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2024, 36(5): 455-473.
doi: 10.21147/j.issn.1000-9604.2024.05.01
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Abstract:
Lung cancer is emerging as a common malignancy worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Two-dimensional (2D) in vitro cell line cultures and animal models are currently used to study NSCLC. However, 2D cell cultures fail to replicate the medication response and neoplastic heterogeneity of parental tumors. Animal models are expensive and require lengthy modeling cycles. The generation of in vitro three-dimensional (3D) tissue cultures called organoids, which exhibit multicellular, anatomical, and functional properties of real organs, is now achievable owing to advancements in stem cell culturing. The genetic, proteomic, morphological, and pharmacological characteristics of tumors are largely preserved in tumor organoids grown in vitro. The design and physiology of human organs can be precisely reconstructed in tumor organoids, opening new possibilities for complementing the use of animal models and studying human diseases. This review summarizes the development of NSCLC organoids and their applications in basic research, drug testing, immunotherapy, and individualized treatments.
Lung cancer is emerging as a common malignancy worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Two-dimensional (2D) in vitro cell line cultures and animal models are currently used to study NSCLC. However, 2D cell cultures fail to replicate the medication response and neoplastic heterogeneity of parental tumors. Animal models are expensive and require lengthy modeling cycles. The generation of in vitro three-dimensional (3D) tissue cultures called organoids, which exhibit multicellular, anatomical, and functional properties of real organs, is now achievable owing to advancements in stem cell culturing. The genetic, proteomic, morphological, and pharmacological characteristics of tumors are largely preserved in tumor organoids grown in vitro. The design and physiology of human organs can be precisely reconstructed in tumor organoids, opening new possibilities for complementing the use of animal models and studying human diseases. This review summarizes the development of NSCLC organoids and their applications in basic research, drug testing, immunotherapy, and individualized treatments.
2024, 36(5): 474-488.
doi: 10.21147/j.issn.1000-9604.2024.05.02
Abstract:
Biliary tract cancer (BTC) is a group of rare malignancies that affect the gallbladder and bile ducts. Although rare, BTC is becoming a significant public health burden in China, particularly among males and older individuals. The increasing trends in BTC incidence and mortality in China are influenced by various demographic, environmental, and lifestyle factors. In this review, we examine available epidemiological data on the incidence, mortality, prognosis, and trends of different BTC subtypes in China. We also discuss the challenges and opportunities for improving the prevention, diagnosis, and management of BTC in China, and identify areas for further research and intervention. The article aims to provide a better understanding of the epidemiological features of BTC in China and to inform public health strategies and clinical practice.
Biliary tract cancer (BTC) is a group of rare malignancies that affect the gallbladder and bile ducts. Although rare, BTC is becoming a significant public health burden in China, particularly among males and older individuals. The increasing trends in BTC incidence and mortality in China are influenced by various demographic, environmental, and lifestyle factors. In this review, we examine available epidemiological data on the incidence, mortality, prognosis, and trends of different BTC subtypes in China. We also discuss the challenges and opportunities for improving the prevention, diagnosis, and management of BTC in China, and identify areas for further research and intervention. The article aims to provide a better understanding of the epidemiological features of BTC in China and to inform public health strategies and clinical practice.
2024, 36(5): 489-502.
doi: 10.21147/j.issn.1000-9604.2024.05.03
Abstract:
ObjectiveMedical images have been increased rapidly in digital medicine era, presenting an opportunity for the intervention of artificial intelligence (AI). In order to explore the value of convolutional neural network (CNN) algorithms in endoscopic images, we developed an AI-assisted comprehensive analysis system for endoscopic images and explored its performance in clinical real scenarios. MethodsA total of 6,270 white light endoscopic images from 516 cases were used to train 14 different CNN models. The images were divided into training set, validation set and test set according to 7:1:2 for exploring the possibility of discrimination of gastric cancer (GC) and benign lesions (nGC), gastric ulcer (GU) and ulcerated cancer (UCa), early gastric cancer (EGC) and nGC, infection of Helicobacter pylori (Hp) and no infection of Hp (noHp), as well as metastasis and no-metastasis at perigastric lymph nodes. ResultsAmong the 14 CNN models, EfficientNetB7 revealed the best performance on two-category of GC and nGC [accuracy: 96.40% and area under the curve (AUC)=0.9959], GU and UCa (accuracy: 90.84% and AUC=0.8155), EGC and nGC (accuracy: 97.88% and AUC=0.9943), and Hp and noHp (accuracy: 83.33% and AUC=0.9096). Whereas, InceptionV3 model showed better performance on predicting metastasis and no-metastasis of perigastric lymph nodes for EGC (accuracy: 79.44% and AUC=0.7181). In addition, the integrated analysis of endoscopic images and gross images of gastrectomy specimens was performed on 95 cases by EfficientNetB7 and RFB-SSD object detection model, resulting in 100% of predictive accuracy in EGC. ConclusionsTaken together, this study integrated image sources from endoscopic examination and gastrectomy of gastric tumors and incorporated the advantages of different CNN models. The AI-assisted diagnostic system will play an important role in the therapeutic decision-making of EGC.
