Search

Objective: DNA damage response (DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation (DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor (ICI) therapy in gastrointestinal (GI) cancer. Methods: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts. Results: The DRIA signature includes three genes (CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients (81.8% vs. 8.8%; P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve (AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein–Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer. Conclusions: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pan-cancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Abstract Immunotherapy is the first-line therapy for esophageal squamous cell carcinoma (ESCC), yet many patients do not respond due to drug resistance and the lack of reliable predictive markers. We collected 73 ESCC patients (including discovery cohort and validation cohort) without immune thrombocytopenia and undergoing anti-PD1 immunotherapy. Proteomic and phosphoproteomic analysis of 73 ESCC treatment-naive samples by mass spectrometry-based label-free quantification were applied to explore the potential resistant and sensitive mechanisms, and identify predictive markers of ESCC immunotherapy. Comparative analysis found the pathways related to immune and mitochondrial functions were associated with ESCC immunotherapy sensitivity; while platelet activation bioprocess showed negative correlation with CD8+ T cells and related to ESCC immunotherapy non-sensitivity. Finally, we identified 10 ESCC immunotherapy predictive biomarkers with high accuracy (≥ 0.90) to predict the immunotherapeutic response, which was validated in the independent cohort.

Xue-Jun Dou,1,&ast; Run-Yang Ma,1,&ast; De-Wang Ren,1 Qiang Liu,2 Peng Yan3 1Department of Thoracic Surgery, Aerospace Center Hospital, Beijing, 100049, People’s Republic of China; 2Department of Thoracic Surgery, Peking University International Hospital, Beijing, 102206, People’s Republic of China; 3Department of Respiratory Medicine, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, 100071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiang Liu, Department of Thoracic Surgery, Peking University International Hospital, Beijing, 102206, People’s Republic of China, Tel +86 15901472799, Email liuqiang8548@163.com Peng Yan, Department of Respiratory Medicine, China Aerospace Science & Industry Corporation 731 hospital, Beijing, 100071, People’s Republic of China, Email yanpeng301@163.comObjective: This study aimed to investigate the effectiveness and tolerability of anlotinib plus PD-1 blockades in patients with previously immunotherapy treated advanced non-small-cell lung cancer (NSCLC).Methods: A total of 67 patients with previously immunotherapy treated advanced NSCLC who received anlotinib plus PD-1 blockades in clinical practice were screened retrospectively. All the PD-1 blockades used in this study were approved in China and consisted of sintilimab, camrelizumab, tislelizumab and pembrolizumab. Effectiveness and safety of anlotinib plus PD-1 blockades were assessed, and all patients were followed up regularly. Clinical significance between response status to previous immune-related treatment regimens and therapeutic outcomes of anlotinib plus PD-1 blockades was further explored.Results: The best overall response among the 67 patients suggested that a partial response was observed in 16 patients, stable disease was noted in 41 patients and progressive disease was found in 10 patients, which yielded an objective response rate of 23.9% (95% CI: 14.3– 35.9%) and a disease control rate of 85.1% (95% CI: 74.3– 92.6%). Prognostic outcomes indicated that the median progression-free survival (PFS) was 6.1 months (95% CI: 2.37– 9.83) and the median overall survival (OS) was 16.5 months (95% CI: 10.73– 22.27). Exploratory analysis highlighted that patients who were intolerant to previous immune-related regimens (17 patients) might have a superior prognosis (median OS: 22.3 months vs 12.5 months, P=0.024). Additionally, adverse reactions with any grades during anlotinib plus PD-1 blockades administration were observed in 62 patients (92.5%), of which 31 patients (46.3%) had ≥grade 3 adverse reactions. Most common adverse reactions were fatigue, hypertension, diarrhea and hepatotoxicity.Conclusion: Anlotinib plus PD-1 blockades demonstrated promising effectiveness and tolerable safety in patients with previously immunotherapy treated advanced NSCLC. Those who were intolerant to previous immune-related regimens might benefit significantly from treatment with anlotinib plus PD-1 blockades. This conclusion should be confirmed in future studies.Keywords: previously immunotherapy treated NSCLC, anlotinib, PD-1 blockades, effectiveness, safety

BackgroundBaseline serological biomarkers have the potential to predict the benefits of adjuvant chemotherapy in patients with gastric cancer. However, the fluctuating nature of postoperative recurrence risk makes precise treatment challenging. We aimed to develop a risk score in real-time predicting outcomes for postoperative GC patients using blood chemistry tests.Materials and methodsThis was a retrospective, multicentre, longitudinal cohort study from three cancer centres in China, with a total of 2737 GC patients in the pTNM stage Ib to III. Among them, 1651 patients with at least two serological records were assigned to the training cohort. Model validation was carried out using separate testing data with area under curve (AUC). The least absolute shrinkage and selection operator (LASSO) and random forest-recursive feature elimination (RF-RFE) algorithm were used to select the parameters.ResultsThe Cox regression model derived six risk factors to construct a composite score (low-risk: 0-2 score; high risk: 3-6 score), including CEA, CA125, CA199, haemoglobin, albumin, and neutrophil to lymphocyte ratio. The risk score accurately predicted mortality in 1000-time bootstrap (AUROCs:0.658; 95% CI: 0.645, 0.670), with the highest AUROC (0.767; 95% CI: 0.743, 0.791) after 1 year since the gastrectomy. In validation dataset, the risk score had an AUROC of 0.586 (95% CI 0.544, 0.628). Furthermore, patients with high risk at 1 month derived significant clinical benefits from adjuvant chemotherapy (P for interaction

Abstract Objectives To analyze psychological states and needs of patients after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Methods Questionnaires were sent to 101 allo‐HSCT survivors and 96 questionnaires were returned. The questionnaire covered several categories: (1) demographics and general information, (2) physical conditions, (3) psychologic status and sleep quality, (4) survivor's comments on transplantation, (5) demands and needs, (6) preferred forms and channels of information. Results Depression and poor sleep quality were major concerns troubling allo‐HSCT survivors. A notable discrepancy exists between clinically diagnosed depression (4.2%) and self‐ reported depression based on BDI‐13 (55.2%). Young adults (18–49 years old), chronic graft‐versus‐host disease, the ECOG performance score of 2–4, surviving within 5 years since HSCT, no or low dose of ATG used and being single were significantly associated with self‐reported depression. Based on the PSQI score, 75% of survivors experienced varying degrees of sleep quality impairment. Young adults, chronic GVHD and the ECOG score of 2–4 were significantly associated with worse sleep quality. The majority of patients reported unmet needs on physical and psychosocial aspects. Nutrition information was the most important topic, followed by disease treatments and fatigue. Differences in informational needs were found in the survivors according to age, time since HSCT and gender. WeChat public account and WeChat applet, mobile interactive platform and one‐to‐one conversation were the favorite channel for information. Conclusions Clinicians should establish more appropriate survivorship care plans focusing on survivors' psychologic states, demands and needs.

Acute myeloid leukemia (AML) is a complex mixed entity composed of malignant tumor cells, immune cells and stromal cells, with intra-tumor and inter-tumor heterogeneity. Single-cell RNA sequencing enables a comprehensive study of the highly complex tumor microenvironment, which is conducive to exploring the evolutionary trajectory of tumor cells. Herein, we carried out comprehensive analyses of aggrephagy-related cell clusters based on single-cell sequencing for patients with acute myeloid leukemia. A total of 11 specific cell types (T, NK, CMP, Myeloid, GMP, MEP, Promono, Plasma, HSC, B, and Erythroid cells) using t-SNE dimension reduction analysis. Several aggrephagy-related genes were highly expressed in the 11 specific cell types. Using Monocle analysis and NMF clustering analysis, six aggrephagy-related CD8+ T clusters, six aggrephagy-related NK clusters, and six aggrephagy-related Mac clusters were identified. We also evaluated the ligand-receptor links and Cell–cell communication using CellChat package and CellChatDB database. Furthermore, the transcription factors (TFs) of aggrephagy-mediated cell clusters for AML were assessed through pySCENIC package. Prognostic analysis of the aggrephagy-related cell clusters based on R package revealed the differences in prognosis of aggrephagy-mediated cell clusters. Immunotherapy of the aggrephagy-related cell clusters was investigated using TIDE algorithm and public immunotherapy cohorts. Our study revealed the significance of aggrephagy-related patterns in tumor microenvironment, prognosis, and immunotherapy for AML.

