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BackgroundMinimally invasive techniques have significantly gained popularity for hepatocellular carcinoma (HCC) based on the Milan criteria. However, whether or not laparoscopic liver resection (LLR) or radiofrequency ablation (RFA) is a better treatment option remains debatable. We conducted a meta-analysis to review the published data comparing LLR and RFA for HCC through Milan criteria depending on tumor recurrence risk and survival.MethodsPubMed, OvidSP, Web of Science, and Cochrane Library databases were searched from inception to December 31, 2023. The studies comparing the outcomes and methods between LLR and RFA for HCC within the Milan criteria were included.ResultsWe recruited 19 cohort studies with 2532 patients. The postoperative complication rate was low, and hospital stays were shorter in the RFA group than in the LLR group. The total tumor recurrence, the local tumor recurrence rate, and the intrahepatic tumor recurrence rate were lower within the LLR group than in the RFA group. There was no significant difference in the extrahepatic recurrence rate between the two groups. Moreover, no significant differences were observed between the groups concerning 1-, 3-, and 5-year overall survival (OS) and 1-year recurrence-free survival (RFS). However, 3-year and 5-year RFS were better within the LLR group than among the RFA group.ConclusionsThe treatment of HCC within the Milan criteria is moving toward multidisciplinary and minimally invasive approaches. Our meta-analysis identified a lower postoperative complication rate and higher recurrence rate for RFA than LLR. RFA could be an alternative treatment due to its comparable long-term efficacy with LLR.

BackgroundEmerging evidence suggests a potential link between psychological distress (anxiety and depression) and lung cancer risk, however, it is unclear whether other factors such as tobacco smoking and genetic susceptibility modify the association.MethodsWe included 405,892 UK Biobank participants free of cancer at baseline. Psychological distress was measured using the Patient Health Questionnaire-4 (PHQ-4). A polygenic risk score (PRS) was calculated using 18 lung cancer-associated genetic loci. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsDuring a median follow-up of 7.13 years, 1754 lung cancer cases were documented. The higher score of psychological distress was associated with an increased risk of lung cancer (HRper 1-SD= 1.07, 95% CI: 1.02-1.11) after adjustment for smoking and other confounders. Mediation analysis revealed that 16.8% (95% CI: 13.0%-20.6%) of the distress-lung cancer association was mediated by smoking. Compared with never smokers with no distress, participants with heavy smoking and high distress had the highest risk of lung cancer (HR=18.57, 95% CI: 14.51-23.76). Both multiplicative and additive interactions were observed between smoking and psychological distress in lung cancer. Furthermore, the greatest relative increase in risk was observed among those with high genetic risk and high distress (HR=1.87, 95%CI: 1.50-2.33), and there was a significant additive interaction between the PRS and psychological distress.ConclusionOur results indicate that psychological distress was associated with an elevated risk of incident lung cancer, and such relation was modified by tobacco smoking and genetic susceptibility.

BackgroundLynch syndrome is a genetic disease characterized by abnormal DNA replication caused by germline variation in the mismatch repair (MMR) gene. There are rare non-classical phenotypes with loss of MMR protein expression and inconsistent microsatellite stability (MSS) in Lynch syndrome-related colorectal cancers. However, the difference between microsatellite instability (MSI) of extraintestinal tumors in a patient with Lynch syndrome has been closely studied. Herein, we reported the non-classical phenotypes of mismatch repair deficiency (dMMR) and MSI in four cases of Lynch syndrome in patients with colorectal cancer and other primary and metastatic tumors.MethodsA retrospective analysis was conducted on four patients diagnosed with Lynch syndrome between 2018 and 2022 in the Department of Pathology of the Rocket Forces Specialized Medical Center. A one-step immunohistochemical (IHC) assay was employed to detect loss in the expression of Lynch syndrome-associated MMR proteins (MLH1, PMS2, MSH2, and MSH6). MSI detection was performed in both primary and metastatic tumors at different sites in the four patients using NCI 2B3D (BAT25, BAT26, D2S123, D17S250, and D5S346) and single nucleotide site (BAT25, BAT26, NR21, NR24, NR27, and MONO27) methods. In addition, related MMR gene germline variation, somatic mutations, and MLH1 gene promoter methylation were analyzed using next-generation sequencing and TaqMan probe-based methylation-specific polymerase chain reaction (MethyLight).ResultsTwo of the four patients were heterozygous for MSH6 germline pathogenic variation, and the other two were heterozygous for MSH2 germline pathogenic variation. In all cases, IHC detection of protein expression of the MMR gene with germline variation was negative in all primary and metastatic tumors; non-classical phenotypes of dMMR and MSI were present between primary and metastatic tumors at different sites. dMMR in Lynch colorectal cancer demonstrated high MSI, whereas MSI in primary and metastatic tumors outside the intestine mostly exhibited MSS or low MSI.ConclusionsThe non-classical dMMR and MSI phenotype are mostly observed in Lynch syndrome, even in the context of MMR protein expression loss. Extraintestinal tumors infrequently present with a high degree of MSI and often exhibit a stable or low degree of MSI.

