review focuses on the latest progress of CAR-NK cells in the treatment of solid tumors.

Comprehensive analysis of the regulatory network of differentially expressed mRNAs, lncRNAs and circRNAs in gastric cancer.

Gastric cancer (GC) is one of the most common types of human cancers. However, the mechanisms underlying GC remained largely unclear. To determine whether the differentially expressed mRNAs, lncRNAs and circRNAs in GC, we screened conducted SBC-ceRNA microarray analysis in 3 pairs of GC and normal tissues. Furthermore, differentially expressed mRNAs mediated protein protein interaction (PPI) networks, lncRNAs mediated cis-regulatory network, and circRNA mediated ceRNA network were for the first time constructed to reveal their potential functions and mechanisms in GC. Quantitative real-time polymerase chain reaction analysis (qRT-PCR) was conducted to validate the microarray analysis. A total of 922 mRNAs, 2112 lncRNAs and 2896 circRNAs were observed to be dysregulated in GC samples. Bioinformatics analysis showed these differentially expressed genes (DEGs) were significantly associated with regulating branched - chain amino acid catabolic process, Glycolysis/Gluconeogenesis and ARF protein signal transduction. Moreover, we found the dysregulation of key mRNAs and lncRNAs were associated with the overall survival time in GC patients. We believe this study provides useful information for understanding the mechanism underlying GC progression and exploring potential therapeutic and prognostic targets for GC.

Long-term prognostic significance of interleukin-17-producing T cells in patients with non-small cell lung cancer.

The presence of interleukin (IL)-17-producing T cells has recently been reported in non-small cell lung cancer (NSCLC) patients. However, the long-term prognostic significance of these populations in NSCLC patients remains unknown. In the present study, we collected peripheral blood from 82 NSCLC patients and 22 normal healthy donors (NC). Percentages of IL-17-producing CD4+ T (Th17), CD8+ T (Tc17) and γδT cells (γδT17) were measured to determine their association with clinical outcomes and overall survival (OS) in NSCLC. All NSCLC patients were followed up until July 2018. Median follow-up time was 13.5 months (range 1-87 months). The 3- and 5-year survival rate was 27% and 19.6%, respectively. We found that Th17 cells and γδT17 cells were significantly increased, whereas Tc17 cells were markedly decreased in patients with NSCLC compared with those in NC. In addition, Th17 cells were significantly positively associated with T helper type 1 cells (Th1), whereas γδT17 cells were significantly negatively associated with γδT + interferon (IFN)-γ+ cells. High percentages of peripheral Tc17 cells were significantly associated with favorable 5-year OS (P = .025), especially in patients with early TNM stage (P = .016). Furthermore, high percentages of peripheral Th17 cells were positively associated with favorable 5-year OS in patients with late TNM stage (P = .002). However, no significant association was observed between γδT17 cells and OS, regardless of the TNM stage. In conclusion, our findings suggest that enhanced Th17 and reduced Tc17 cells in the peripheral blood could be a significant predictor of a favorable prognosis for NSCLC patients.

Application of immune checkpoint blockades in treatment of digestive malignant cancers / 中国肿瘤生物治疗杂志

@#消化系统肿瘤是人类常见的恶性肿瘤，其中胃癌、结直肠癌、胰腺癌的发病率和病死率均较高。免疫治疗作为一种新 的治疗方法，正逐步成为多种肿瘤的有效治疗策略之一。CTLA-4和PD-1是通过不同机制负调控T细胞活化的关键免疫检查点 分子。针对这些免疫检查点抑制剂，已经显示出临床疗效，并已获美国FDA批准用于多种实体瘤的治疗。其中，纳武单抗在延长 晚期肝癌患者生存期方面超过了索拉非尼，派姆单抗在PD-L1阳性晚期食管癌有效率可达30%，纳武单抗与伊匹单抗联合治疗 dMMR/MSI-H晚期结直肠癌的客观缓解率达到55%。本文就近年来免疫检查点抑制剂在消化系统肿瘤治疗中的研究进展进行 综述。

Cantharidin represses invasion of pancreatic cancer cells through accelerated degradation of MMP2 mRNA.

Cantharidin is an active constituent of mylabris, a traditional Chinese medicine, and is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in cell cycle control, apoptosis, and cell-fate determination. In the present study, we found that cantharidin repressed the invasive ability of pancreatic cancer cells and downregulated matrix metalloproteinase 2 (MMP2) expression through multiple pathways, including ERK, JNK, PKC, NF-κB, and ß-catenin. Interestingly, transcriptional activity of the MMP2 promoter increased after treatment with PP2A inhibitors, suggesting the involvement of a posttranscriptional mechanism. By using an mRNA stability assay, we found accelerated degradation of MMP2 mRNA after treatment of cantharidin. Microarray analyses revealed that multiple genes involved in the 3' → 5' decay pathway were upregulated, especially genes participating in cytoplasmic deadenylation. The elevation of these genes were further demonstrated to be executed through ERK, JNK, PKC, NF-κB, and ß-catenin pathways. Knockdown of PARN, RHAU, and CNOT7, three critical members involved in cytoplasmic deadenylation, attenuated the downregulation of MMP2. Hence, we present the mechanism of repressed invasion by cantharidin and other PP2A inhibitors through increased degradation of MMP2 mRNA by elevated cytoplasmic deadenylation.

Tamoxifen enhances the anticancer effect of cantharidin and norcantharidin in pancreatic cancer cell lines through inhibition of the protein kinase C signaling pathway.

Cantharidin is an active constituent of mylabris, a traditional Chinese therapeutic agent. Cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A). Cantharidin has been previously reported to efficiently repress the growth of pancreatic cancer cells. However, excessively activated protein kinase C (PKC) has been shown to improve cell survival following the adminstration of cantharidin. Tamoxifen is widely used in the treatment of estrogen receptor-positive breast cancer. In addition, an increasing number of studies have found that tamoxifen selectively inhibits PKC and represses growth in estrogen receptor-negative cancer cells. Administration of a combination of PKC inhibitor and PP2A inhibitors has been demonstrated to exert a synergistic anticancer effect. The proliferation of pancreatic cancer cells was analyzed by 3-(4,5-dimethyltiazol-2-yl]2, 5-diphenyltetrazo-lium bromide assay. The expression levels of ERα and ERß in various pancreatic cancer cell lines were determined by reverse transcription polymerase chain reaction. In addition, the protein levels of PKCα and phosphorylated PKCα in pancreatic cell lines were analyzed by western blot analysis. In the present study, tamoxifen was found to exert a cytotoxic effect against pancreatic cancer cells independent of the hormone receptor status. Tamoxifen repressed the phosphorylation of PKC, and amplified the anticancer effect induced by cantharidin and norcantharidin. The findings reveal a novel potential strategy against pancreatic cancer using co-treatment with tamoxifen plus cantharidin or cantharidin derivatives.