Abstract Background The incidence rate of non-small cell lung cancer (NSCLC) has been increasing worldwide, and the correlation of circadian rhythm disruption with a raised risk of cancer and worse prognosis has been shown by accumulating evidences recently. On the other hand, drug resistance and the impact of tumor heterogeneity have been inevitable in NSCLC therapy. These both lead to an urgent need to identify more useful prognostic and predictive markers for NSCLC diagnosis and treatment, especially on the aspect of circadian clock genes. Methods The expression of the main clock genes in cancer was probed with TIMER and Oncomine databases. The prognostic value of key clock genes was probed systematically with the Kaplan–Meier estimate and Cox regression on samples from TCGA database. RT-qPCR was performed on patient tissue samples to further validate the results from databases. The functional enrichment analysis was performed using the “ClusterProfiler” R package, and the correlation of key clock genes with tumor mutation burden, immune checkpoint, and immune infiltration levels were also assessed using multiple algorithms including TIDE, TIMER2.0, and XCELL. Results TIMELESS was significantly upregulated in lung tissue of clinical lung cancer patients as well as TCGA and Oncomine databases, while RORA was downregulated. Multivariate Cox regression analysis indicated that TIMELESS (P = 0.004, HR = 1.21 [1.06, 1.38]) and RORA (P = 0.047, HR = 0.868 [0.755, 0.998]) has a significant correlation with overall survival in NSCLC. Genes related to TIMELESS were enriched in the cell cycle and immune system, and the function of RORA was mainly focused on oncogenic signaling pathways or glycosylation and protein activation. Also, TIMELESS was positively correlated with tumor mutation burden while RORA was negatively correlated with it. TIMELESS and RORA were also significantly correlated with immune checkpoint and immune infiltration levels in NSCLC. Additionally, TIMELESS showed a significant positive relationship with lipid metabolism. Conclusions TIMELESS and RORA were identified as key clock genes in NSCLC, and were independent prognostic factors for overall survival in NSCLC. The function of them were assessed in many aspects, indicating the strong potential of the two genes to serve as biomarkers for NSCLC progression and prognosis.

Aims: We present a 5-case series of low-grade oncocytic tumour of the kidney to further discuss their clinicopathological characteristics.Methods and results: Five patients were included in this study. There were three females and two males aged 45–66 years, with a median age of 65 years. Four tumours were located in the right kidney, and one was located in the left kidney. Most of the tumour sections were yellow-brown in colour. Tumour sizes ranged from 2.5 to 4.5 cm, with a median size of 3 cm. Microscopically, the tumours were well-circumscribed but lacked a fibrous capsule; the tumours consisted of monomorphous oncocytic cells arranged mainly in solid and nested architectural patterns. The tumour cells had uniformly round to oval nuclei and often had perinuclear halos but lacked significant irregularities. Immunohistochemically, the tumour cells showed a diffuse and strong positivity for CK7 and were negative for CD117. The tumour cells were also positive for GATA3, E-cadherin, Pax-8, Succinate dehydrogenase B (SDHB) and Fumarate hydratase (FH), and negative for vimentin, Carbonic anhydrase 9 (CA9), CD10, P504s, CK20, TFE3, TFEB, HMB45, ALK and Forkhead box protein I1 (FOXI1). Next-generation sequencing identified genetic variations in these tumours, including MTOR gene mutations (4/5) and PIK3CA gene mutation (1/5). All patients were alive without disease progression at a median follow-up of 32 months (range 10–57 months).Conclusion: LOT is an emerging renal entity of indolent behaviour that has morphologic overlap with some renal tumours with eosinophilic cytoplasm, primarily with oncocytoma and eosinophilic variant of chromophobe renal cell carcinoma. Familiarity with the distinctive morphological features, immunophenotype and molecular genetics of LOT helps avoid misdiagnosis.

Abstract WNT family member 4 (WNT4), which belongs to the conserved WNT protein family, plays an important role in the development and differentiation of many cell types during the embryonic development and adult homeostasis. Increasing evidence has shown that WNT4 is a special ligand that not only activates the β-catenin independent pathway but also acts on β-catenin signaling based on different cellular processes. This article is a summary of the current knowledge about the expression, regulation, and function of WNT4 ligands and their signal pathways in cell differentiation and human disease processes. WNT4 is a promoter in osteogenic differentiation in bone marrow stromal cells (BMSCs) by participating in bone homeostasis regulation in osteoporotic diseases. Non-canonical WNT4 signaling is necessary for metabolic maturation of pancreatic β-cell. WNT4 is also necessary for decidual cell differentiation and decidualization, which plays an important role in preeclampsia. WNT4 promotes neuronal differentiation of neural stem cell and dendritic cell (DC) into conventional type 1 DC (cDC1). Besides, WNT4 mediates myofibroblast differentiation in the skin, kidney, lung, and liver during scarring or fibrosis. On the negative side, WNT4 is highly expressed in cancer tissues, playing a pro-carcinogenic role in many cancer types. This review provides an overview of the progress in elucidating the role of WNT4 signaling pathway components in cell differentiation in adults, which may provide useful clues for the diagnosis, prevention, and therapy of human diseases.

Bladder cancer (BC) is a common malignant tumor of the urinary system. Common white light cystoscopy is the most important method in the diagnosis and treatment of BC, but its ability to identify small tumors and residual tumors at surgical sites is limited, so it is urgent to develop new diagnosis and treatment techniques. With the rise of the concept of precision medicine, a group of targeted molecules that can specifically bind to BC at the cellular and molecular levels have been discovered in recent years, and the molecular image and targeted therapy based on them can significantly improve the diagnosis and treatment efficiency of BC, with a great potential for clinical application. Based on the latest progress and the research work of our research group, this paper comprehensively analyzes and systematically summarizes the application of targeted molecular carriers in the diagnosis and treatment of BC.

Abstract Objective The aim of this study was to evaluate the predictive factors of central lymph node metastasis (CLNM) and BRAF V600E mutation in Chinese patients with papillary thyroid carcinoma (PTC). Methods A total of 943 PTC patients who underwent thyroidectomy from 2014 to 2016 at our hospital were enrolled. Those patients were divided into PTC > 10 mm and papillary thyroid microcarcinoma (PTMC) groups by tumor size. The BRAF V600E mutation was examined by quantitative real-time PCR. Univariate and multivariate analyses were used to examine risk factors associated with CLNM and the BRAF V600E mutation. Results The frequency of CLNM was 53% (505/943). Both univariate and multivariate analyses suggested that the risk factors for CLNM in PTC patients were male, younger age, and larger tumor size (P < 0.05). Coexistent Hashimoto thyroiditis (HT) was an independent protective factor against CLNM when the tumor was > 10 mm (P = 0.006). Stratified analysis revealed that male, age ≤ 30 years, and tumor size > 5 mm were independent risk factors for CLNM. The BRAF V600E mutation rate was 85%. Multivariate logistic regression analysis revealed that age (P < 0.001) and coexistent HT (P = 0.005) were independent predictive factors of BRAF V600E mutation in PTC patients. Only age was a risk factor for the BRAF V600E mutation when the tumor was > 10 mm (P = 0.004). In the PTMC group, the BRAF V600E mutation was significantly correlated with tumor size (P < 0.001) and coexistent HT (P = 0.03). Stratified analysis revealed that age > 30 years and tumor size > 5 mm were independent predictive factors of BRAF V600E mutation. Furthermore, the incidence of CLNM was significantly higher in BRAF V600E mutation-positive patients (P = 0.009) when the tumor was ≤ 5 mm. Conclusion The factors male, younger age (≤ 30 years), large tumor size (> 5 mm), and coexistent HT are independent predicative factors for CLNM. The BRAF V600E mutation is associated with both large size and without HT in PTMC patients, age > 30 years in the PTC > 10 mm group. The BRAF V600E mutation was an independent risk factor for CLNM when the tumor was ≤ 5 mm. For optimal management, these features should be comprehensively evaluated to determine the initial surgical approach for PTC patients.