IntroductionOver the past decade, several studies on the microvascular invasion (MVI) of hepatocellular carcinoma (HCC) have been published. However, they have not quantitatively analyzed the remarkable impact of MVI. Therefore, a more comprehensive understanding of the field is now needed. This study aims to analyze the evolution of HCC-MVI research and to systematically evaluate the scientific outputs using bibliometric citation analysis.MethodsA systematic search was conducted on the Web of Science Core Collection on 2 May 2022 to retrieve studies on HCC-MVI published between 2013 and 2022. Then, a bibliometric analysis of the publications was performed using CiteSpace, VOSviewer, and other visualization tools.ResultsA total of 1,208 articles on HCC MVI were identified. Of these, China (n = 518) was the most prolific country, and Fudan University (n = 90) was the most notable institution. Furthermore, we observed that Lau Wan Yee participated in most studies (n = 26), and Frontiers in Oncology (IF2020:6.24) published the highest number of documents (n = 49) on this subject, with 138 publications. The paper “Bray F, 2018, CA-CANCER J CLIN, V68, P394” has the highest number of co-cited references, with 119 citations. In addition, the top three keywords were “survival”, “recurrence”, and “microvascular invasion”. Moreover, the research hot spots and frontiers of HCC-MVI for the last 3 years included imaging characteristics and transarterial chemoembolization (TACE) therapy studies.ConclusionsThis study comprehensively summarized the most significant HCC-MVI documents from past literature and highlighted key contributions made to the advancement of this subject and the advancement of this field over the past decade. The trend of MVI research will gradually shift from risk factors and prognosis studies to imaging characteristics and TACE therapy studies.

Blood vessel passage on CT exerts a vital part in early diagnosis as well as treatment of carcinoma of the lungs. Intratumoral microvascular density (iMVD) has gradually become the focus of research on biological behavior, appearance, and evolution of malignant tumors nowadays. The aim of this paper was to verify whether there is a correlation between the iMVD and the vascular morphology of ground glass nodules (GGNs). A total of 109 patients with pulmonary GGN were classified into three groups (I,II, and III) according to the vascular morphology on CT, and their expression of CD31-, CD34-, and CD105-labeled iMVD was detected by the streptoavidin–biotin method, statistically analyzing the iMVD values of each group. The expression of CD31, CD34, and CD105 in different lung tissues was significantly different, with remarkably higher iMVD in lung cancer tissues than in adjacent normal lung tissues. In the imaging sort of types I, II, and III according to the means of vascular passage, the iMVD expression of CD31, CD34, and CD105 was significantly different between groups. These data suggest that the presence and the abnormal morphology of vessels seen within GGNs indicate the occurrence and progression of lung cancer in pathology. It offers a strong theoretical foundation for early diagnosis of carcinoma of the lungs, thus providing a more precise clinical diagnosis and prognosis of early-stage lung cancer.

ObjectThe prediction of hepatocellular carcinoma (HCC) prognosis faced great challenge due to tumor heterogeneity. The purpose of this study was to explore the correlation between the immune infiltrate and prognosis. Moreover, we aimed to establish a risk prediction model for survival in HCC patients based on clinicopathological and immune indicators.MethodsIn this study, 316 patients with HCC who underwent radical resection in West China Hospital from 2009 to 2014 were included. Clinicopathological data and pathological specimens were collected. H&E staining and immunohistochemical staining were performed on the pathological tissue sections. The evaluation of tumor-infiltrating lymphocyte (TIL) density was based on H&E slices, and the assessment of the expressions of CD8, CD68, Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin domain and mucin domain-3 (TIM-3), Programmed Cell Death Protein 1 (PD-1), Programmed Cell Death Ligand 1 (PD-L1), OX40, CD66b, and Tryptase. was performed on the immunohistochemical slices. A risk prediction model for survival in HCC patients was established by integrating immune-related biomarkers and clinicopathological indicators.ResultsThe Barcelona Clinic Liver Cancer (BCLC) stage; the microvascular invasion status; the density of TILs; the expressing levels of CD66b, OX40, and PD-L1 in the immune cell; CD68; and CD8 were the predictors of patients’ overall survival (OS). The BCLC stage; the density of TILs; and the expressions of OX40, CD68, and CD8 were associated with disease-free survival (DFS). The expressions of CD66b, CD68, OX40, and CD8 had a cumulative effect on prognosis. The area under the curve of the prediction model for OS based on clinicopathological features was improved from 0.62 to 0.74 by adding to CD8, OX40, CD68, CD66b, and TILs, whereas it was improved from 0.59 to 0.73 for the DFS prediction model.ConclusionOur results, if confirmed, indicated that immune-related biomarkers should be taken into account or stratified in survival analysis for HCC.

