Hypoxia-responsive lncRNA G077640 promotes ESCC tumorigenesis via the H2AX-HIF1α-glycolysis axis.

Long noncoding RNAs (lncRNAs) contribute to esophageal squamous cell carcinoma (ESCC) progression, but the underlying mechanisms remain elusive. In this study, we verified a hitherto uncharacterized hypoxia-responsive lncRNA, G077640, which is upregulated in human ESCC cells and tissues, supporting the proliferation and migration of ESCC cells. Mechanistically, G077640 prevented hypoxia-inducible factor-1α (HIF1α) from being degraded by directly interacting with histone H2AX and further modulated the interaction of HIF1α and H2AX. In addition, G077640 reprogrammed glycolytic metabolism by regulating the expression of glucose transporter 4 (GLUT4), hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1) for ESCC proliferation and migration. Clinically, G077640 was associated with poor prognosis in ESCC patients. Taken together, our findings identified a hypoxia-responsive lncRNA that contributes to ESCC cells proliferation and migration, and targeting G077640 and its pathway might be a potential therapeutic strategy for ESCC.

Meta-analysis comparing the perioperative efficacy of single-port versus two and multi-port video-assisted thoracoscopic surgical anatomical lung resection for lung cancer.

BACKGROUND: As a new surgical procedure for non-small cell lung cancer, single-port video-assisted thoracoscopic surgery (VATS) has lately gained popularity; nevertheless, it is unknown if single-port VATS offers any advantages over multi-portal. The study aims to assess the different impacts of using single-port VATS versus 2-port or multi-port VATS such as operation and drainage time, blood loss volume, number of resected lymph nodes, and hospital stay in lung cancer patients. METHODS: Inclusion criteria included studies from different languages that compare single-port against 2 or multi-port VATS. The outcomes of these studies were analyzed using a random-effect model and it was used to calculate the mean difference with 95 percent confidence intervals to quantify the impact of different surgical techniques on clinical parameters. RESULTS: Single or Uni-portal video-assisted thoracoscopic surgery results in significantly lower drainage time after surgery compared with 2-port (P = .03) and multi-port (P < .001) VATS. In contrast to the resection of lymph nodes, there was no significant difference between uni-port and 2-port (P = .49) or multiport (P = .29) VATS. While operation time, blood loss, complications, and hospital stay were significantly lower in uni-port compared with multi-port VATS (P = .04, P = .002, P < .001, respectively), but not with 2-port VATS (P = .44, 0.06, P = .13). There were no significant differences between uni-port and multi-port VATS regarding conversion rate, mortality, and staging. CONCLUSION: Single or Uni-portal video-assisted thoracoscopic surgery has high efficacy and lower side effects compared with multi-port regarding the perioperative outcomes. Two-port VATS has similar results with uni-port in several parameters.

Comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG Uptake in Esophageal Cancer.

Purpose: Accurate clinical staging is crucial to managing esophageal cancer. [68Ga]Ga-DOTA-FAPI-04 exhibits good diagnostic performance in various tumors, showing a promising alternative to [18F]FDG. Here, we investigated the diagnostic performance of [68Ga]Ga-DOTA-FAPI-04 PET/CT and [18F]FDG PET/CT in the diagnosis of primary and metastatic lesions of esophageal cancer. Methods: Patients with esophageal cancer who underwent concurrent [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT between January 2020 and June 2021 were retrospectively analyzed. [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT uptakes were compared by using the paired samples t test. The McNemar test was used to compare the diagnostic performance between the two techniques. Results: Thirty-five patients (ranging from 44-83 years old with a median age of 63.5 years) were evaluated in our study. In treatment-naive patients (n=25), [68Ga]Ga-DOTA-FAPI-04 PET could detect all esophageal cancers, whereas 1 patient with superficial esophageal cancer was negative in FDG but positive in [68Ga]Ga-DOTA-FAPI-04 (T1). [68Ga]Ga-DOTA-FAPI-04 uptake was higher than [18F]FDG in primary lesions (13.8 ± 6.9 vs 10.9 ± 6.8, respectively, P=0.004), involved lymph nodes (9.3 ± 5.2 vs 6.4 ± 5.9, respectively, P=0.002), and bone and visceral metastases (10.4 ± 6.0 vs 6.1 ± 7.5, respectively, P=0.001). In addition, [68Ga]Ga-DOTA-FAPI-04 PET/CT has a higher detection sensitivity than [18F]FDG PET/CT for primary tumors [100% (25/25) vs. 96.0% (24/25), respectively], lymph nodes [95.0% (57/60) vs 75.0% (45/60), P<0.001], and bone and visceral metastases [100% (25/25) vs 72% (18/25), respectively; P= 0.008]. Conclusion: [68Ga]Ga-DOTA-FAPI-04 PET/CT has higher tracer uptake value and is superior to [18F]FDG PET/CT in detecting primary and metastatic lesions in patients with esophageal cancer.

Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial.

Platinum-based chemotherapy is the standard first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). In this phase 3 study (ClinicalTrial.gov: NCT03829969), 514 patients with treatment-naïve advanced ESCC were randomized (1:1) to receive toripalimab or placebo in combination with paclitaxel plus cisplatin (TP) every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS is observed for the toripalimab arm over the placebo arm (hazard ratio [HR] = 0.58; 95% CI, 0.46-0.74; p < 0.0001). The prespecified interim analysis of overall survival (OS) also reveals a significant OS improvement for patients treated with toripalimab plus TP over placebo plus TP (HR = 0.58; 95% CI, 0.43-0.78; p = 0.0004). The incidences of grade ≥3 treatment-emergent adverse events are similar between the two arms. Toripalimab plus TP significantly improves PFS and OS in patients with treatment-naïve, advanced ESCC, with a manageable safety profile.

KDM6B promotes ESCC cell proliferation and metastasis by facilitating C/EBPß transcription.

BACKGROUND: As an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression, KDM6B has been implicated in the development and malignant progression in various types of cancers. However, its potential roles in esophageal squamous cell carcinoma (ESCC) have not been explored. METHODS: The expression of KDM6B in human ESCC tissues and cell lines was examined using RT-qPCR, immunohistochemical staining and immunoblotting. The effects of KDM6B on the proliferation and metastasis of ESCC were examined using in vitro and in vivo functional tests. RNA-seq and ChIP-seq assay were used to demonstrate the molecular biological mechanism of KDM6B in ESCC. RESULTS: We show that the expression level of KDM6B increased significantly in patients with lymph node metastasis. Furthermore, we confirmed that KDM6B knockdown reduces proliferation and metastasis of ESCC cells, while KDM6B overexpression has the opposite effects. Mechanistically, KDM6B regulates TNFA_SIGNALING_VIA_NFκB signalling pathways, and H3K27me3 binds to the promoter region of C/EBPß, leading to the promotion of C/EBPß transcription. Besides, we show that GSK-J4, a chemical inhibitor of KDM6B, markedly inhibits proliferation and metastasis of ESCC cells. CONCLUSIONS: The present study demonstrated that KDM6B promotes ESCC progression by increasing the transcriptional activity of C/EBPß depending on its H3K27 demethylase activity.

A novel immune-related gene signature predicts survival in esophageal squamous cell carcinoma.