BackgroundCholangiocarcinoma (CCA) is one of the most aggressive malignancies, lacking novel diagnostic and prognostic biomarkers. Exosome noncoding RNAs (ncRNA) were previously proposed as a potential source of biomarkers in several cancers. This study aimed to interpret the value of specific bile-derived ncRNA as predictors for early diagnosis and prognosis of CCA.MethodsWe recruited 100 patients who received endoscopic retrograde cholangiopancreatography at our hospital for bile duct obstruction due to CCA (n = 50) and biliary stone (n = 50). They were further divided into training set and validation set (3:2). A panel of CCA-specific ncRNAs including 5 miRNAs (PMID: 30165035) and 2 lncRNAs (PMID: 29050258) were detected in both serum and bile exosomes. The diagnostic accuracy was assessed using the area under the receiver operating characteristic curve. Logistic analysis was used to classify the potential predictors of CCA and further establish the diagnostic model. And the prognostic value of the ncRNAs was also assessed.ResultsExosomes were successfully collected from bile and serum. Exosomal miR-141-3p, miR-200a-3p, miR-200c-3p in serum and bile, as well as miR-200b-3p and ENST00000588480.1 in bile showed AUCs of >0.70 in the diagnosis of CCA. Bile exosomal miR-200c-3p displayed the best diagnostic value with the AUC of 0.87. The combination of serum CA19-9 into the model could increase the AUC to 0.906. Bile exosomal miR-200a-3p and miR-200c-3p were found to be independent predictors of CCA. Among exosomal ncRNAs in human bile and blood, 3 (serum and bile exosomal miR-200c-3p, bile exosomal miR-200a-3p) showed significant value in predicting cancer recurrence and 1 (serum exosomal miR-200c-3p) had great predictive ability of cancer death. High levels of serum exosomal miR-200c-3p showed unfavorable tumor-free survival and overall survival.ConclusionThe bile exosomal miR-200 family, particularly miR-200c-3p, was verified to be a potential biomarker for the early detection of CCA. The diagnostic ability of exosomal ncRNAs in human bile is better than that in blood. Moreover, high levels of bile exosomal miR-200a-3p, miR-200c-3p, and serum exosomal miR-200c-3p represented adverse clinical outcomes.

BackgroundMantle cell lymphoma (MCL) with Epstein–Barr virus (EBV) infection is rarely reported. The objective of this study was to analyze the prevalence and clinicopathological features of MCL with EBV infection in the largest series thus far.MethodsAfter screening 138 cases of MCL, we identified eight cases of MCL with EBV infection.ResultsMost of them (7/8) had non-neoplastic bystander cells with positivity for EBV and no expression of latent membrane protein 1 (LMP1) and EBV nuclear antigen 2 (EBNA2). The cases of MCL with EBER positivity did not have abnormal immune function or other lymphomas. Moreover, their histopathological morphology was indicative of classical MCL. Cases of MCL with EBER positivity exhibited statistically significant differences in lactate dehydrogenase, anemia status, and MCL international prognostic index grouping (P=0.008, P=0.02, P=0.001, and P=0.011, respectively). The differences between the two groups in age, sex ratio, clinical manifestations, and immunohistochemical phenotypes were not statistically significant.ConclusionsThe incidence of MCL with EBV infection was low (5.8%). Clinicopathologically, cases of MCL with EBER positivity were similar to their EBV-negative counterparts. Our findings revealed that most cells infected by EBV in MCL are background cells rather than tumor cells. This is inconsistent with data from previous studies, indicating that tumor cells in MCL may not be prone to EBV infection.

Human epidermal growth factor receptor 2 (HER2) positive (+) classical type invasive lobular carcinoma (cILC) of the breast is extremely rare and its clinicopathologic features have not been well characterized. We compared features of HER2(+) and HER2 negative (−) cILCs. A total of 29 cases were identified from the clinical database at our institution from 2011-2019; 9 were HER2(+) cILC tumors and 20 were HER2(−) cILC tumors. The results reveal that HER2(+) cILC group had significantly increased Ki-67 expression and reduced estrogen receptor (ER) expression compared to HER2(−) cILC group (both p < 0.05). In addition, HER2(+) cILCs tended to be diagnosed at a younger age and more common in the left breast, and appeared to have a higher frequency of nodal or distant metastases. These clinicopathologic features suggest HER2(+) cILC tumors may have more aggressive behavior than their HER2(−) counterpart although both groups of tumors showed similar morphologic features. Future directions of the study: (1) To conduct a multi-institutional study with a larger case series of HER2(+) cILC to further characterize its clinicopathologic features; (2) to compare molecular profiles by next generation sequencing (NGS) assay between HER2(+) cILC and HER2(−) cILC cases to better understand tumor biology of this rare subset of HER2(+) breast cancer; and (3) to compare molecular characteristics of HER2(+) cILC and HER2(+) high grade breast cancer in conjunction with status of tumor response to anti-HER2 therapy to provide insight to management of this special type of low grade breast cancer to avoid unnecessary treatment and related toxicity

Abstract TOB1 participates in various kinds of cancers. However, its role in pancreatic cancer has rarely been reported. In this study, we explored the expression and mechanisms of TOB1 in regulating the malignant phenotype of pancreatic cancer cells. TOB1 expression was determined by data mining and immunohistochemistry (IHC), and its localization was observed by immunofluorescence. CCK‐8 cell proliferation, colony formation, flow cytometric, transwell migration, and Western blot (WB) assays were used to examine how it impacts the malignant phenotype of pancreatic cancer. Furthermore, Foxa2 binding to TOB1 was tested by dual‐luciferase reporter assays, and RNA‐Seq was performed to identify signaling pathways. We found TOB1 was downregulated in pancreatic cancer tissues and was mainly located in the cytoplasm. TOB1 overexpression reduced the proliferation of K‐Ras wild‐type pancreatic cancer cells but made no difference to cell migration and invasion. Foxa2 overexpression significantly enhanced TOB1 promoter activity. Moreover, overexpressing TOB1 substantially enriched the calcium pathway in K‐Ras wild‐type pancreatic cancer cells. In conclusion, TOB1 may suppress the proliferation of K‐Ras wild‐type pancreatic cancer cells by regulating calcium pathway genes.

Objective: The systemic inflammation index and body mass index (BMI) are easily accessible markers that can predict mortality. However, the prognostic value of the combined use of these two markers remains unclear. The goal of this study was therefore to evaluate the association of these markers with outcomes based on a large cohort of patients with gastric cancer. Methods A total of 2,542 consecutive patients undergoing radical surgery for gastric or gastroesophageal junction adenocarcinoma between 2009 and 2014 were included. Systemic inflammation was quantified by the preoperative neutrophil-to-lymphocyte ratio (NLR). High systemic inflammation was defined as NLR ≥ 3, and underweight was defined as BMI < 18.5 kg/m2. Results Among 2,542 patients, NLR ≥ 3 and underweight were common [627 (25%) and 349 (14%), respectively]. In the entire cohort, NLR ≥ 3 or underweight independently predicted overall survival (OS) [hazard ratio (HR): 1.236, 95% confidence interval (95% CI): 1.069–1.430; and HR: 1.600, 95% CI: 1.350–1.897, respectively] and recurrence-free survival (RFS) (HR: 1.230, 95% CI: 1.054–1.434; and HR: 1.658, 95% CI: 1.389–1.979, respectively). Patients with both NLR ≥ 3 and underweight (vs. neither) had much worse OS (HR: 2.445, 95% CI: 1.853–3.225) and RFS (HR: 2.405, 95% CI: 1.802–3.209). Furthermore, we observed similar results in subgroup analyses according to pathological stage, age, and postoperative chemotherapy. Conclusions Our results showed that preoperative elevated NLR and decreased BMI had a significant negative effect on survival. Underweight combined with severe inflammation could enhance prognostication. Taking active therapeutic measures to reduce inflammation and increase nutrition may help improve outcomes.