ObjectivesTo evaluate the short-term outcomes of uniportal video–assisted thoracoscopic surgery (UVATS) and Da Vinci robot–assisted thoracoscopic surgery (RATS) in lobectomy and lymph node (LN) dissection.MethodsThe two groups of patients with primary non-small cell lung cancer (NSCLC; RATS group, UVATS group) were matched by the propensity score to compare LN dissection and recent clinical outcomes. The results were analyzed by univariate analysis. From November 2020 to November 2021, 412 NSCLC patients (54 RATS and 358 UVATS) from a single institution of the Provincial Hospital affiliated with Shandong First Medical University were included in the analysis. Age, sex, lung lobe, surgical resection scope, solid nodules, and core tumor ratios were matched according to different surgical methods.ResultsFrom November 2020 to November 2021, 412 patients with NSCLC (54 RATS, 358 UVATS) from the Provincial Hospital affiliated with Shandong First Medical University were included in the analysis. According to our matching results, LN dissection was more thorough in the RATS group.ConclusionRATS has potential advantages over UVATS in radical lung cancer surgery.

The RE1 Silencing Transcription Factor (REST) is a major regulator of neurogenesis and brain development. Medulloblastoma (MB) is a pediatric brain cancer characterized by a blockade of neuronal specification. REST gene expression is aberrantly elevated in a subset of MBs that are driven by constitutive activation of sonic hedgehog (SHH) signaling in cerebellar granular progenitor cells (CGNPs), the cells of origin of this subgroup of tumors. To understand its transcriptional deregulation in MBs, we first studied control of Rest gene expression during neuronal differentiation of normal mouse CGNPs. Higher Rest expression was observed in proliferating CGNPs compared to differentiating neurons. Interestingly, two Rest isoforms were expressed in CGNPs, of which only one showed a significant reduction in expression during neurogenesis. In proliferating CGNPs, higher MLL4 and KDM7A activities opposed by the repressive polycomb repressive complex 2 (PRC2) and the G9A/G9A-like protein (GLP) complex function allowed Rest homeostasis. During differentiation, reduction in MLL4 enrichment on chromatin, in conjunction with an increase in PRC2/G9A/GLP/KDM7A activities promoted a decline in Rest expression. These findings suggest a lineage-context specific paradoxical role for KDM7A in the regulation of Rest expression in CGNPs. In human SHH-MBs (SHH-α and SHH-β) where elevated REST gene expression is associated with poor prognosis, up- or downregulation of KDM7A caused a significant worsening in patient survival. Our studies are the first to implicate KDM7A in REST regulation and in MB biology.

BackgroundThe spontaneous rupture of hepatocellular carcinoma (HCC) is associated with high mortality rates, and liver resection can provide better outcomes than other available treatments. However, the survival length of patients subjected to hepatectomy after spontaneous rupture of hepatocellular carcinoma remains controversial.MethodArticles reporting the comparison of the survival outcome between patients with rupture HCC (rHCC) and non-rupture HCC (nrHCC) from the inception until December 31, 2021 by PubMed, Web of Science, OVID, and the Cochrane Library databases were included. The high-quality propensity score matching analysis was used to investigate the impact of rupture on disease-free survival (DFS) and overall survival (OS) between the rHCC and nrHCC group with no heterogeneity.ResultA total of 606 patients from six cohort studies were included. The major baseline characteristics of the eligible patients were well balanced between rHCC and nrHCC group. The 1-, 3-, and 5-year hazard ratios of DFS were 3.45 (95% confidence interval [CI] 2.54–4.68), 3.63 (95% CI 2.87–4.60), and 3.72 (95% CI 2.93–4.72), respectively. The 1-, 3-, and 5-year hazard ratios of OS were 5.01 (95% CI 3.26–7.69), 5.49 (95% CI 4.08–7.39), and 4.20 (95% CI 3.20–5.51), respectively.ConclusionThe present meta-analysis demonstrated that the DSF and OS were significantly shorter in the rHCC group than in the nrHCC group, thus revealing that spontaneous HCC rupture was a predictor of poor survival.

BackgroundIt remains undetermined whether neuroticism affects the risk of lung cancer. Therefore, we performed complementary observational and Mendelian randomization (MR) analyses to investigate the association between neuroticism and lung cancer risk.MethodsWe included 364,451 UK Biobank participants free of cancer at baseline. Neuroticism was ascertained using the 12-item of Eysenck Personality Inventory Neuroticism Scale. Multivariable Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Two-sample MR analysis was carried out with summary genetic data from UK Biobank (374,323 individuals) and International Lung Cancer Consortium (29,266 lung cancer cases and 56,450 controls). Furthermore, we calculated a polygenic risk score of lung cancer, and examined the joint-effect and interaction between neuroticism and genetic susceptibility on lung cancer risk.ResultsDuring a median follow-up of 7.13 years, 1573 lung cancer cases were documented. After adjusting for smoking and other confounders, higher neuroticism was associated with an increased risk of lung cancer (HR per 1 SD=1.07, 95% CI: 1.02-1.12). Consistently, MR analysis suggested a causal effect of neuroticism on lung cancer risk (OR IVW=1.10, 95% CI: 1.03-1.17). Compared to individuals with low neuroticism and low PRS, those with both high neuroticism and high PRS had the greatest risk of lung cancer (HR=1.82, 95%CI: 1.51-2.20). Furthermore, there was a positive additive but no multiplicative interaction between neuroticism and genetic risk.ConclusionsOur findings suggest that neuroticism is associated with an elevated risk of incident lung cancer, which is strengthened by the genetic susceptibility to lung cancer. Further studies are necessary to elucidate underlying mechanisms.