BACKGROUND: Immune-related genes (IRGs) are highly relevant to the progression and prognosis of esophageal squamous cell carcinoma (ESCC). A prognostic signature could be reliable in stratifying ESCC patients according to the risk score, which may help manage systematic treatments. In this study, a systematic and reliable immune signature was developed to estimate the prognostic stratification in ESCC. METHODS: Ribonucleic acid (RNA) expression data of 79 ESCC samples from the Cancer Genome Atlas (TCGA) database and 269 normal esophageal mucosal samples from the Genotype-Tissue Expression (GTEx) project database were downloaded from the University of California, Santa Cruz (UCSC) website to form a TCGA-GTEx dataset. First, we screened differentially expressed genes (DEGs) and then filtered IRGs based on the Immunology Database and Analysis Portal (ImmPort) database to obtain immune-related DEGs (IRDEGs). Next, a novel prognostic signature based on IRDEGs was developed using multivariable Cox analysis. Immune infiltration status was evaluated via single-sample gene set enrichment analysis (ssGSEA). ESCC tissues were grouped into three clusters in terms of immune infiltration (Immunity-L, Immunity-M, and Immunity-H) by applying an unsupervised hierarchical clustering algorithm. Finally, the samples were divided into high- and low-risk groups using the median of the risk score scores for GSEA pathway enrichment analysis in the three clusters. RESULTS: The prognostic signature based on IRDEGs (FCER1G, ISG20, and EGFR) performed moderately in prognostic predictions, with a concordance index (C-index) value of 0.73 [95% (confidence interval) CI: 0.63-0.84, P=2.02E-05] and an area under the curve (AUC) value of 0.817. The xenobiotic metabolism pathway was significantly enriched and up-regulated both in the high-risk group of the immunity-M and immunity-H clusters. CONCLUSIONS: The novel immune-related prognostic signature we constructed has a good prognostic, predictive ability and can be used as an independent prognostic indicator. Our study provides clinicians with a quantitative tool to predict the probability of individual survival time and helps clinicians select targets for immunotherapies and individualized treatment strategies for ESCC patients.

Identification of RHEX as a novel biomarker related to progression and immunity of non-small cell lung carcinoma.

BACKGROUND: The therapeutic response and prognosis of patients with non-small cell lung carcinoma (NSCLC) are widely related to immunity. To improve the prognosis of patients and provide reliable information to guide appropriate personalized treatment strategies, it is necessary to identify reliable prognostic or predictive indicators closely related to tumor phenotype and immune traits in NSCLC. METHODS: Based on The Cancer Genome Atlas (TCGA)-NSCLC mRNA expression profile data, a novel approach combining differential gene expression analysis, single-sample gene set enrichment analysis (ssGSEA), and weighted gene co-expression network analysis (WGCNA) was used to screen hub genes. Subsequently, the regulator of hemoglobinization and erythroid cell expansion (RHEX) was identified as a key gene using the log-rank test and confirmed in the ArrayExpress database. The relationship between RHEX and clinicopathological parameters was analyzed using the Wilcoxon rank-sum test. More importantly, through gene set enrichment analysis (GSEA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithms, and with reference to the Tumor IMmune Estimation Resource (TIMER) database, we explored the relevant pathways of RHEX and its relationship with tumor-infiltrating immune cells (TICs). Finally, we depicted the association between RHEX and immunomodulators in the TCGA and a web portal TISIDB. RESULTS: The RHEX mRNA expression levels in tumor tissues were lower than those in normal tissues and declined with the progression of NSCLC. Meanwhile, RHEX overexpression was associated with high immune infiltration levels and a favorable clinical prognosis. RHEX may participate in tumor microenvironment (TME) regulation through multiple tumor-immune related pathways, especially the JAK-STAT signaling pathway. Furthermore, RHEX expression affected the infiltrating abundance of multiple TICs and positively correlated with most of the immunomodulators in NSCLC. CONCLUSIONS: Our study is the first to propose that RHEX is an immune-related gene with prognostic value in NSCLC and reveals the underlying mechanism between RHEX and tumor-immune system interactions. These results ultimately provide guidance for prognosis and immunotherapy for NSCLC patients.

MiR-654-3p Suppresses Non-Small Cell Lung Cancer Tumourigenesis by Inhibiting PLK4.