2024, 36(5): 503-516.
doi: 10.21147/j.issn.1000-9604.2024.05.04
Abstract:
ObjectiveTo explore the impact of visceral fat area (VFA) on the short- and long-term efficacy of indocyanine green (ICG)-guided D2 lymphadenectomy for gastric cancer (GC). MethodsA post hoc analysis was performed in patients who participated in a phase 3 randomized clinical trial of ICG-guided laparoscopic radical gastrectomy vs. conventional laparoscopic radical gastrectomy from November 2018 to July 2019. The VFA was calculated based on preoperative computed tomography images. Short-term efficacy included the quality of lymph node (LN) dissection and surgical outcomes, while long-term efficacy included overall survival (OS) and recurrence-free survival (RFS). ResultsThis study included 126 patients each in the ICG (high-VFA, n=43) and non-ICG groups (high-VFA, n=38). Compared with the non-ICG group, the ICG group had significantly more retrieved LNs (low-VFA: 50.1 vs. 43.9, P=0.001; high-VFA: 49.6 vs. 37.5, P<0.001) and a significantly lower LN noncompliance rate (low-VFA: 32.5% vs. 50.0%, P=0.020; high-VFA: 32.6% vs. 73.7%, P<0.001), regardless of the VFA. The ICG group had a shorter postoperative hospital stay and fewer intra-abdominal infections than the ICG group in the high-VFA patients (P=0.025 and P=0.020, respectively) but not in the low-VFA patients. Regardless of the VFA, the 3-year OS (RFS) was better in the ICG group than in the non-ICG group [low-VFA: 83.1% (76.9%) vs. 73.9% (67.0%); high-VFA: 90.7% (90.7%) vs. 73.7% (73.5%); P for interaction =0.474 (0.547)]. ConclusionsThe short- and long-term efficacies of ICG tracing were not influenced by visceral obesity.
2024, 36(5): 517-529.
doi: 10.21147/j.issn.1000-9604.2024.05.05
Abstract:
ObjectiveHepatocellular carcinoma (HCC) is a prevalent malignancy with poor survival. Different cell types in the tumor microenvironment participate in the tumorigenesis and progression of HCC. This study aimed to analyze the immune microenvironment of HCC and its relationship with clinical outcomes. MethodsWe analyzed HCC RNA-seq for cell type identification and prognosis by estimating relative subsets of RNA transcripts using CIBERSORTx. The interaction between B cells and macrophages in HCC was analyzed using a Hepa1-6 orthotopic transplantation mouse model and flow cytometry. The effect of Zinc finger protein 296 (ZNF296) on the interaction of B cells and macrophages was verified using human HCC tissues analyzed through western blot, quantitative real-time polymerase chain reaction (qPCR), and multiplex immunofluorescence. A comparative analysis of immune cells associated with HCC prognosis was performed using RNA-seq data from The Cancer Genome Atlas (TCGA), bulk multimodal data, and single-cell transcriptomic data from existing HCC single-cell transcriptomic data employing the Single Cell Inferred Site Specific Omics Resource for Tumor Microenvironments (SCISSOR). ResultsLiver hepatocellular carcinoma (LIHC) RNA-seq analysis of TCGA showed that high eosinophil infiltration promoted HCC progression. The proportion of B cells correlated with that of macrophages (r=−0.24) and affected the infiltration and programmed death ligand 1 (PD-L1) expression of macrophages in HCC. ZNF296 may participate in the interaction between B cells and macrophages to accelerate the HCC progression by regulating PAFAH1B3 and H2AFX. Moreover, ZNF296 expression positively correlated with LAG3 (r=0.27) and CTLA4 (r=0.31) expression levels. Among the immune cell phenotypes related to survival and death identified by SCISSOR analysis, T cells correlated with an excellent prognosis of HCC. The normal function of liver and dendritic cells was also associated with a good prognosis in HCC. ConclusionsThis study analyzed the interaction of the immune microenvironment with HCC prognosis, identifying ZNF296 as a promising diagnostic and therapeutic target for HCC.
