Liver cancer accounts for 6% of all malignancies causing death worldwide, and hepatocellular carcinoma (HCC) is the most common histological type. HCC is a heterogeneous cancer, but how the tumour ...microenvironment (TME) of HCC contributes to the progression of HCC remains unclear. In this study, we investigated the immune microenvironment by multiomics analysis. The tumour immune infiltration characteristics of HCC were determined at the genomic, epigenetic, bulk transcriptome and single-cell levels by data from The Cancer Genome Atlas portal and the Gene Expression Omnibus (GEO). An epigenetic immune-related scoring system (EIRS) was developed to stratify patients with poor prognosis. SPP1, one gene in the EIRS system, was identified as an immune-related predictor of poor survival in HCC patients. Through receptor-ligand pair analysis in single-cell RNA-seq, SPP1 was indicated to mediate the crosstalk between HCC cells and macrophages via SPP1-CD44 and SPP1-PTGER4 association. In vitro experiments further validate SPP1 can trigger the polarization of macrophages to M2-phenotype tumour-associated macrophages (TAMs).
Pancreatic cancer is a devastating disease that is characterized by persistent hypoxia. The roles of hypoxia-inducible factor-2α (hif-2α) are different to those of hif-1α, although both are critical ...for tumor cells to adapt to the hypoxic microenvironment. However, unlike the well-studied hif-1α, the role of hif-2α in tumors, including pancreatic cancer, is poorly understood.
Herein, we used a mutated hif-2α (A530T) to figure out the problem that wild-type hif-2α is quickly degraded which limits the study of its function. Using several cell lines, mouse models, and human tissues, we obtained a general picture of hif-2α in pancreatic cancer progression.
Functional assays revealed that hif-2α promotes epithelial-to-mesenchymal transition, enhances tumor proliferation and invasion, increases stemness, facilitates angiogenesis, and up-regulates aerobic glycolysis. We identified an interaction between hif-2α and β-catenin, and found that hif-2α/β-catenin complex formation increased the activity of β-catenin and the protein stability of hif-2α. In vivo study confirmed the pro-oncogenic role of hif-2α, whose expression correlated with those of E-cadherin, vimentin, Ki-67, and CD31, but not hif-1α. A human tissue study showed that hif-2α was associated with lymph node metastasis, pathological grade, stroma abundance, vascularization and patient survival. High expression of hif-2α was also identified as an independent indicator of poor prognosis in patients with pancreatic cancer.
Our systematic study revealed the roles of hif-2α in pancreatic cancer, and may provide a novel target for this highly malignant disease.
Preoperative chemotherapy has shown benefits for locally advanced and borderline resectable pancreatic cancer. Neoadjuvant chemotherapy (NAC) has also been attempted in resectable pancreatic cancer ...(RPC); however, its role remains controversial. This study aimed to compare the clinical difference between NAC and upfront resection (UR) in RPC.
Electronic databases including PubMed, Embase, Medline, Web of Science, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials were searched for relevant articles from inception to February 2019 that addressed the overall survival in patients with RPC treated with or without NAC to identify eligible studies. Eleven studies were included in the final meta-analysis. The quality assessment of the included studies was based on the Newcastle–Ottawa quality scale. Data of the unresectable rate, R0 resection rate, and positive lymph node rate were also extracted in each study for further analysis. Pooled hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (CIs) were calculated to assess the strength of the association.
A total of eleven studies (eight cohort studies and three randomized controlled trials) involving 9773 patients were included. Ten of the eleven studies followed the “intention-to-treat” principle. NAC was found to be significantly associated with a higher R0 resection rate (P < 0.0001; OR = 2.62, 95% CI 1.70–4.03) and increased negative lymph node rate (P < 0.00001; OR = 0.34, 95% CI 0.31–0.37). However, compared with the UR group, NAC was related to a lower surgical resection rate (P = 0.0004; OR = 2.18, 95% CI 1.41–3.37). Overall, the NAC group exhibited no benefits in terms of overall survival compared with that in the UR group (P = 0.10; HR = 0.86, 95% CI 0.73–1.03). In the subgroup analysis, however, patients who received gemcitabine-based regimen as the NAC strategy had more favorable overall survival than that in the UR group (P = 0.04; HR = 0.75, 95% CI 0.57–0.99).
NAC may be associated with a lower resection rate; however, it is associated with an increased R0 resection rate and lymph node negative rate. Although overall survival was similar in patients with or without NAC, gemcitabine-based NAC might provide longer overall survival. Further large-volume, randomized controlled trials are needed to validate the improved prognosis of patients undergoing NAC.
Matched therapy based on next-generation sequencing is now a part of routine care to guide the treatment of patients with advanced solid tumors. However, whether and to what extent patients can ...benefit from this strategy on a large scale remains uncertain. In the past decade, several clinical studies were performed in this field, among which only one was a randomized trial. We reviewed the literature on this topic and summarize the existing data about the efficacy of this treatment strategy. Currently, the evidence is promising but not solid. Multiple ongoing trials are also summarized. We also discuss the limitations of this treatment strategy and certain unsolved important problems, including how to select the sample and target level, how to interpret the results, and the problem of drug accessibility. All these issues should receive more attention in future clinical trial design and the application of target therapy in cancer treatment.