PURPOSE: MiR-654-3p plays important roles in many types of malignant tumours. However, the biological function of miR-654-3p in non-small cell lung cancer (NSCLC) remains unknown. In this study, the role of miR-654-3p in NSCLC was investigated. METHODS: qRT-PCR was used to evaluate the level of miR-654-3p in NSCLC tissues and cell lines, while Cell Counting Kit-8, Annexin V/propidium iodide dual staining or TUNEL staining were used to investigate proliferation and apoptosis of NSCLC cells. Luciferase assays and Western blotting were performed to validate potential targets of miR-654-3p. RESULTS: MiR-654-3p levels were significantly decreased in NSCLC patients and cell lines and were significantly correlated with the tumour size and tumour node metastasis stage of NSCLC patients. In A549 cells, miR-654-3p overexpression significantly increased apoptosis and inhibited growth both in vivo and in vitro, while downregulation of miR-654-3p had the opposite effects. In addition, polo-like kinase 4 (PLK4) was shown to be a target gene of miR-654-3p that is negatively regulated by miR-654-3p in A549 cells. Furthermore, PLK4 was observed to be highly expressed in NSCLC tissues and cells, and PLK4 overexpression abolished the inhibitory effects of miR-654-3p overexpression on NSCLC cell proliferation. Finally, the animal experiment results further demonstrated that miR-654-3p inhibits tumour growth and regulates PLK4 expression. CONCLUSION: Our results demonstrate that miR-654-3p functions as a growth-suppressing miRNA by targeting PLK4 in NSCLC.

Cannabis and cannabinoids in cancer pain management.

PURPOSE OF REVIEW: An increasing number of patients are turning to cannabis and cannabinoids for management of their palliative and nonpalliative cancer pain and other cancer-related symptoms. Canadians have a legal framework for access to medical cannabis, which provides a unique perspective in a setting lacking robust clinical evidence. This review seeks to delineate the role of cannabis and cannabinoids in cancer pain management and offers insight into the Canadian practice. RECENT FINDINGS: A cohort study using nabiximols on advanced cancer pain in patients already optimized on opioids, over 3 weeks, demonstrated improved average pain score. A large observational study of cancer patients using cannabis over 6 months demonstrated a decreased number of patients with severe pain and decreased opioid use, whereas the number of patients reporting good quality of life increased. SUMMARY: Good preclinical animal data and a large body of observational evidence point to the potential efficacy of cannabinoids for cancer pain management. However, there are relatively weak data pointing to clinical efficacy from clinical trial data to date. In Canada, the burgeoning cannabis industry has driven the population to embrace a medicine before clinical evidence. There remains a need for high-quality randomized controlled trials to properly assess the effectiveness and safety of medical cannabis, compared with placebo and standard treatments for cancer-related symptoms.

Mobile phone app Vs bucket test as a subjective visual vertical test: a validation study.

BACKGROUND: The SVV tests the ability of a person to perceive the gravitational vertical. A tilt in SVV indicates vestibular imbalance in the roll plane, and thus injuries to the utricle or its connecting nerves. A validated bedside method (et, al., 2009, 72(19):1689-1692, Neurol, Zwergal) is the bucket method, in which the subject estimates the true vertical by attempting to properly align a straight line visible on the bottom of a bucket that is rotated at random by the examiner. In our study, the subjects need to align the plumb line on the Visual Vertical iOS app to the vertical direction. METHODS: Measurements of the SVV were made in 22 healthy subjects (16 females and 6 males). Each subject conducted 10 iterations of bucket test and 10 iterations of iOS app test. The reliability and validity of the iOS app was analyzed by SPSS21. RESULTS: Cronbach's α for the plumb line method was 0.976, and the iOS app was 0.978. Statistical comparison of SVV values measured by the iOS app and the bucket method showed no significant difference in distribution (Mann Whitney U test U = 0.944). CONCLUSION: The Visual Vertical iOS app is an effective and accessible substitute to the plumb line for the measurement of the validated bucket test.

CLDN1 induces autophagy to promote proliferation and metastasis of esophageal squamous carcinoma through AMPK/STAT1/ULK1 signaling.

