The rapid evolution of treatment for advanced lung cancer is a story of how scientists have struggled to move from nonselective cytotoxic chemotherapy to personalized precision medicine. In this ...century, extraordinary advances have been made in the management of advanced and metastatic non-small cell lung cancer, especially in the development of small molecules targeting specific tyrosine kinase receptors and immune checkpoint inhibitors. These developments have led to a significant improvement in survival for lung cancer patients with metastatic disease. Now, the core guidelines to treat non-small cell lung cancer are based on the identification of targetable driver mutations and immune checkpoints. Continued investigations of newly identified druggable genetic alterations, explorations of biomarkers of immune checkpoint inhibitors, development of next-generation immunotherapy, and optimization of combination therapy are necessary to provide better treatment outcomes for lung cancer patients in the future.
Pedestrian trajectory prediction in dynamic scenes remains a challenging and critical problem in numerous applications, such as self-driving cars and socially aware robots. Challenges concentrate on ...capturing pedestrians' motion patterns and social interactions, as well as handling the future uncertainties. Recent studies focus on modeling pedestrians' motion patterns with recurrent neural networks, capturing social interactions with pooling- or graph-based methods, and handling future uncertainties by using the random Gaussian noise as the latent variable. However, they do not integrate specific obstacle avoidance experiences (OAEs) that may improve prediction performance. For example, pedestrians' future trajectories are always influenced by others in front. Here, we propose the Graph-based Trajectory Predictor with Pseudo-Oracle (GTPPO), an encoder-decoder-based method conditioned on pedestrians' future behaviors. Pedestrians' motion patterns are encoded with a long short-term memory unit, which introduces temporal attention to highlight specific time steps. Their interactions are captured by a graph-based attention mechanism, which draws OAE into the data-driven learning process of graph attention. Future uncertainties are handled by generating multimodal outputs with an informative latent variable. Such a variable is generated by a novel pseudo-oracle predictor, which minimizes the knowledge gap between historical and ground-truth trajectories. Finally, the GTPPO is evaluated on ETH, UCY, and Stanford Drone datasets, and the results demonstrate state-of-the-art performance. Besides, the qualitative evaluations show successful cases of handling sudden motion changes in the future. Such findings indicate that GTPPO can peek into the future.
Angiopoietin‐like protein 1 (ANGPTL1) has been shown to act as a tumor suppressor by inhibiting angiogenesis, cancer invasion, and metastasis. However, little is known about the effects of ANGPTL1 on ...sorafenib resistance and cancer stem cell properties in hepatocellular carcinoma (HCC) and the mechanism underlying these effects. Here, we show that ANGPTL1 expression positively correlates with sorafenib sensitivity in HCC cells and human HCC tissues. ANGPTL1 significantly decreases epithelial‐mesenchymal transition (EMT)‐driven sorafenib resistance, cancer stemness, and tumor growth of HCC cells by repressing Slug expression. ANGPTL1 directly interacts with and inactivates MET receptor, which contributes to Slug suppression through inhibition of the extracellular receptor kinase/protein kinase B (ERK/AKT)‐dependent early growth response protein 1 (Egr‐1) pathway. ANGPTL1 expression inversely correlates with Slug expression, poor sorafenib responsiveness, and poor clinical outcomes in HCC patients. Conclusion: ANGPTL1 inhibits sorafenib resistance and cancer stemness in HCC cells by repressing EMT through inhibition of the MET receptor−AKT/ERK−Egr‐1−Slug signaling cascade. ANGPTL1 may serve as a novel MET receptor inhibitor for advanced HCC therapy. (Hepatology 2016;64:1637‐1651)
Gefitinib, erlotinib and afatinib are approved for first‐line treatment of advanced non‐small cell lung cancer (NSCLC) bearing an activating epidermal growth factor receptor (EGFR) mutation. However, ...the clinical outcomes among the three EGFR tyrosine kinase inhibitors (TKIs) are still controversial. We aimed to evaluate clinical outcomes and secondary EGFR T790M mutation among the three EGFR TKIs. From May 2014 to January 2016, a total of 301 patients received treatment with gefitinib, erlotinib or afatinib, for first‐line treatment of advanced NSCLC with an activating EGFR mutation, based on their clinicians’ choice. The median overall survival (OS) was 37.0 months. Although the baseline characteristics of patients were unequal, progression‐free survival and OS did not differ among the 3 groups. Multivariate analysis found that gefitinib (adjusted odds ratio aOR 3.29, 95% confidence interval CI, 1.15–9.46, p = 0.027), EGFR TKI treatment duration more than 13 months (aOR 3.16, 95% CI, 1.20–8.33, p = 0.020), male (aOR 3.25, 95% CI, 1.10–9.66, p = 0.034), initial liver metastasis (aOR 4.97, 95% CI 1.18–20.96, p = 0.029) and uncommon EGFR mutation (aOR 0.14, 95% CI, 0.02–0.97, compared to EGFR deletion 19, p = 0.047) were independent factors for secondary T790M mutation. In real‐world practice, choosing first line EGFR TKI based on the patients’ clinical characteristics yielded good clinical outcomes. First‐line gefitinib, longer EGFR TKI treatment duration, male, initial liver metastasis and uncommon EGFR mutations may be independent factors for secondary EGFR T790M mutation.