Pathway-level analysis is a powerful approach enabling the interpretation of post-genomic data at a higher level than that of individual molecules. Molecular-targeted therapy focusing on cascade signaling pathways has become a new paradigm in anticancer therapy, instead of a single protein. However, the approaches to narrowing down the long list of biological pathways are limited. Here, we proposed a strategy for in silico Drug Prescription on biological pathways across pan-Cancers (CDP), by connecting drugs to candidate pathways. Applying on a list of 120 traditional Chinese medicines (TCM), we especially identified the “TCM–pathways–cancers” triplet and constructed it into a heterogeneous network across pan-cancers. Applying them into TCMs, the computational prescribing methods deepened the understanding of the efficacy of TCM at the molecular level. Further applying them into Western medicines, CDP could promote drug reposition avoiding time-consuming developments of new drugs.

Cancer is a severe public health issue that is a leading cause of mortality globally. It is also an impediment to improving life expectancy worldwide. Furthermore, the global burden of cancer incidence and death is continuously growing. Current therapeutic options are insufficient for patients, and tumor complexity and heterogeneity necessitate customized medicine or targeted therapy. It is critical to identify potential cancer therapeutic targets. Aberrant activation of the PI3K/AKT/mTOR pathway has a significant role in carcinogenesis. This review summarized oncogenic PI3K/Akt/mTOR pathway alterations in cancer and various cancer hallmarks associated with the PI3K/AKT/mTOR pathway, such as cell proliferation, autophagy, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT), and chemoresistance. Importantly, this review provided recent advances in PI3K/AKT/mTOR inhibitor research. Overall, an in-depth understanding of the association between the PI3K/AKT/mTOR pathway and tumorigenesis and the development of therapies targeting the PI3K/AKT/mTOR pathway will help make clinical decisions.

Fangbin Song,1,2 Hui Du,1,2 Aimin Xiao,1,2 Chun Wang,1,2 Xia Huang,1,2 Peisha Yan,1,2 Zhihong Liu,1,2 Xinfeng Qu,3 Jerome L Belinson,4,5 Ruifang Wu1,2 1Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, People’s Republic of China; 2Shenzhen Key Laboratory on Technology for Early Diagnosis of Major Gynecological Diseases, Shenzhen, People’s Republic of China; 3Sanming Project of Medicine in Shenzhen, Peking University Shenzhen Hospital, Shenzen, People’s Republic of China; 4Preventive Oncology International, Inc., Cleveland Heights, OH, USA; 5Gynecologic Oncology Division, Women’s Health Institute, Cleveland Clinic, Cleveland, OH,USACorrespondence: Ruifang Wu; Hui DuDepartment of Obstetrics and Gynecology, Peking University Shenzhen Hospital, No. 1120 Lianhua Road, Shenzhen, Guangdong 518036, People’s Republic of ChinaEmail wurfpush@126.com; duhui_107108@163.comPurpose: When used for cervical cancer primary screening, liquid-based cytology (LBC) has a high specificity but a low sensitivity. For histological diagnosis of high-grade lesions, p16INK4a immunostaining has proven to be useful. Therefore, our objective was to evaluate the use of p16INK4a immuno-cytology as a primary screen and a secondary screen after primary high-risk human papillomavirus (hrHPV) screening or LBC screening.Methods: A total of 1197 cytology slides were immuno-stained using automatic p16INK4a staining system (PathCIN®p16INK4a) in two studies from cervical screening programs. In the primary screening study, 875 slides were randomly selected and analyzed for p16INK4a. In the secondary screening study, 322 of the remaining slides were chosen by virtue of being HPV 16/18+, other hrHPV+/LBC≥ASC-US, or HPV-negative/LBC ≥LSIL. The sensitivity and specificity for detection of cervical intraepithelial neoplasia 2/3 or worse (CIN2+/CIN3+) were compared based on p16INK4a, LBC and HPV test results.Results: In combining two studies, there were 431 cases with biopsy pathology. They included 83 cases with CIN2+ and 41 cases with CIN3+. The p16 positivity rate increased with pathologic and cytologic severity (P< 0.0001). For primary screening: p16 immuno-cytology was more specific than HPV testing and was similar in sensitivity. Also, p16 immuno-cytology compared favorably with routine LBC (≥ASC-US or ≥LSIL) in sensitivity and specificity. For secondary screening: after LBC screening, “Triaging ASC-US with p16” gave a higher specificity and a similar sensitivity as compared to the “Triaging ASC-US with hrHPV” algorithm. After HPV primary screening, p16 immuno-cytology was more specific than LBC (≥ASC-US); the calculated colposcopy referral rate was also decreased by using p16 immuno-cytology as triage. Triage of “HPV16/18 and p16” had higher specificity and similar sensitivity as compared to triage of “HPV16/18 and LBC ≥ASC-US”.Conclusion: For primary screening, p16INK4a immuno-cytology compares favorably to routine LBC and HPV testing. p16INK4a immunostaining could be an efficient triage to reduce the colposcopy referral rate after primary hrHPV screening or LBC screening. Therefore, p16INK4a immuno-cytology may be applicable as a favorable technology for cervical cancer screening.Keywords: cervical intraepithelial neoplasia, human papillomavirus, p16, immunochemical staining, cervical cancer screening

Circulating tumor DNA (ctDNA) is cell-free DNA (cfDNA) fragment in the bloodstream that originates from malignant tumors or circulating tumor cells. Recently, ctDNA has emerged as a promising non-invasive biomarker in clinical oncology. Analysis of ctDNA opens up new avenues for individualized cancer diagnosis and therapy in various types of tumors. Evidence suggests that minimum residual disease (MRD) is closely associated with disease recurrence, thus identifying specific genetic and molecular alterations as novel MRD detection targets using ctDNA has been a research focus. MRD is considered a promising prognostic marker to identify individuals at increased risk of recurrence and who may benefit from treatment. This review summarizes the current knowledge of ctDNA and MRD in solid tumors, focusing on the potential clinical applications and challenges. We describe the current state of ctDNA detection methods and the milestones of ctDNA development and discuss how ctDNA analysis may be an alternative for tissue biopsy. Additionally, we evaluate the clinical utility of ctDNA analysis in solid tumors, such as recurrence risk assessment, monitoring response, and resistance mechanism analysis. MRD detection aids in assessing treatment response, patient prognosis, and risk of recurrence. Moreover, this review highlights current advancements in utilizing ctDNA to monitor the MRD of solid tumors such as lung cancer, breast cancer, and colon cancer. Overall, the clinical application of ctDNA-based MRD detection can assist clinical decision-making and improve patient outcomes in malignant tumors.

Abstract Background Doxorubicin-based chemotherapy is currently the most frequently used treatment for triple negative breast cancer (TNBC), yet the response rate is not high due to the lack of a biomarker allowing identification of responsive patients before the chemotherapy is initiated. We have demonstrated that doxorubicin inhibits proliferation of cancer cells through proteolytic activation of a transcription factor called CREB3L1 (cAMP response element binding protein 3-like 1), and that CREB3L1 expression in cancer cells is a key determinant of their sensitivity to doxorubicin when they are cultured in vitro or established as xenograft tumors in mice. The purpose of this study is to determine whether CREB3L1 expression in tumor cells of TNBC patients can be established as a biomarker to predict outcomes of doxorubicin-based chemotherapy. Methods We performed a retrospective analysis on breast core biopsy tissue samples taken from 18 TNBC patients before they were treated with doxorubicin-based chemotherapy. CREB3L1 expression in the cancer cells was analyzed by immunohistochemistry and quantified using the Immunoreactive Score (IRS). Outcomes of the chemotherapy were measured by the residual cancer burden (RCB) system. Results CREB3L1 expression levels in TNBC responsive to doxorubicin-based chemotherapy (RCB class 0-2) were significantly higher than that in resistant cancers (RCB class 3) (unpaired two-tailed t test, p = 0.0005; Statistical power 99.8 at 95% confidence level). All cancers expressing higher levels of CREB3L1 (IRS 4-12) responded to doxorubicin-based chemotherapy, whereas all cancers resisting the treatment expressed lower levels of CREB3L1 (IRS 0-3). Conclusions These results suggest that CREB3L1 expression level may be used as a biomarker to identify TNBC patients who are more likely to benefit from doxorubicin-based chemotherapy.