Hepatitis B virus (HBV) infection is regarded as the main etiological risk factor in the process of hepatocellular carcinoma (HCC), as it promotes an immunosuppressive microenvironment that is ...partially mediated by the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling pathway. The tumor microenvironment (TME) of HBV-related HCC is indeed more immunosuppressive than microenvironments not associated with viruses. And compared to TME in hepatitis C virus (HCV) infected HCC, TME of HBV-related HCC is less vascularized and presents different immune components resulting in similar immunosuppression. However, few studies are focusing on the specific side effects and efficacy of PD-1/PD-L1 blockade immunotherapy in HBV-related HCC patients, as well as on the underlying mechanism. Herein, we reviewed the basic research focusing on potential TME alteration caused by HBV infection, especially in HCC patients. Moreover, we reviewed PD-1/PD-L1 blockade immunotherapy clinical trials to clarify the safety and efficacy of this newly developed treatment in the particular circumstances of HBV infection. We found that patients with HBV-related HCC displayed an acceptable safety profile similar to those of non-infected HCC patients. However, we could not determine the antiviral activity of PD-1/PD-L1 blockade because standard anti-viral therapies were conducted in all of the current clinical trials, which made it difficult to distinguish the potential influence of PD-1/PD-L1 blockade on HBV infection. Generally, the objective response rates (ORRs) of PD-1/PD-L1 blockade immunotherapy did not differ significantly between virus-positive and virus-negative patients, except that disease control rates (DCRs) were obviously lower in HBV-infected HCC patients.
Single-agent immune checkpoint blockade has shown no clinical benefits in pancreatic cancer. Recently, the programmed cell death protein 1 (PD-1) antibody pembrolizumab has been recommended as a ...treatment option for high tumor mutational burden (TMB) solid tumors based on the data from a basket trial. However, no pancreatic cancer patients were enrolled in that trial. Whether pancreatic cancer patients with high TMB respond to PD-1 blockade as well remains unclear. Here, we report a case with a partial response to single-agent immunotherapy with pembrolizumab in pancreatic cancer with high TMB after the failure of several lines of chemotherapy. This result indicates that single-agent immunotherapy may be effective in pancreatic cancer patients with high TMB. In addition, in order to understand the basic immune state of our patients, we also analyzed the changes in immune cells in peripheral blood with cytometry by time-of-flight mass spectrometry (CyTOF) before and after pembrolizumab treatment.
Chimeric antigen receptors-based cell therapies have shown impressive preclinical and clinical success and revolutionized biomedicine. However, the link between science and invention, the impact of ...international cooperation, and the influence and prestige of CARs research have not been explored. This study analyzed the landscape of peer-reviewed articles and patents related to CARs. A total of 5,681 publications were analyzed using bibliometrics and machine learning-based text mining to assess publication metrics, subject areas, and research hotspots. 5,010 Inpadoc families were also analyzed for patent filing trends, priority countries, and applicant and inventor rankings. The results show that CARs research has the following distinctive features: high research prestige among research community; strong global geographical bias in both academic output and patenting patterns; strong links between science and invention, but significant differences among countries; and an inverse relationship between country size and international collaboration rates.
KRAS mutations have been characterized as the major predictive biomarkers for resistance to cetuximab treatment. However, studies indicate that not all KRAS mutations are associated with equivalent ...treatment outcomes. KRAS G13D mutations were observed to account for approximately 16% of all KRAS mutations in advanced colorectal cancer patients, and whether these patients can benefit from cetuximab has not been determined.
An established KRAS G13D mutant colorectal cancer (CRC) patient-derived xenograft (PDX) model was treated with cetuximab. After repeated use of cetuximab, treatment-resistant PDX models were established. Tissue samples were collected before and during treatment, and multiomics data were subsequently sequenced and processed, including whole-exome, mRNA and miRNA data, to explore potential dynamic changes.
Cetuximab treatment initially slowed tumor growth, but resistance developed not long after treatment. WES (whole-exome sequencing) and RNA sequencing found that 145 genes had low P values (< 0.01) when analyzed between the locus genotype and its related gene expression level. Among these genes, SWAP70 was believed to be a probable cause of acquired resistance. JAK2, PRKAA1, FGFR2 and RALBP1, as well as 10 filtered immune-related genes, also exhibited dynamic changes during the treatment.
Cetuximab may be effective in KRAS G13D mutation patients. Dynamic changes in transcription, as determined by WES and RNA sequencing, occurred after repeated drug exposure, and these changes were believed to be the most likely cause of drug resistance.
Following publication of this article the Authors noted mislabelling in Figure 2k. The label ITGA2 had been duplicated and CDH1 had been omitted. The correct version of the figure is included below.
Purpose
The existing medical imaging tools have a detection accuracy of 97% for peritoneal metastasis(PM) bigger than 0.5 cm, but only 29% for that smaller than 0.5 cm, the early detection of PM is ...still a difficult problem. This study is aiming at constructing a deep convolution neural network classifier based on meta-learning to predict PM.
Method
Peritoneal metastases are delineated on enhanced CT. The model is trained based on meta-learning, and features are extracted using multi-modal deep Convolutional Neural Network(CNN) with enhanced CT to classify PM. Besides, we evaluate the performance on the test dataset, and compare it with other PM prediction algorithm.
Results
The training datasets are consisted of 9574 images from 43 patients with PM and 67 patients without PM. The testing datasets are consisted of 1834 images from 21 testing patients. To increase the accuracy of the prediction, we combine the multi-modal inputs of plain scan phase, portal venous phase and arterial phase to build a meta-learning-based multi-modal PM predictor. The classifier shows an accuracy of 87.5% with Area Under Curve(AUC) of 0.877, sensitivity of 73.4%, specificity of 95.2% on the testing datasets. The performance is superior to routine PM classify based on logistic regression (AUC: 0.795), a deep learning method named ResNet3D (AUC: 0.827), and a domain generalization (DG) method named MADDG (AUC: 0.834).
Conclusions
we proposed a novel training strategy based on meta-learning to improve the model’s robustness to “unseen” samples. The experiments shows that our meta-learning-based multi-modal PM predicting classifier obtain more competitive results in synchronous PM prediction compared to existing algorithms and the model’s improvements of generalization ability even with limited data.
PDF