Liver cancer is the third most common cause of cancer-related death following lung and stomach cancers. As a highly lethal disease, liver cancer is diagnosed frequently in less developed countries. Natural compounds extracted from herbs, animals and natural materials have been adopted by traditional Chinese medicine (TCM) practices and reported to be effective in the development of new medications for the treatment of diseases. It is important to focus on the mechanisms of action of natural compounds against hepatocellular carcinoma (HCC), particularly in terms of cell cycle regulation, apoptosis induction, autophagy mediation and cell migration and invasion. In this review, we characterize novel representative natural compounds according to their pharmacologic effects based on recently published studies. The aim of this review is to summarize and explore novel therapeutic drug targets of natural compounds, which could accelerate the discovery of new anticancer drugs.

ObjectiveIn this study, we retrieved the data available in the Surveillance, Epidemiology, and End Results database to identify the prognostic factors for patients with pancreatic head cancer who had undergone pancreaticoduodenectomy and developed a prediction model for clinical reference.MethodsWe screened the data between 1973 and 2015. Propensity score matching (PSM) was used to control for the confounding factors. Kaplan-Meier (log-rank test) curves were used to compare the survival rates. A nomogram was established using multifactorial Cox regression.ResultsIn total, 4099 patients were identified. Their median survival was 22 months, with 74.2%, 36.5%, and 26.2% survival after 1, 3, and 5 years, respectively. The median cancer-specific survival was 24.0 months, with 71.1%, 32.6%, and 21.9% survival after 1, 3, and 5 years, respectively. The results of the Cox proportional risk regression showed that age, insurance status, gender, histological type, degree of tissue differentiation, T and N stages, tumor size, extent of regional lymph node dissection, and postoperative radiotherapy or chemotherapy are independent factors affecting prognosis. PSM was used twice to eliminate any bias from the unbalanced covariates in the raw data. After PSM, the patients who had received postoperative radiotherapy were found to have a better survival prognosis and disease-specific survival prognosis than those who had not received radiotherapy [HR = 0.809, 95% CI (0.731–0.894), P < 0.001 and HR = 0.814, 95% CI (0.732–0.904), P < 0.001; respectively]. A similar result was observed for the patients who had received postoperative chemotherapy versus those who had not [HR = 0.703, 95% CI (0.633–0.78), P < 0.001 and HR = 0.736, 95% CI (0.658–0.822), P < 0.001, for survival and disease-specific survival prognoses, respectively]. Finally, the β coefficients of the Cox proportional risk regression were used to establish a nomogram.ConclusionAge, insurance status, gender, histological type, degree of differentiation, T and N stages, tumor size, regional lymph node dissection, and postoperative radiotherapy or chemotherapy are factors affecting the prognosis in pancreatic head cancer after pancreaticoduodenectomy. Postoperative radiotherapy and chemotherapy can improve patient survival. These still need to be further validated in the future.

BackgroundNivolumab and pembrolizumab disrupt the programmed cell death-1 immune checkpoint and display promising efficacy and safety results in advanced hepatocellular carcinoma (HCC). However, the benefits remain limited. The preliminary results of lenvatinib (LEN) combined with immune checkpoint inhibitors (ICIs) reveal that the combinations were well-tolerated and encouraging. This study aimed to analyze the safety and efficacy of LEN plus ICIs in a real-world cohort of patients with advanced HCC.MethodBetween June 4, 2017, and June 30, 2019, 16 patients received LEN plus nivolumab, and 13 patients were treated with LEN plus pembrolizumab, with the confirmed advanced HCC retrospectively analyzed. The clinical parameters, as well as the outcomes, were assessed.ResultsAll the patients had Barcelona Clinical Liver Cancer Stage C. LEN with ICIs was used as systemic second-, third-, and fourth-line treatments in seven (24.1%), 14 (48.3%), and eight (27.6%) patients, respectively. At the time of data cutoff, six patients (37.5%) were still receiving LEN with nivolumab, while another six patients (46.2%) were still receiving LEN with pembrolizumab. An objective response was recorded in seven patients (25.9%), while the best overall responses were from one complete response and six partial responses. The 6- and 12-month over survival (OS) rates were 62.6% and 53.7%, respectively. Furthermore, the 6- and 12-month progression-free survival (PFS) rates were 43.5% and 31.8%, respectively. In the subgroup analyses, the 6- and 12-month OS and PFS rates for patients treated with LEN plus nivolumab were 62.5% and 52.1%, respectively, and 43.8% and 30.0%, respectively. The 6- and 12-month OS and PFS rates for patients treated with LEN plus pembrolizumab were 51.3% and 51.3%, respectively, and 49.2% and 49.2%, respectively. A total of 11 (31%) deaths were reported in this study, four of which were attributed to grade 5 adverse events presented as fatal treatment-related hepatitis.ConclusionThe combination of LEN and ICIs is a promising new strategy for the treatment of HCC patients. However, high-grade hepatic toxicity was observed and further evaluation of this combination is still required.

BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most frequently diagnosed cancers in the world with a high mortality rate. The mechanism about ESCC development and whether miRNAs play a critical role remains unclear and needs carefully elucidated.Materials and MethodsHigh-throughput miRNA sequencing was used to identify the different expression miRNAs between the ESCC tissues and paired adjacent normal tissues. Next, both CCK-8, Transwell and apotosis assay were used to evaluate the role of miRNA in ESCCcells. In addition, we used bioinformatic tools to predict the potential target of the miRNAs and verified by Western Blot. The function of miRNA-target network was further identified in xenograft mice model.ResultsIn ESCC, we identified two miRNAs, miR-17-5p and miR-4443, were significantly upregulated in ESCC tissues than adjacent normal tissues. TIMP2 was proved to be the direct target of both two miRNAs. The miR-17-5p/4443- TIMP2 axis was shown to promote the tumor progression in vitro and in vivo experiments.ConclusionsThis study highlights two oncomiRs, miR-17-5p and miR-4443, and its potential role in ESCC progression by regulating TIMP2 expression, suggesting miR-17-5p and miR-4443 may serve as a novel molecular target for ESCC treatment.

BackgroundCholangiocarcinoma (CCA), including intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCA, is a highly aggressive malignancy originating from bile duct. The prognosis of CCA is very poor, and the biomarker study is unsatisfactory compared with other common cancers.Materials and methodsIn our study, we investigated the expression of dual-specificity phosphatase 11(DUSP11) in eight pairs of iCCAs, pCCAs, and dCCAs, and their corresponding tumor-adjacent tissues, as well as their tumor-adjacent tissues with qPCR. Moreover, we investigated the expression of DUSP11 in 174 cases of CCAs with immunohistochemistry, including 74 iCCAs, 64 pCCAs, and 36 dCCAs. We classified these patients into subsets with low and high expressions of DUSP11, and evaluated the correlations between the DUSP11 subsets and clinicopathological factors. With univariate and multivariate analyses, we assessed the correlation between DUSP11 and the overall survival (OS) rates in these CCA patients.ResultsIn all the CCA subtypes, DUSP11 was elevated in CCAs compared with their paired adjacent tissues. In iCCA, pCCA, and dCCA, the percentages of DUSP11 high expression were 44.59%, 53.85%, and 55.56%, respectively. In iCCA, high DUSP11 expression was significantly associated with an advanced T stage and a poor prognosis. However, the prognostic value of DUSP11 in pCCA and dCCA was not significant. To decrease the statistical error caused by the small sample size of the dCCA cohort, we merged pCCA and dCCA into extracellular CCA (eCCA). In the 101 cases of eCCA, DUSP11 expression was also not significantly associated with the prognosis.ConclusionsDUSP11 expression was associated with tumor infiltration and the OS rate in iCCA, but not in pCCA and dCCA. DUSP11 was an independent biomarker of iCCA indicating a poor prognosis. Our results suggested that a high expression of DUSP11 was a post-operational risk factor, and detecting DUSP11 could guide the individual treatment for patients with CCA.

Long noncoding RNAs (lncRNAs) have recently received growing substantial attention in cancer research due to their important roles in various cancer types. However, the underlying mechanisms and functions of lncRNAs, especially in lung adenocarcinoma (LUAD), remain elusive. Based on pan-cancer screening analyses, we identified that the noncoding RNA LINC00665 was up-regulated in lung adenocarcinoma, which was subsequently confirmed in clinical samples and cell lines. Higher expression of LINC00665 was positively associated with poor prognosis and advanced T stage. Next, using gain- and loss- of function approaches, we revealed that LINC00665 promotes cell proliferation, cell migration, invasion, and suppresses cell apoptosis in LUAD through in vitro and in vivo experiments. Additionally, our findings showed that LINC00665 was predominately localized in the cytoplasm so as to interact with Ago2 protein, which could function as miRNA sponges. The results of bioinformatics prediction and RNA pull-down assay indicated that LINC00665 directly interacted with miR-195-5p. This was also confirmed by fluorescence colocalization. Furthermore, luciferase reporter assay demonstrated that Myc binding protein (MYCBP, also called AMY-1), which enhanced c-Myc transcriptional activity, was the target gene of LINC00665 dependent on miR-195-5p. Finally, rescue functional assay results uncovered that the oncogenic capability of LINC00665 was dependent on miR-195-5p and c-Myc transcriptional activity. In summary, this work elucidates that LINC00665 accelerates LUAD progression via the miR-195-5p/MYCBP axis by acting as a competing endogenous RNA (ceRNA), suggesting that LINC00665 may represent a potential therapeutic target for clinical intervention of LUAD.