Abstract Background Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related deaths worldwide. Despite new technologies in diagnosis and treatment, the incidence and mortality of HCC continue rising. And its pathogenesis is still unclear. As a highly conserved protein of the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3) has been shown to be involved in tumorigenesis of HCC. This study aimed to explore the exact oncogenic mechanism of GOLPH3 and provide a novel diagnose biomarker and therapeutic strategy for patients with HCC. Methods Firstly, the expression of GOLPH3 was detected in the HCC tissue specimens and HCC cell lines. Secondly, RNA interference was used for GOLPH3 gene inhibition. Thirdly, cell proliferation was analyzed by MTT; cell apoptosis was analyzed by Annexin-V/PI staining, Hoechst 33,342 staining and caspase 3/7 activity assay. Fourthly, xenograft tumor model was used to study the function of GOLPH3 in tumor growth in vivo. Finally, western blotting and immunohistochemistry were used to investigate the role of GOLHP3 in the mTOR signaling pathway. Results Data showed that the mRNA and protein expression of GOLPH3 were up-regulated in HCC tumor tissue and cell lines compared with those of control (P

Background and objective Among frequently-used tumor markers in lung cancer, carcinoembryonic antigen (CEA) and carbohydrate antigen 125 (CA125), cytokeratin 19 (CYFRA21-1) and squamous carcinoma antigen (SCC), neuron specific enolase (NSE) and pro-gastrin-releasing peptide (ProGRP) are respectively expressed highly in lung adenocarcinoma, lung squamous carcinoma and small cell lung cancer. By comparing patients with multiple increased tumor markers (group A) and patients with increase of CEA and/or CA125 (group B), this study aims to investigate the utility of multiple increased tumor markers in therapeutic evaluation and prediction of disease relapsing in patients with advanced lung adenocarcinoma. Methods Patients with stage IV lung adenocarcinoma who receiving the first line chemotherapy in Cancer Hospital, Chinese Academy of Medical Sciences were enrolled and retrospectively analyzed. Clinical characteristic, serum tumor markers before chemotherapy, efficacy evaluation, progression-free survival (PFS) were analyzed. Results Except CEA and CA125, the highest ratio of increased tumor markersin group A was CYFRA21-1 (93%), then was NSE (36%), SCC (13%) and ProGRP (12%). Patients with multiple increased tumor markers tend to have more distant metastasis (P

Background and objective Amorphigenin, a rotenoid compouns, from seeds of Amorpha fruticosa, has been shown to possess anti-proliferation activities in several cancer cells. To explore the antitumor effects of amorphigenin on cisplatin-resistant human lung adenocarcinoma A549/DDP cells and explore the underlying mechanisms. Methods CCK-8 assay was used to measure the proliferation of A549/DDP cells; Colony formation assay was used to measure the colony formation of A549/DDP cells; Flow cytometry assay was used to detect the apoptosis rates; Western blot analysis was used to explore the expression of apoptosis-related proteins (caspase-3 protein, PARP protein) and lung resistance protein (LRP). Results Our results demonstrated that amorphigenin could inhibit the proliferation of A549/DDP cells with a inhibition concentration of 50% cell growth (IC50) at 48 h of (2.19±0.92) μmol/L. Amorphigenin could inhibit the colony formation ability and induce apoptosis of A549/DDP cells; Furthermore, amorphigenin combined with cisplatin showed synergistic proliferation-inhibitory effect and apoptosis-promoting effect in A549/DDP cells; reduced the expression of LRP of A549/DDP cells. Conclusion Amorphigenin remarkably inhibits the proliferation and induces apoptosis in A549/DDP cells. Combination of amorphigenin with cisplatin had the synergistic inhibitory effect on A549/DDP cells by downregulating the expression of LRP.

Objectives: The interaction between the quorum sensing (QS) molecules of gut microbiota and the immunity of colorectal cancer (CRC) has not been investigated before. Methods: We measured the concentration of autoinducer-2 (AI-2) in samples of stool, colorectal tissue, saliva and serum of CRC patients, and compared this to AI-2 levels in colorectal adenoma (AD) and normal colon mucosa (NC). To explore the activated signaling pathways involved, we utilized AI-2 extracted from Fusobacterium nucleatum to stimulate macrophages and validated these in vitro findings in human CRC tissues. Results: The AI-2 concentration in both colorectal tissue and stool of CRC patients was significantly higher when compared to that in AD and NC (all P values < .01). The AI-2 concentration along with the progression of CRC in both tissues and stools was significantly increased (P= .045，P= .0003, respectively). After AI-2 stimulation, TNFSF9 was the most significantly increased protein in macrophage cells (P < .01). TNFSF9 expression was significantly higher in CRC tissues when compared to NCs (P< .0001), which was mainly derived from macrophages in the tumor microenvironment. Moreover, AI-2 level was positively associated with CD3 + T cell numbers (P= .0462), and negatively associated with CD4/CD8 ratio (P= .0113) within CRC tissues. Conclusions: We demonstrated for the first time that AI-2 may serve as a novel marker for screening CRC in the clinic. AI-2 was associated with tumor immunity in CRCs through tumor-associated macrophages and CD4/CD8 ratio in a TNFSF9-dependent manner.

Background and objective Small cell lung cancer (SCLC) is a rapidly growing tumor with characteristic of neuroendocrine cellular function. Neuron specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP) and lactic dehydrogenase (LDH) are valuable in diagnosis and treatment of SCLC. By analyzing the variation of NSE, ProGRP and LDH before and after treatment, the aim of this study is to investigate the efficacy of tumor markers in diagnostic staging, therapeutic evaluation and prediction of disease relapsing. Methods Patients with SCLC who receiving the first line chemotherapy in Cancer Hospital, Chinese Academy of Medical Sciences were enrolled and retrospectively analyzed. Clinical characteristic (includes NSE, ProGRP and LDH level before and after 2 cycles chemotherapy), efficacy evaluation, progression-free survival (PFS) were analyzed. Results Before treatment, Serum NSE, ProGRP and LDH in patients with extensive disease (ED) were significantly higher than those with limited disease (LD)(all P4 cycles chemotherapy and with obvious decrease of ProGRP than those who accepted ≤4 cycles chemotherapy and with less obvious decrease of ProGRP in LD group; ED patients with no more than 2 distant metastasis, normal LDH level before treatment and obvious decrease of ProGRP after chemotherapy had lower short term relapse risk. In addition, the types of relapse (sensitive relapse, drug resistance relapse and refractory relapse) were negatively correlated with decrease of ProGRP (P=0.044). By multivariate analysis, numbers of chemotherapy cycle was independent prognostic factor for PFS in LD SCLC; numbers of distant metastasis and decrease of ProGRP were independent prognostic factors for PFS in ED SCLC. Conclusion Increase level of serum tumor markers is related to tumor burden. Decrease level of ProGRP after treatment may prognose efficacy and relapse risk.

Background and objective This study aims to explore the effect of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) on the lymphangiogenesis of lung cancer with EGFR mutation, as well as to determine the function of EGFR targeted therapy in relation to the inhibition of lymphangiogenesis during lung cancer treatment. Methods The EGFR double mutant lung cancer cell line NCI-H1975 is used to construct lung cancer xenograft models. The models are divided into two groups: the solvent control group and the EGFR-TKI treatment group. Each group includes five mice. The inhibitory effect of EGFR-TKI on the growth of transplanted tumors was observed. Immunohistochemical method and lymphatic endothelium specific antibody D2-40 were used in the experiment to observe the influence of EGFR-TKI on lymphangiogenesis in lung cancer. Results The weight and relative volume of tumors in the EGFR-TKI treated group were less than those in the solvent control group. The average lymphatic vessel density of EGFR-TKI-treated mice was 6.44 per case. This value was 10.70 per case in the solvent control group. Lower density of lymphangiogenesis was found in the EGFR-TKI treated group (P=0.023). The area and longest diameter of neonatal lymphatic vessel of the EGFR-TKI treated group were less than those of the solvent control group. Moreover, EGFR-TKI exhibited no significant effect on the invasion of tumor cells into the lymphatic vessel (P=0.519). Conclusion EGFR-TKI can inhibit lymphangiogenesis in EGFR mutant lung cancer while suppressing vessel diameter and expansion area.