Tight junction is a structural constitution in cell-cell adhesion and play an important role in the maintenance of permeability and integrity of normal epithelial cell barrier. The protein encoded by Claudin 1 (CLDN1), a member of the claudin family, is an integral membrane protein and a component of tight junction strands. CLDN1 has been proved to regulate the proliferation and metastasis of multiple tumors, but little is known about its role in esophageal squamous cell carcinoma (ESCC). Here, we found that CLDN1 was aberrantly increased in ESCC tissues and cell lines, and mainly distributed in the nucleus of tumor cells. Furthermore, we confirmed that CLDN1 promoted the proliferation and metastasis of ESCC by triggering autophagy both in vitro and in vivo. Mechanically, we validated that CLDN1-induced autophagy via increasing Unc-51 like autophagy activating kinase 1 (ULK1) expression through AMP-activated protein kinase (AMPK)/signal transducer and activator of transcription 1 (STAT1) signaling pathway in ESCC cells. Taken together, our findings demonstrated that aberrant expression and distribution of CLDN1 promoted the proliferation and metastasis of esophageal squamous carcinoma by triggering autophagy through AMPK/STAT1/ULK1 signaling pathway.

Diphenhydramine Use Disorder and Complicated Withdrawal in a Palliative Care Patient.

Diphenhydramine (DPH) is an over-the-counter antihistamine medication commonly used for symptom management in palliative care. Despite the ease of access and perceived safety of DPH, there is documented evidence of potential for abuse of this medication. We present a case of a 61-year-old man with metastatic carcinoma of the distal esophagus, who was initially admitted with a pain crisis but subsequently developed a severe DPH withdrawal syndrome consisting of hyperactive delirium, autonomic dysfunction, and increased muscle tone. With careful selection of the antipsychotic agent loxapine, additional symptom management medications and scheduled tapering the patient was able to be discharged home for end-of-life care. We highlight the challenges of recognizing and managing a withdrawal syndrome in patients with terminal illnesses at end of life.

IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma.

BACKGROUND: Recurrence and metastasis are the leading causes of tumour-related death in patients with oesophageal squamous cell carcinoma (ESCC). Tumour-infiltrating natural killer cells (NK cells) display powerful cytotoxicity to tumour cells and play a pivotal role in tumour therapy. However, the phenotype and functional regulation of NK cells in oesophageal squamous cell carcinoma (ESCC) remains largely unknown. METHODS: Single cell suspensions from blood and tissue samples were isolated by physical dissociation and filtering through a 70 µm cell strainer. Flow cytometry was applied to profile the activity and function of NK cells, and an antibody chip experiment was used to identify and quantitate cytokine levels. We studied IL-6 and IL-8 function in primary oesophageal squamous carcinoma and NK cell co-cultures in vitro and by a xenograft tumour model in vivo. Western blotting was used to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Finally, we performed an IHC array to analyse IL-6/IL-8 (interleukin 6/interleukin 8) expression in 103 pairs of tumours and matched adjacent tissues of patients with ESCC to elucidate the correlation between IL-6 or IL-8 and clinical characteristics. RESULTS: The percentages of NK cells in both peripheral blood and tumour tissues from patients with ESCC were significantly increased in comparison with those in the controls and correlated with the clinical characteristics. Furthermore, the decrease in activating receptors and increase in inhibitory receptors on the surface of tumour-infiltrating NK cells was confirmed by flow cytometry. The level of granzyme B, the effector molecule of tumour-infiltrating NK cells, was also decreased. Mechanistically, primary ESCC cells activated the STAT3 signalling pathway on NK cells through IL-6 and IL-8 secretion, leading to the downregulation of activating receptors (NKp30 and NKG2D) on the surface of NK cells. An ex vivo study showed that blockade of STAT3 attenuated the IL-6/IL-8-mediated impairment of NK cell function. Moreover, the expression of IL-6 or IL-8 in tumour tissues was validated by immunohistochemistry to be positively correlated with tumour progression and poor survival, respectively. CONCLUSIONS: Tumour cell-secreted IL-6 and IL-8 impair the activity and function of NK cells via STAT3 signalling and contribute to oesophageal squamous cell carcinoma malignancy.