BackgroundDespite the implementation of the 8th American Joint Committee on Cancer (AJCC) TNM staging system for gastric cancer (GC) in 2017, it still holds a significant level of stage migration which affects patients’ proper classification and accurate prognosis. Here, to reduce this effect, we evaluated the prognostic value of a lymph node ratio (LNR) and established a novel tumor–ratio–metastasis (TRM) staging system.MethodThe data of 15,206 GC patients from the Sun Yat-sen University Cancer Center (Training set; n=2,032) and the US Surveillance, Epidemiology, and End Results (SEER) database (Validation set; n=13,174) were analyzed. The training set was classified into 5 LNR categories, based on which the novel TRM staging system was constructed. The overall survival (OS) between the TRM and AJCC TNM systems was compared in the training set and validated in the validation set. The likelihood ratio x2, liner trend x2, C-index, and Akaike information criterion (AIC) values were used to measure the discriminatory ability between the two different staging systems. Decision curve analyses (DCAs) were conducted to test the clinical value of the two staging systems.ResultThe patients were classified into the following categories: LNR0: 0%, LNR1: 0%60%. Univariate analyses demonstrated that the log-rank x2 of the LNR stage (Training/Validation set: x2 = 463.1/2880.8) was larger than the AJCC pN stage (Training/Validation set: x2 = 281.5/2240.8). For both the training set and validation set, stratified analyses using the Kaplan-Meier method identified significantly heterogeneous OS in every pN category but only one using the LNR. The TRM staging system had higher likelihood ratio x2, liner trend x2, C-index and smaller AIC values than the TNM system.ConclusionThe TRM staging system demonstrated improved homogeneity and discriminatory ability in predicting the prognosis of GC patients compared with the AJCC TNM staging system.

ObjectivesTo investigate the value of contrast-enhanced computer tomography (CT)-based on radiomics in discriminating high-grade and low-grade hepatocellular carcinoma (HCC) before surgery.MethodsThe retrospective study including 161 consecutive subjects with HCC which was approved by the institutional review board, and the patients were divided into a training group (n = 112) and test group (n = 49) from January 2013 to January 2018. The least absolute shrinkage and selection operator (LASSO) was used to select the most valuable features to build a support vector machine (SVM) model. The performance of the predictive model was evaluated using the area under the curve (AUC), accuracy, sensitivity, and specificity.ResultsThe SVM model showed an acceptable ability to differentiate high-grade from low-grade HCC, with an AUC of 0.904 in the training dataset and 0.937 in the test dataset, accuracy (92.2% versus 95.7%), sensitivity(82.5% versus 88.0%), and specificity (92.7% versus 95.8%), respectively.ConclusionThe machine learning-based radiomics reflects a better evaluating performance in differentiating HCC between low-grade and high-grade, which may contribute to personalized treatment.

Objectives: To evaluate whether incorporating the radiomics, genomics, and clinical features allows prediction of metastasis in colorectal cancer (CRC) and to develop a preoperative nomogram for predicting metastasis.Methods: We retrospectively analyzed radiomics features of computed tomography (CT) images in 134 patients (62 in the primary cohort, 28 in the validation cohort, and 44 in the independent-test cohort) clinicopathologically diagnosed with CRC at Dazhou Central Hospital from February 2018 to October 2019. Tumor tissues were collected from all patients for RNA sequencing, and clinical data were obtained from medical records. A total of 854 radiomics features were extracted from enhanced venous-phase CT of CRC. Least absolute shrinkage and selection operator regression analysis was utilized for data dimension reduction, feature screen, and radiomics signature development. Multivariable logistic regression analysis was performed to build a multiscale predicting model incorporating the radiomics, genomics, and clinical features. The receiver operating characteristic curve, calibration curve, and decision curve were conducted to evaluate the performance of the nomogram.Results: The radiomics signature based on 16 selected radiomics features showed good performance in metastasis assessment in both primary [area under the curve (AUC) = 0.945, 95% confidence interval (CI) 0.892–0.998] and validation cohorts (AUC = 0.754, 95% CI 0.570–0.938). The multiscale nomogram model contained radiomics features signatures, four-gene expression related to cell cycle pathway, and CA 19-9 level. The multiscale model showed good discrimination performance in the primary cohort (AUC = 0.981, 95% CI 0.953–1.000), the validation cohort (AUC = 0.822, 95% CI 0.635–1.000), and the independent-test cohort (AUC = 0.752, 95% CI 0.608–0.896) and good calibration. Decision curve analysis confirmed the clinical application value of the multiscale model.Conclusion: This study presented a multiscale model that incorporated the radiological eigenvalues, genomics features, and CA 19-9, which could be conveniently utilized to facilitate the individualized preoperatively assessing metastasis in CRC patients.