Background and objective More than 35% Ib stage lung cancers have metastasised or recurrenced after operation, whose prognosis still remain poor. There’re much controversy over the necessity of adjuvant chemotherapy to them. This aim of this study is investigated the clinical and pathological characters influencing prognosis of the stage Ib non-small cell lung cancer (NSCLC) and to explore the indication of postoperative chemotherapy. Methods NSCLC patients (281 cases) who underwent lobectomy were examined. Cox proportional-hazards ratios were used to identify independent prognostic factors for survival. Kaplan-Meier survival curves were calculated to estimate survival rates. Results Kaplan-Meier analysis show that, cancerous embolus in the blood vessel or lymphatic vessel, histologic grade and tumor location were remarkerbly associated with mortality risk (P

Despite evidence that kinesin family member 14 (KIF14) can serve as a prognostic biomarker in various solid tumors, how it contributes to tumorigenesis remains unclear. We observed that experimental decrease in KIF14 expression increases docetaxel chemosensitivity in estrogen receptor–negative/progesterone receptor–negative/human epidermal growth factor receptor 2-negative, “triple-negative” breast cancers (TNBC). To investigate the oncogenic role of KIF14, we used noncancerous human mammary epithelial cells and ectopically expressed KIF14 and found increased proliferative capacity, increased anchorage-independent grown in vitro, and increased resistance to docetaxel but not to doxorubicin, carboplatin, or gemcitabine. Seventeen benign breast biopsies of BRCA1 or BRCA2 mutation carriers showed increased KIF14 mRNA expression by fluorescence in situ hybridization compared to controls with no known mutations in BRCA1 or BRCA2, suggesting increased KIF14 expression as a biomarker of high-risk breast tissue. Evaluation of 34 cases of locally advanced TNBC showed that KIF14 expression significantly correlates with chemotherapy-resistant breast cancer. KIF14 knockdown also correlates with decreased AKT phosphorylation and activity. Live-cell imaging confirmed an insulin-induced temporal colocalization of KIF14 and AKT at the plasma membrane, suggesting a potential role of KIF14 in promoting activation of AKT. An experimental small-molecule inhibitor of KIF14 was then used to evaluate the potential anticancer benefits of downregulating KIF14 activity. Inhibition of KIF14 shows a chemosensitizing effect and correlates with decreasing activation of AKT. Together, these findings show an early and critical role for KIF14 in the tumorigenic potential of TNBC, and therapeutic targeting of KIF14 is feasible and effective for TNBC.

Introduction. Breast conserving surgery (BCS) requires tumor excision with negative margins. Reexcision rates of 30–50% are reported. Ultrasound localization, intraoperative margin pathology, and specimen mammography have reduced reexcisions, but require new equipment. Cavity shave margin (CSM) is a technique, utilizing existing equipment, that potentially reduces reexcision. This study evaluates CSM reexcision impact. Methods. 522 cancers treated with BCS were reviewed. Patients underwent standard partial mastectomy (SPM) or CSM. Data collected included demographics, pathology, and treatments. Results. 455 SPMs were compared to 67 CSMs. Analysis revealed no differences in pathology, intraductal component, or neoadjuvant chemotherapy. Overall reexcision rate = 43%. Most reexcisions were performed for DCIS at margin. SPMs underwent 213 reexcisions (46.8%), versus 16/67 (23.9%) CSMs (P = 0.0003). Total mastectomy as definitive procedure was performed after more SPMs (P = 0.009). Multivariate analysis revealed CSM, % DCIS, tumor size, and race to influence reexcisions. Conclusions. CSM is a technique that reduces reexcisions and mastectomy rates.

Introduction Exercise may improve cancer outcomes. Neoadjuvant chemotherapy (NC) for breast cancer provides a unique setting to evaluate intervention effects. Treatments leading to decreased post-neoadjuvant Ki-67 levels, smaller tumor size, and higher pathologic response are associated with improved survival and lower recurrence. This randomized, prospective pilot trial evaluates the feasibility of supervised exercise during NC for breast cancer. Methods Stage II-III, ER positive, cancer patients with BMI > 25 receiving NC were randomized to standard NC with supervised bootcamp (NC + BC) or NC alone. Ki-67, C-peptide, BMI, and tumor size were measured before chemotherapy and at time of surgery. Results There were no initial differences between groups in regards to tumor size, C-peptide, BMI, and Ki-67. The NC + BC (n = 5) group had a lower mean BMI at the conclusion of NC compared with those (n = 5) in the NC group (28.0 versus 35.8, P = 0.03). Final tumor size was 2.59 cm in the NC + BC group versus 3.16 cm for NC ( P = 0.76) Mean Ki-67 for NC + BC was 7% versus 29% with NC ( P = 0.14). C-peptide (ng/mL) was equivalent between the two groups (4.55 NC + BC versus 4.74 NC, P = 0.85). Conclusions Adding a supervised exercise program to NC is feasible, decreases BMI, and may lead to lower Ki-67 levels and improved survival.

We report an extremely rare case with a total of 50 fibroadenomas simultaneously presented in bilateral breasts and left axillary accessory breast, up to 8 cm in size, in a 20 year-old Chinese woman. The histopathologic and immunophenotypic features of the fibroadenomas are described and possible underlying pathogenesis is discussed. To our knowledge, this is the first case with such a large number of bilateral multiple breast fibroadenomas in a young female reported in the literature.

There is a paucity of data regarding molecular subtypes of pure ductal carcinoma in situ (pDCIS). We evaluated the expression of ER, PR, HER2, Ki67, and p53 and DNA ploidy in 118 pDCIS and 100 invasive breast carcinomas (IBCAs) by routine IHC and classified them according to molecular subtypes. Quantification of biomarkers and DNA ploidy was performed by image analysis. Expression of ER, PR, and high ki67 was more frequent in pDCIS compared to IBCA. High-grade tumors had lower ER and PR expression, high Ki67, overexpression of HER2 and p53, and DNA aneuploidy. Luminal A and HER2 subtypes were more common in pDCIS, and triple negative was more prevalent in IBCA. In both groups, HER2 and triple negative subtypes were characterized by high ki67, overexpression of p53, and DNA aneuploidy compared to luminal subtypes. Molecular subtypes of IBCA are distinct from those of pDCIS. Invasion is characterized by change in phenotype in some tumors.

Abstract Background Conjugated linoleic acid (CLA), a naturally occurring fatty acid found in ruminant products such as milk and beef, has been shown to possess anti-cancer activities in in vivo animal models and in vitro cell culture systems. In human breast cancer, the overall duration of estrogen exposure is the most important risk factor for developing estrogen-responsive breast cancer. Accordingly, it has been suggested that estrogen exposure reduces apoptosis through the up-regulation of the anti-apoptosis protein, Bcl-2. Bcl-2, an anti-apoptotic protein, regulates apoptosis and plays a crucial role in the development and growth regulation of normal and cancerous cells. Our research interest is to examine the effects of CLA on the induction of apoptosis in human breast tissues. Methods The localization of Bcl-2 in both normal and cancerous human breast tissues was determined by immunohistochemical staining and the Bcl-2 protein expression was tested by western blot analysis. Co-culture of epithelial cells and stromal cells was carried out in the presence or absence of CLA to evaluate apoptosis in the context of a cell-cell interaction. Results The results showed that both normal and cancerous breast tissues were positive for Bcl-2 staining, which was higher overall in mammary ducts but very low in the surrounding stromal compartment. Interestingly, by quantifying the western blot data, basal Bcl-2 protein levels were higher in normal breast epithelial cells than in cancerous epithelial cells. Furthermore, treatment with 17β-estradiol (E2) stimulated growth and up-regulated Bcl-2 expression in estrogen responsive breast epithelial cells; however, these carcinogenic effects were diminished by either CLA or 4-Hydroxytamoxifen (Tam) and were suppressed further by the combination of CLA and Tam. In both one cell type cultured and co-culture systems, CLA induced cell apoptosis in ERα transfected MDA-MB-231 cells but not in the wild type MDA-MB-231 cells. Conclusion These data, therefore, demonstrate that ERα plays important roles in CLA induced apoptosis in human breast tissues.

Abstract Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes.