2024, 36(5): 530-544.
doi: 10.21147/j.issn.1000-9604.2024.05.06
Abstract:
ObjectiveWe aimed to compare the quality-adjusted time without symptoms or toxicity (Q-TWiST) in acute myeloid leukemia (AML) patients who received haploidentical-related donor (HID) and identical sibling donor (ISD) hematopoietic stem cell transplantation (HSCT). MethodsFive clinical health states were defined: toxicity (TOX), acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD), time without symptoms and toxicity (TWiST) and relapse (REL). The equation used in this study was as follows: Q-TWiST=UTOX × TOX + UTWiST × TWiST + UREL × REL + UaGVHD × aGVHD + UcGVHD × cGVHD. ResultsA total of 239 AML patients were enrolled. We established a mathematical model, i.e., Q-TWiST HID HSCT > Q-TWiST ISD HSCT, to explore the range of utility coefficients satisfying the inequality. Based on the raw data, the utility coefficient is equivalent to the following inequality: \begin{document}$ 10.57067{U}_{TOX}-46.27733{U}_{REL}+ $\end{document} \begin{document}$ 105.9374+3.388078{U}_{aGVHD}-210.8198{U}_{cGVHD} > 0 $\end{document} \begin{document}$ {U}_{TOX} $\end{document} \begin{document}$ {U}_{REL} $\end{document} \begin{document}$ {U}_{aGVHD} $\end{document} \begin{document}$ {U}_{cGVHD} $\end{document} \begin{document}$ {U}_{TOX} $\end{document} \begin{document}$ {U}_{REL} $\end{document} \begin{document}$ {U}_{aGVHD} $\end{document} \begin{document}$ {U}_{cGVHD} $\end{document} ConclusionsWe first observed that Q-TWiST was comparable between AML patients receiving HID HSCT and those receiving ISD HSCT.
2024, 36(5): 545-561.
doi: 10.21147/j.issn.1000-9604.2024.05.07
Abstract:
ObjectiveThe assessment of lateral lymph node metastasis (LLNM) in patients with papillary thyroid carcinoma (PTC) holds great significance. This study aims to develop and evaluate a deep learning-based automatic pipeline system (DLAPS) for diagnosing LLNM in PTC using computed tomography (CT). MethodsA total of 1,266 lateral lymph nodes (LLNs) from 519 PTC patients who underwent CT examinations from January 2019 to November 2022 were included and divided into training and validation set, internal test set, pooled external test set, and prospective test set. The DLAPS consists of an auto-segmentation network based on RefineNet model and a classification network based on ensemble model (ResNet, Xception, and DenseNet). The performance of the DLAPS was compared with that of manually segmented DL models, the clinical model, and Node Reporting and Data System (Node-RADS). The improvement of radiologists’ diagnostic performance under the DLAPS-assisted strategy was explored. In addition, bulk RNA-sequencing was conducted based on 12 LLNs to reveal the underlying biological basis of the DLAPS. ResultsThe DLAPS yielded good performance with area under the receiver operating characteristic curve (AUC) of 0.872, 0.910, and 0.822 in the internal, pooled external, and prospective test sets, respectively. The DLAPS significantly outperformed clinical models (AUC 0.731, P<0.001) and Node-RADS (AUC 0.602, P<0.001) in the internal test set. Moreover, the performance of the DLAPS was comparable to that of the manually segmented deep learning (DL) model with AUCs ranging 0.814−0.901 in three test sets. Furthermore, the DLAPS-assisted strategy improved the performance of radiologists and enhanced inter-observer consistency. In clinical situations, the rate of unnecessary LLN dissection decreased from 33.33% to 7.32%. Furthermore, the DLAPS was associated with the cell-cell conjunction in the microenvironment. ConclusionsUsing CT images from PTC patients, the DLAPS could effectively segment and classify LLNs non-invasively, and this system had a good generalization ability and clinical applicability.