What's new?
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) commonly are used as first‐line therapy for advanced non‐small cell lung cancer (NSCLC). However, the actual extent of their clinical performance, including impacts on secondary EGFR T790M mutation, the most frequent EGFR‐TKI resistance mechanism, remains uncertain. Here, analyses of first‐line EGFR‐TKIs afatinib, erlotinib, gefitinib in advanced EGFR‐mutant NSCLC, with TKIs chosen by clinicians’ discretion, shows median overall survival to be 37 months, which is longer than previously reported. Secondary EGFR T790M mutation was independently associated with multiple factors, including first‐line gefitinib therapy and EGFR TKI use for more than 13 months.
This study combines applied mathematics, visual analysis technology, information science with an approach of Scientometrics to systematically analyze the development status, research distribution and ...future trend of intelligent vehicles research. A total number of 3933 published paper index by SCIE and SSCI from 2000 to 2019 are researched based on Mapping Knowledge Domain (MKD) and Scientometrics approaches. Firstly, this paper analyzes the literature content in the field of intelligent vehicles by including the literature number, literature productive countries, research organization, co-authorship of main research groups and the journals from which the articles are mainly sourced. Then, co-citation analysis is used to obtain five major research directions in the field of intelligent vehicles, which include "system framework", "internet of vehicles", "intersection control algorithms", "influence on traffic flow", and "policies and barriers", respectively. The keyword co-occurrence analysis is applied to identify four dominant clusters: "planning and control system", "autonomous vehicle questionnaire", "sensor and vision", and "connected vehicles". Finally, we divide burst keywords into three phases according to the publication date to show more clearly the change of research focus and direction over time.
Abstract
Carbonic anhydrase IX (CA9) expression level has been considered as a poor prognostic factor in hepatocellular carcinoma (HCC) patients. However, the judging criteria of CA9 level is hard to ...define for potential clinical applications. Unlike CA9 expression level, CA9 polymorphism is poorly documented in HCC. Here, we found that people carry A allele at CA9 rs1048638, a 3′UTR SNP, has higher risk of HCC. rs1048638-CA correlates with advanced stages, larger tumor sizes, more vascular invasion, and shorter survival of HCC patients. A allele at CA9 rs1048638 impairs miR-34a, a tumor suppressor miRNA in HCC, binding to CA9 3′UTR and desensitizes CA9 mRNA to miR-34a-dependent RNA degradation. CA9 expression levels were also correlated with miR-34a levels and rs1048638 genotypes in HCC patients. rs1048638 influences HCC risk and progression through effects on miR-34a-targeted CA9 expression in HCC. In conclusion, genetic variations of the CA9 3′UTR play important roles in regulating CA9 expression and cancer progression, which is a novel determinant and target for HCC metastasis and prognosis.
Intraductal papillary neoplasm of the bile duct (IPNB) is a mass-forming neoplasm in the bile duct considered to be the biliary counterpart of pancreatic intraductal papillary mucinous neoplasm ...(IPMN). By its cell lineage, IPNB can be classified into gastric, intestinal, pancreatobiliary, and oncocytic types. Recently, a group of Japanese and Korean pathologists proposed that IPNB be classified into two types, with type 1, being the histological counterpart of IPMN and type 2, having a more complex histological architecture. We used targeted next-generation sequencing to study the molecular change of 37 IPNBs and identified frequent mutations of KRAS (49%), GNAS (32%), RNF43 (24%), APC (24%), TP53 (24%), and CTNNB1 (11%) in IPNBs. Intestinal-type IPNB was associated with KRAS, GNAS, and RNF43 mutations. Japan-Korea consensus type 1 was associated with KRAS and GNAS mutations. All four IPNBs with CTNNB1 mutations were of pancreatobiliary type and located in the extrahepatic bile duct. A hierarchical analysis identified three distinct groups within IPNB: group 1 was Japan-Korea consensus type 1 tumors with macroscopic mucin, old age, and frequent KRAS, GNAS, and RNF43 mutations. Group 2 was Japan-Korea consensus type 2 with intestinal differentiation and frequent KRAS mutation but rare GNAS mutation, MUC2 expression, and macroscopic mucin. Group 3 was characterized by CTNNB1 mutation, extrahepatic location, lack of expression of intestinal markers, Japan-Korea consensus type 2, and lack of mutations in KRAS, APC, RNF43, and GNAS. Our results indicated that IPNB is a heterogeneous disease and that the activation of Ras-mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and G-protein-coupled receptor (GPCR)-cAMP signaling is the main oncogenic mechanism of IPNB.