Abstract Background Neuroendocrine tumors (NETs) are rare neoplasms that originate from peptidergic neurons and neuroendocrine cells. Due to their increasing incidence, effective treatment strategies are required. Surufatinib, a novel small-molecule inhibitor with antiangiogenic and immunomodulatory effects, has shown promise in clinical trials for advanced NETs. However, the efficacy and safety of surufatinib are influenced by multiple factors, and there is currently a lack of sufficient real-world studies to explore these potential influencing factors. Methods We conducted a retrospective study on 133 patients with NETs who were treated with surufatinib at Sun Yat-sen University Cancer Center. Patients were histologically confirmed to have primary NETs. Statistical analyses, including Cox regression models and Kaplan-Meier curves, were conducted to assess the impact of the primary tumor site on progression-free survival (PFS) and overall survival (OS). Results Patients with gastroenteropancreatic NETs (GEP-NETs) exhibited significantly longer PFS and OS compared to extraGEP-NETs patients. Subgroup analyses also revealed variations in survival outcomes among patients with liver metastases depending on the primary tumor site. Adverse events (AEs), including proteinuria and increased bilirubin, were more common in GEP-NETs patients. These findings emphasize the importance of considering primary tumor site in treatment decisions for NETs. Conclusions Primary tumor site is a critical factor influencing the efficacy of surufatinib in NETs. Clinicians should consider this factor when determining treatment strategies.

Abstract Objective This study aims to develop and validate a predictive model that integrates clinical features, MRI radiomics, and nutritional-inflammatory biomarkers to forecast progression-free survival (PFS) in cervical cancer (CC) patients undergoing concurrent chemoradiotherapy (CCRT). The goal is to identify high-risk patients and guide personalized treatment. Methods We performed a retrospective analysis of 188 patients from two centers, divided into training (132) and validation (56) sets. Clinical data, systemic inflammatory markers, and immune-nutritional indices were collected. Radiomic features from three MRI sequences were extracted and selected for predictive value. We developed and evaluated five models incorporating clinical features, nutritional-inflammatory indicators, and radiomics using C-index. The best-performing model was used to create a nomogram, which was validated through ROC curves, calibration plots, and decision curve analysis (DCA). Results Model 5, which integrates clinical features, Systemic Immune-Inflammation Index (SII), Prognostic Nutritional Index (PNI), and MRI radiomics, showed the highest performance. It achieved a C-index of 0.833 (95% CI: 0.792–0.874) in the training set and 0.789 (95% CI: 0.679–0.899) in the validation set. The nomogram derived from Model 5 effectively stratified patients into risk groups, with AUCs of 0.833, 0.941, and 0.973 for 1-year, 3-year, and 5-year PFS in the training set, and 0.812, 0.940, and 0.944 in the validation set. Conclusions The integrated model combining clinical features, nutritional-inflammatory biomarkers, and radiomics offers a robust tool for predicting PFS in CC patients undergoing CCRT. The nomogram provides precise predictions, supporting its application in personalized patient management.

Abstract Background In the era of immunotherapy, neoadjuvant immunochemotherapy (NAIC) for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC) is used clinically but lacks of high‐level clinical evidence. This study aimed to compare the safety and long‐term efficacy of NAIC followed by minimally invasive esophagectomy (MIE) with those of neoadjuvant chemotherapy (NAC) followed by MIE. Methods A prospective, single‐center, open‐label, randomized phase III clinical trial was conducted at Henan Cancer Hospital, Zhengzhou, China. Patients were randomly assigned to receive either neoadjuvant toripalimab (240 mg) plus paclitaxel (175 mg/m2) + cisplatin (75 mg/m2) (toripalimab group) or paclitaxel + cisplatin alone (chemotherapy group) every 3 weeks for 2 cycles. After surgery, the toripalimab group received toripalimab (240 mg every 3 weeks for up to 6 months). The primary endpoint was event‐free survival (EFS). The pathological complete response (pCR) and overall survival (OS) were key secondary endpoints. Adverse events (AEs) and quality of life were also assessed. Results Between May 15, 2020 and August 13, 2021, 252 ESCC patients ranging from T1N1‐3M0 to T2‐3N0‐3M0 were enrolled for interim analysis, with 127 in the toripalimab group and 125 in the chemotherapy group. The 1‐year EFS rate was 77.9% in the toripalimab group compared to 64.3% in the chemotherapy group (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.39 to 1.00; P = 0.05). The 1‐year OS rates were 94.1% and 83.0% in the toripalimab and chemotherapy groups, respectively (HR = 0.48; 95% CI = 0.24 to 0.97; P = 0.037). The patients in the toripalimab group had a higher pCR rate (18.6% vs. 4.6%; P = 0.001). The rates of postoperative Clavien‐Dindo grade IIIb or higher morbidity were 9.8% in the toripalimab group and 6.8% in the chemotherapy group, with no significant difference observed (P = 0.460). The rates of grade 3 or 4 treatment‐related AEs did not differ between the two groups (12.5% versus 12.4%). Conclusions The interim results of this ongoing trial showed that in resectable ESCC, the addition of perioperative toripalimab to NAC is safe, may improve OS and might change the standard treatment in the future.

Abstract Objective Radiotherapy is a crucial treatment modality for pelvic cancers, but uncertainties persist in defining the clinical target volume (CTV) for the inguinal lymphatic drainage region. Suboptimal CTV delineation may compromise treatment efficacy and result in subpar disease control. This study aimed to investigate and map the distribution of lymph node metastases (LNM) in the groin area to facilitate an improved and detailed CTV definition using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Methods Inguinal LNM in patients with biopsy-proven pelvic malignancies were identified using 18F-FDG PET/CT scan. The longitudinally nearest axial plane was determined based on six typical bony landmarks, and the axial direction relative to the femoral artery of LNM was recorded. The distances from the LNM to the nearest edge of the femoral artery were measured on the axial plane. An optimal margin to cover 95% of LNM was estimated to develop contouring recommendations. Results In this study, 500 positive LNM were identified by 18F-FDG PET/CT among 185 patients with primary pelvic malignancies. Relative to the femoral artery, lymph nodes were distributed laterally (10:00–11:00, n = 35), anteriorly (12:00–1:00, n = 213), and medially (2:00–4: 00, n = 252). For CTV delineation, the recommended distances from the femoral artery on the SFH were lateral 19 mm, anterior 19 mm, and medial 25 mm; on the SGT were lateral 26 mm, anterior 20 mm, and medial 25 mm; on the SPS were lateral 28 mm, anterior 29 mm, and medial 26 mm; on the IPS were anterior 29 mm and medial 28 mm; on the IIT were anterior 27 mm and medial 27 mm; on the ILT were anterior 25 mm and medial 23 mm. Use interpolation to contour the area between six axial slices, including any radiographically suspicious LNM. Conclusions Using 18F-FDG PET/CT, we investigated the distribution pattern of inguinal LNM and propose a more comprehensive guideline for inguinal CTV delineation.

Abstract Background Anoikis and epithelial-mesenchymal transition (EMT) are pivotal in the distant metastasis of lung adenocarcinoma (LUAD). A detailed understanding of their interplay and the identification of key genes is vital for effective therapeutic strategies against LUAD metastasis. Methods Key prognostic genes related to anoikis and EMT were identified through univariate Cox regression analysis. We utilized ten machine learning algorithms to develop the Anoikis and EMT-Related Optimal Model (AEOM). The TCGA-LUAD dataset served as the training cohort, while six additional international multicenter LUAD datasets were employed as validation cohorts. The average concordance index (c-index) was used to evaluate model performance and identify the most effective model. Subsequent multi-omics analyses were conducted to explore differences in pathway enrichment, immune infiltration, and mutation landscapes between high and low AEOM groups. Experimental validation demonstrated that RHPN2, a key biomarker within the model, acts as an oncogene facilitating LUAD progression. Results The AEOM displayed superior prognostic predictive performance for LUAD patients, outperforming numerous previously published LUAD signatures. Biologically, the AEOM was notably associated with immune features; the high AEOM group exhibited decreased immune activity and a tendency towards immune-cold tumors, as well as a higher tumor mutational burden (TMB). Subgroup analysis revealed that the low AEOM + high TMB group had the most favorable prognosis. The high AEOM group was primarily enriched in cell cycle-related pathways, promoting cancer cell proliferation. RHPN2, a crucial gene within the AEOM (correlation = 0.85, P