Pancreatic squamous cell carcinoma (SCC) is a rare primary pancreatic malignancy with a poor prognosis. The median overall survival (OS) for metastatic setting is only 4 months and the optimal management remains poorly defined. In the present study, we report a 52-year-old female patient with stage IV primary SCC of the pancreas harboring a deleteous BRCA2 somatic mutation. After 10 cycles of chemotherapy of cisplatin combined with nanoparticle albumin-bound paclitaxel, metastatic lesions in the liver and lymph nodes achieved radiographic complete responses and pancreatic lesion shrank from 5.7 to 1.5 cm in diameter. The patient subsequently underwent a posterior radical antegrade modular pancreatosplenectomy with R0 resection and residual liver lesions were also resected. After 3 months, a tumor relapsed in the liver. She was then treated with olaparib combined with pembrolizumab and achieved stable disease on the liver lesion. The patient eventually died from cerebral hemorrhage with a long OS of 21 months. Our case demonstrated a favorable clinical activity and survival advantage of the combined cisplatin and nanoparticle albumin-bound paclitaxel, which might serve as a therapeutic option for the patient with BRCA-mutant pancreatic SCC.

Collagens are major components of the ECM in various organs, including the lungs. Ectopic expression of collagens can regulate the tumor progression and disease outcome through remodeling of the extracellular matrix (ECM). However, it remains largely unexplored whether collagens are involved in the tumor progression of lung adenocarcinoma (LUAD). Analysis of three LUAD transcriptional expression profiles showed that COL10A1 mRNA expression was up-regulated and associated with poor prognosis. Gain- and loss-of-function studies were performed to observe that up-regulated COL10A1 promotes LUAD cell proliferation and invasion in vitro and in vivo. In molecular mechanism study, we found that COL10A1 interacts with DDR2 and affects the downstream FAK signaling pathway to regulate LUAD cell progression. The expression of COL10A1 on tissue microarray (TMA) was also measured to explore the association between COL10A1 expression and patient outcome. The results addressed that COL10A1 is up-regulated and positively correlated with lymph node metastasis in lung adenocarcinoma, and the COL10A1 expression is also an independent prognostic factor. In summary, the up-regulated COL10A1 remodels the ECM and the COL10A1/DDR2/FAK axis regulates the proliferation and metastasis of LUAD cells, implying that COL10A1 is a promising therapeutic target and prognostic marker for LUAD patients.

Motor neuron and pancreas homeobox 1 (MNX1) is a development-related genes and has been found to be highly expressed in several cancers. However, its biological function in cervical cancer remains largely unexplored. QRT-PCR, western blot, and IHC showed that MNX1 was abnormally overexpressed in cervical cancer tissues and cell lines. The high expression level of MNX1 correlated with poorer clinicopathologic characteristics in cervical cancer patients. Evaluated by RTCA (Real Time Cellular Analysis) proliferation assay, colony formation assay, EdU assay, transwell assay, and matrigel assay, we found that knockdown of MNX1 inhibited proliferation, migration and invasion of cervical cancer in vitro, while overexpression of MNX1 promoted malignant phenotype of cervical cancer. And subcutaneous xenograft model confirmed the malignant phenotype of MNX1 in vivo. Furthermore, flow cytometry, chromatin immunoprecipitation, and luciferase reporter assay indicated that MNX1 accelerated cell cycle transition by transcriptionally downregulating cyclin-dependent kinases p21cip1. In summary, our study revealed that MNX1 exerted an oncogenic role in cervical cancer via repressing the transcription of p21cip1 and thus accelerating cell cycle progression. Our results suggested that MNX1 was a potential diagnostic marker and therapeutic target for cervical cancer patients.

Objective: Identification of tumor invasiveness of pulmonary adenocarcinomas before surgery is one of the most important guides to surgical planning. Additionally, preoperative diagnosis of lung adenocarcinoma with micropapillary patterns is also critical for clinical decision making. We aimed to evaluate the accuracy of deep learning models on classifying invasiveness degree and attempted to predict the micropapillary pattern in lung adenocarcinoma.Methods: The records of 291 histopathologically confirmed lung adenocarcinoma patients were retrospectively analyzed and consisted of 61 adenocarcinoma in situ, 80 minimally invasive adenocarcinoma, 117 invasive adenocarcinoma, and 33 invasive adenocarcinoma with micropapillary components (>5%). We constructed two diagnostic models, the Lung-DL model and the Dense model, based on the LeNet and the DenseNet architecture, respectively.Results: For distinguishing the nodule invasiveness degree, the area under the curve (AUC) value of the diagnosis with the Lung-DL model is 0.88 and that with the Dense model is 0.86. In the prediction of the micropapillary pattern, overall accuracies of 92 and 72.91% were obtained for the Lung-DL model and the Dense model, respectively.Conclusion: Deep learning was successfully used for the invasiveness classification of pulmonary adenocarcinomas. This is also the first time that deep learning techniques have been used to predict micropapillary patterns. Both tasks can increase efficiency and assist in the creation of precise individualized treatment plans.