2024, 36(5): 562-576.
doi: 10.21147/j.issn.1000-9604.2024.05.08
Abstract:
ObjectiveGenome-wide association studies (GWAS) have identified over 150 risk loci linked to colorectal cancer (CRC), including the 17p13.3 locus with the tag single nucleotide polymorphism (SNP) rs12603526 in the Asian population. However, the specific causal gene and the functional regulatory mechanisms in this region remain unresolved, necessitating further investigation to elucidate the underlying mechanisms of CRC. MethodsWe employed an RNA interference-based functional approach to identify genes critical for CRC cell proliferation at the GWAS locus 17p13.3. Bioinformatic fine-mapping analysis was conducted to prioritize causal variants. A large-scale study involving 7,013 cases and 7,329 controls from a Chinese population, along with another cohort of 5,158 cases and 20,632 controls from the UK Biobank, was performed to validate the association between the candidate variant and the gene. A series of biological experiments was conducted to explore the function of the candidate gene and its regulatory mechanisms. ResultsWe identified FAM57A as a key oncogene that promotes CRC cell proliferation, and confirmed its carcinogenic role through in vitro proliferation assays. The variant rs526835 was prioritized as a causal candidate for CRC risk, located in a functional region with enhancer properties, and showed a significant quantitative association with FAM57A expression. The rs526835 [T] variant was associated with a 1.17-fold increase in CRC risk [95% confidence interval (95% CI): 1.11−1.23, P=1.23×10−9] in the large-scale Chinese cohort, which was further corroborated in the UK Biobank cohort. Mechanistically, we demonstrated that rs526835 enhances a promoter-enhancer interaction mediated by the transcription factor JUN, leading to increased expression of FAM57A. ConclusionsWe reveal the underlying mechanisms of CRC predisposition at the GWAS locus 17p13.3. Additionally, our findings highlight the critical role of FAM57A in CRC pathogenesis and introduce a novel enhancer-promoter interaction between FAM57A and rs526835, which could inform future precision prevention and personalized cancer therapies.
2024, 36(5): 577-586.
doi: 10.21147/j.issn.1000-9604.2024.05.09
Abstract:
ObjectiveSeveral studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracil-based or capecitabine-based chemoradiotherapy (CRT) regimens as significantly increasing the toxic response without benefit to survival. In this study, we further explored the role of these two postoperative CRT regimens in patients with pathological stage N2 rectal cancer. MethodsThis study was a subgroup analysis of a randomized clinical trial. A total of 180 patients with pathological stage N2 rectal cancer were eligible, 85 received capecitabine with radiotherapy (RT), and 95 received capecitabine and oxaliplatin with RT. Patients in both groups received adjuvant chemotherapy [capecitabine and oxaliplatin (XELOX); or fluorouracil, leucovorin, and oxaliplatin (FOLFOX)] after CRT. ResultsAt a median follow-up of 59.2 [interquartile range (IQR), 34.0−96.8] months, the three-year disease- free survival (DFS) was 53.3% and 64.9% in the control group and the experimental group, respectively [hazard ratio (HR), 0.63; 95% confidence interval (95% CI), 0.41−0.98; P=0.04]. There was no significant difference between the groups in overall survival (OS) (HR, 0.62; 95% CI, 0.37−1.05; P=0.07), the incidence of locoregional recurrence (HR, 0.62; 95% CI, 0.24−1.64; P=0.33), the incidence of distant metastasis (HR, 0.67; 95% CI, 0.42−1.06; P=0.09) and grade 3−4 acute toxicities (P=0.78). For patients with survival longer than 3 years, the conditional overall survival (COS) was significantly better in the experimental group (HR, 0.39; 95% CI, 0.16−0.96; P=0.03). ConclusionsOur results indicated that adding oxaliplatin to capecitabine-based postoperative CRT is safe and effective in patients with pathological stage N2 rectal cancer.