Abstract Background Lung adenocarcinoma (LUAD) is still one of the most prevalent malignancies. Interleukin factors are closely associated with the initiation and progression of cancer. However, the relationship between interleukin factors and LUAD has not been fully elucidated. This study aimed to use Mendelian randomization (MR) and RNA sequencing (RNA-seq) analyses to identify the interleukin factors associated with the onset and progression of LUAD. Methods Exposure-related instrumental variables were selected from interleukin factor summary datasets. The LUAD summary dataset from FINGENE served as the outcome. MR and sensitivity analyses were conducted to screen for interleukin factors associated with LUAD occurrence. Transcriptome analyses revealed the role of interleukin factors in lung tissues. The results were validated through Western blotting and further confirmed with driver gene-negative patients from multiple centers. Potential mechanisms influencing LUAD occurrence and development were explored using bulk RNA-seq and single-cell RNA-seq data. Results MR analysis indicated that elevated plasma levels of IL6RB, IL27RA, IL22RA1, and IL16 are causally associated with increased LUAD risk, while IL18R1 and IL11RA exhibit the opposite effect. Transcriptome analyses revealed that IL11RA, IL18R1, and IL16 were downregulated in tumor tissues compared with normal lung tissue, but only higher expression of IL11RA correlated with improved prognosis in patients with LUAD from different centers and persisted even in driver-gene negative patients. The IL11RA protein level was lower in various LUAD cell lines than in human bronchial epithelial cells. The genes co-expressed with IL11RA were enriched in the Ras signaling pathway and glycosylation processes. Fibroblasts were the primary IL11RA-expressing cell population, with IL11RA+fibroblasts exhibiting a more immature state. The genes differentially expressed between IL11RA+and IL11RA- fibroblasts were involved in the PI3K-Akt/TNF signaling pathway. Conclusion According to the MR and transcriptome analyses, the downregulation of IL11RA was closely related to the occurrence and development of LUAD. Graphical Abstract

Abstract Objectives Pancreatic cancer with peritoneal metastasis presents a challenging prognosis, with limited effective treatment options available. This study aims to evaluate the efficacy and safety of combining cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as a treatment strategy for this patient group. Methods A retrospective analysis was conducted on patients with peritoneal metastasis of pancreatic cancer who underwent CRS + HIPEC treatment at Beijing Shijitan Hospital from March 2017 to December 2023. The study focused on assessing clinical features, the incidence of sever adverse events (SAEs), and overall survival (OS). Results A total of 10 patients were enrolled in this study. The median OS was 24.2 months, suggesting an improvement over traditional therapies. While SAEs were noted, including two cases of severe complications necessitating additional surgical interventions, no perioperative fatalities were recorded. The overall survival time for patients with CC0/1 was not significantly different from that of patients with CC2/3, and no prognostic predictors were identified. Conclusions The combination of CRS and HIPEC appears to be a viable and promising treatment modality for patients with peritoneal metastasis of pancreatic cancer, offering an improved survival rate with manageable safety concerns. Further research is needed to refine patient selection criteria and to explore the long-term benefits of this approach.

Abstract Background Tumor metastasis is a major threat to cancer patient survival. The organ‐specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis‐associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer. Methods Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single‐cell RNA‐sequencing (scRNA‐seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3‐dioxygenase‐positive matrix fibroblasts (TDO2+ MFs) in lung metastasis. Results We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet‐derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF‐depleted experimental metastatic mouse models. We found that TDO2+ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MF‐secreted chemokines C‐C motif chemokine ligand 8 (CCL8) and C‐C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2+ MF‐derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation. Conclusions Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs’ immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung‐specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.

Abstract This study profiled global single cell-spatial-bulk transcriptome landscapes of hepatocellular carcinoma (HCC) ecosystem from six HCC cases and a non-carcinoma liver control donor. We discovered that intratumoral heterogeneity mainly derived from HCC cells diversity and pervaded the genome-transcriptome-proteome-metabolome network. HCC cells are the core driving force of taming tumor-associated macrophages (TAMs) with pro-tumorigenic phenotypes for favor its dominant growth. Remarkably, M1-types TAMs had been characterized by disturbance of metabolism, poor antigen-presentation and immune-killing abilities. Besides, we found simultaneous cirrhotic and HCC lesions in an individual patient shared common origin and displayed parallel clone evolution via driving disparate immune reprograms for better environmental adaptation. Moreover, endothelial cells exhibited phenotypically conserved but executed differential functions in a space-dependent manner. Further, the spatiotemporal traits of rapid recurrence niche genes were identified and validated by immunohistochemistry. Our data unravels the great significance of HCC cells in shaping vibrant tumor ecosystems corresponding to clinical scenarios.

Abstract Background The aim of this study was to assess the prognostic significance of serum direct bilirubin (DBIL) for patients newly diagnosed with myelodysplastic syndromes (MDS). Methods The clinical, laboratory, and follow-up data of MDS patients were collected, and the associations of DBIL levels with overall survival (OS) and leukemia-free survival (LFS) were analyzed. Result In total, 262 MDS patients were assigned to the high DBIL level group or the normal DBIL level group in the retrospective study. High DBIL was associated with older age, reduced hemoglobin, higher levels of β2-microglobin, lactate dehydrogenase, and serum ferritin, along with the number of co-mutations (> 1) and a higher frequency of ASXL1, KIT, and KRAS mutations. Multivariate analyses found that high DBIL level was an independent adverse predictor for OS (p = 0.002, hazard ratio = 2.723, 95%CI = 1.442–5.143) but not for LFS (p = 0.057, hazard ratio = 1.678, 95%CI = 0.986–2.857). A novel nomogram based on DBIL, sex, age, β2-microglobulin, lactate dehydrogenase, the Revised International Prognostic Scoring System (IPSS-R) was constructed, which demonstrated superior accuracy compared with the IPSS-R (C-index, 0.790 vs. 0.731, respectively). Conclusion An elevated DBIL level was identified as an independent adverse prognostic factor for MDS patients. An individualized prediction model was established and validated to improve prediction of OS and LFS.

Abstract Background Predicting chemorefractory disease in advanced epithelial ovarian cancer (EOC) remains challenging. This study aimed to identify clinicopathological factors and hemogram data as predictive markers for chemorefractory EOC and to explore potential therapeutic approaches that may mitigate these unfavorable conditions. Methods We conducted a retrospective analysis of patients with advanced EOC treated with chemotherapy. Hemogram data and clinicopathological variables were collected. We employed logistic regression to assess factors associated with chemorefractory EOC and used the Kaplan–Meier method for survival analysis. Results Among the 191 patients analyzed, suboptimal surgery, lymphocyte count

Abstract Background This study aims to investigate a novel instrument OM-100 with low-frequency magnetic fields (LFMFs) for its potential applicability in the treatment of liver cancer. Methods Liver cancer cell lines (HepG2 and Huh7) and normal liver cell line THLE-2 were exposed to OM-100 at LFMFs of 0, 10, 25, 50, and 100 kHz for 2 h in the morning, noon, and evening, respectively. The effects of LFMF on cell viability, apoptosis, migration, and invasion capabilities were examined. Additionally, impacts of LFMF on ROS production was assessed. In vivo studies were conducted to examine the safety profile of OM-100 and its effects on tumor growth. Results In vitro, OM-100 reduced the viability of liver cancer cells, increased cell apoptosis, and inhibited cell migration and invasion abilities in a frequency-dependent manner (P

Abstract HER2 antagonists remain the cornerstone of therapy for patients with HER2-positive breast cancer. This study introduces a novel small-molecule inhibitor of DNA methyltransferase 1 (DNMT-1), referred to as DI-1, designed to synergize with HER2 antagonists in treating HER2-positive breast cancer cells. Clinical data reveal a negative correlation between DNMT-1 expression and PTEN levels, and a positive correlation with the methylation rates of PTEN's promoter. In experiments with SKBR3 and BT474 cells, DI-1 effectively reduced the methylation of PTEN's promoter region, thereby upregulating PTEN expression. This upregulation, in turn, enhanced the cells' sensitivity to HER2 antagonists, indicating that DI-1’s mechanism involves inhibiting DNMT-1’s recruitment to PTEN's promoter region. Consequently, by increasing PTEN expression, DI-1 amplifies the sensitivity of HER2-positive breast cancer cells to treatment, suggesting its potential as a promising therapeutic strategy in this context.