Identification of the primary site of cancer is essential for the treatment of patients with cancer. Numerous immunohistochemical markers have been developed to determine the differentiation of tumor ...cells and suggest possible primary sites, but markers of gastric and pancreatic adenocarcinomas are still lacking. Claudin-18 is a tight-junction protein uniquely expressed in gastric epithelial cells and has been shown to be expressed in gastric and pancreatic adenocarcinoma. Whether claudin-18 can be used as a marker for identifying the primary site of cancer is still unclear. In this study, we used the immunohistochemical method to stain claudin-18 in tissue arrays containing 575 carcinomas from different anatomic sites and representative sections of 157 metastatic adenocarcinomas. In the group of primary tumors, claudin-18 was frequently expressed in gastric, pancreatic, and pulmonary mucinous adenocarcinomas. Half of cholangiocarcinomas and ovarian mucinous carcinomas and some colorectal and pulmonary adenocarcinomas were also positive for claudin-18. In the metastatic cohort, 15 of 17 (88%) gastric adenocarcinomas, 18 of 23 (78%) pancreatic adenocarcinomas, and 4 of 7 (57%) cholangiocarcinomas and gallbladder adenocarcinomas were positive for claudin-18. Only 4 tumors that originated outside the stomach and pancreatobiliary tract were positive for claudin-18. After normalization to the tumor frequency, the sensitivity of claudin-18 for identifying the stomach and pancreatobiliary tract as primary tumor sites was 79%, and the specificity was 93%. The positive and negative predictive values were 76% and 94%, respectively. In conclusion, claudin-18 represents a sensitive and specific marker for stomach and pancreatobiliary adenocarcinoma that may be a useful diagnostic tool in routine surgical pathology.
Abstract Background Programmed cell death-ligand 1 (PD-L1) is expressed in a subgroup of lung cancer that may benefit from immunotherapy. The interaction between PD-L1 expression and tumour ...infiltrating lymphocytes (TIL) remains poorly understood. This study investigated the expression of PD-L1 in surgically resected stage I pulmonary squamous cell carcinoma (SqCC) and correlated it with TILs in tumour microenvironments, common driver mutations, and clinical outcomes. Materials and methods One hundred and five patients with surgically resected stage I squamous cell carcinoma were examined. Paraffin-embedded tumour sections were stained with PD-L1 antibody. Tumours with moderate-to-strong membrane staining in ≥5% of tumour cells were scored as positive for PD-L1 expression. The driver mutation epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and v-raf murine sarcoma viral oncogene homolog B (BRAF) were examined by direct sequencing, while anaplastic lymphoma kinase (ALK), phosphoinositide 3-kinase catalytic alpha (PI3KCA), and fibroblast growth factor receptor 1 (FGFR1) were analysed by immunohistochemistry. The correlations of PD-L1 expression with each subtype of TIL, driver mutations, clinicopathologic parameters, and clinical outcomes were analysed. Results There was positive PD-L1 expression in 56.2% (59/105) of patients. PD-L1 expression was not associated with the common clinicopathologic features and mutations of EGFR, KRAS, BRAF, ALK, PI3KCA, and FGFR1. As regards TILs composition, tumour PD-L1 expression was significantly associated with increased tumour epithelial CD8+ T cells and stromal CD4+ T cells. Otherwise, PD-L1 (+) tumour cells were negatively correlated with PD-L1 (+) immune cells within tumour stroma. By multivariate analysis, tumour PD-L1 expression and increased CD4+ T cell infiltrations in the tumour stroma were independent predictors of better overall survival and had a trend of better disease-free survival. Conclusions PD-L1 expression is associated with a favourable immune microenvironment in stage I pulmonary SqCC and correlates with better clinical outcome.
Phase 3 studies suggest that induction chemotherapy (ICT) of cisplatin and 5-fluorouracil plus docetaxel (TPF) is effective but toxic for patients with squamous-cell carcinoma of the head and neck ...(SCCHN). Dose-dense chemotherapy may yield favorable outcomes compared with standard-dose chemotherapy, yet the optimal induction regimen remains undefined. We assessed the efficacy and tolerability of biweekly dose-dense TPF ICT in patients with SCCHN.
In this prospective phase II study, We enrolled patients with stage III/IV (AJCC 7th edition) unresectable squamous cell carcinoma of head and neck cancer. Patients received dose-dense TPF (ddTPF) with cisplatin and docetaxel 50 mg/m2 on day 1, leucovorin 250 mg/m2 on day1, followed by 48-h continuous infusion of 2500 mg/m2 of 5-fluorouracil on day 1 and 2, every 2 weeks for 6 cycles followed by radiotherapy. The primary endpoint was the response rate (RR) after ICT.
Fifty-eight patients were enrolled from June 2014 to September 2015. Overall RR after ICT was 89.6% complete response (CR), 31%; partial response (PR), 58.6%. Grade 3/4 neutropenia, mucositis, and diarrhea incidences were 25.9, 1.7, and 1.7%, respectively. 94.8% of patients completed all treatment courses of ICT without dose reduction. The 3-year overall survival (OS) was 54.3% (95%CI: 39.7 to 66.8%) and progression-free survival (PFS) was 34.3% (95%CI: 22.0 to 46.9%). Multivariate analysis showed that CR after ICT is an independent prognostic factor for OS and PFS.
Six cycles of ddTPF is an active, well-tolerated induction regimen for patients with SCCHN. The presence of CR after ICT predicted long-term survival.
ClinicalTrials.gov Identifier: NCT04397341 , May 21, 2020, retrospectively registered.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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