The treatment of melanoma has remained a difficult challenge. Targeting the tumor stroma has recently attracted attention for developing novel strategies for melanoma therapy. Activating transcription factor 3 (ATF3) plays a crucial role in regulating tumorigenesis and development, but whether the expression of ATF3 in human dermal fibroblasts (HDFs) can affect melanoma development hasn't been studied. Our results show that ATF3 expression is downregulated in stromal cells of human melanoma. HDFs expressing high levels of ATF3 suppressed the growth and migration of melanoma cells in association with downregulation of different cytokines including IL-6 in vitro. In vivo, HDFs with high ATF3 expression reduced tumor formation. Adding recombinant IL-6 to melanoma cells reversed those in vitro and in vivo effects, suggesting that ATF3 expression by HDFs regulates melanoma progression through the IL-6/STAT3 pathway. More importantly, HDFs pretreated with cyclosporine A or phenformin to induce ATF3 expression inhibited melanoma cell growth in vitro and in vivo. In summary, our study reveals that ATF3 suppresses human melanoma growth and that inducing the expression of ATF3 in HDFs can inhibit melanoma growth, a new potential melanoma therapeutic approach.

Background: The immune landscape of hepatocellular carcinoma (HCC) is heterogeneous. This study aims to develop the immune type which could improve predictive value of HCC survival.Methods: A total of 208 HCC patients in the testing cohort, 112 patients in the validation cohort and 365 HCC patients in the TCGA database were included in this study. Immune features were assessed by immunohistochemical staining or CIBERSORT method. We constructed prognostic classifiers by LASSO COX analyses in the TCGA cohort, which identified five features out of the 22 types of immune cells.Results: The formulas based on the immunohistochemical staining are as follows: ISOS = 0.648* Macrophagestromal + 0.444*Neutrophilsstromal + 0.218*Tregsstromal – 0.703*Memory T cellsstromal; ISDFS = 0.285*B cellsstromal + 0.494*Neutrophilsstromal + 0.431*Tregsstromal – 0.736*Memory T cellsstromal. We classified HCC patients into immune type A subgroup (IS-A) and type B subgroup (IS-B) based on immune scores. The immune type was an independent prognostic indicator for disease-free survival (DFS) and overall survival (OS) in both testing and validation cohorts. Two nomograms (for OS and DFS) that integrated the immune type and clinicopathologic risk factors also showed good predictive accuracy and discriminatory power. IS-A group was correlated with higher immune checkpoint molecule expression. In addition, patients with IS-A and IS-B had distinct mutation signature.Conclusion: The immune types could predict survival and recurrence of HCC effectively. In addition, the immunosuppressive pathways and mutation signature are distinct between two immune types.

PurposeThe aim of this study was to develop a radiomics nomogram based on grayscale ultrasound (US) for preoperatively predicting Lymphovascular invasion (LVI) in patients with pathologically confirmed T1 (pT1) breast invasive ductal carcinoma (IDC).MethodsOne hundred and ninety-two patients with pT1 IDC between September 2020 and August 2022 were analyzed retrospectively. Study population was randomly divided in a 7: 3 ratio into a training dataset of 134 patients (37 patients with LVI-positive) and a validation dataset of 58 patients (19 patients with LVI-positive). Clinical information and conventional US (CUS) features (called clinic_CUS features) were recorded and evaluated to predict LVI. In the training dataset, independent predictors of clinic_CUS features were obtained by univariate and multivariate logistic regression analyses and incorporated into a clinic_CUS prediction model. In addition, radiomics features were extracted from the grayscale US images, and the radiomics score (Radscore) was constructed after radiomics feature selection. Subsequent multivariate logistic regression analysis was also performed for Radscore and the independent predictors of clinic_CUS features, and a radiomics nomogram was developed. The performance of the nomogram model was evaluated via its discrimination, calibration, and clinical usefulness.ResultsThe US reported axillary lymph node metastasis (LNM) (US_LNM) status and tumor margin were determined as independent risk factors, which were combined for the construction of clinic_CUS prediction model for LVI in pT1 IDC. Moreover, tumor margin, US_LNM status and Radscore were independent predictors, incorporated as the radiomics nomogram model, which achieved a superior discrimination to the clinic_CUS model in the training dataset (AUC: 0.849 vs. 0.747; P < 0.001) and validation dataset (AUC: 0.854 vs. 0.713; P = 0.001). Calibration curve for the radiomic nomogram showed good concordance between predicted and actual probability. Furthermore, decision curve analysis (DCA) confirmed that the radiomics nomogram had higher clinical net benefit than the clinic_CUS model.ConclusionThe US-based radiomics nomogram, incorporating tumor margin, US_LNM status and Radscore, showed a satisfactory preoperative prediction of LVI in pT1 IDC patients.