Serum IGFBP-1 as a promising diagnostic and prognostic biomarker for colorectal cancer.

Our previous study showed that levels of circulating insulin-like growth factor binding protein-1 (IGFBP-1) has potential diagnostic value for early-stage upper gastrointestinal cancers. This study aimed to assess whether serum IGFBP-1 is a potential diagnostic and prognostic biomarker for CRC patients. IGFBP-1 mRNA expression profile data of peripheral blood in colorectal cancer (CRC) patients were downloaded and analyzed from Gene Expression Omnibus database. We detected serum IGFBP-1 in 138 CRC patients and 190 normal controls using enzyme-linked immunosorbent assay. Blood IGFBP-1 mRNA levels were higher in CRC patients than those in normal controls (P = 0.027). In addition, serum IGFBP-1 protein levels in the CRC group were significantly higher than those in normal control group (P < 0.0001). Serum IGFBP-1 demonstrated better diagnostic accuracy for all CRC and early-stage CRC, respectively, when compared with carcinoembryonic antigen (CEA), carbohydrate antigen19-9 (CA 19-9) or the combination of CEA and CA19-9. Furthermore, Cox multivariate analysis revealed that serum IGFBP-1 was an independent prognostic factor for OS (HR = 2.043, P = 0.045). Our study demonstrated that serum IGFBP-1 might be a potential biomarker for the diagnosis and prognosis of CRC. In addition, the nomogram might be helpful to predict the prognosis of CRC.

Secreted proteins encoded by super enhancer-driven genes could be promising biomarkers for early detection of esophageal squamous cell carcinoma.

BACKGROUND: Early detection of cancer remains an unmet need in clinical practice, and high diagnostic sensitivity and specificity biomarkers are urgently required. Here, we attempted to identify secreted proteins encoded by super-enhancer (SE)-driven genes as diagnostic biomarkers for esophageal squamous cell carcinoma (ESCC). METHODS: We conducted an integrative analysis of multiple data sets including ChIP-seq data, secretome data, CCLE data and GEO data to screen secreted proteins encoded by SE-driven genes. Using ELISA, we further identified up-regulated secreted proteins through a small size of clinical samples and verified in a multi-centre validation stage (345 in test cohort and 231 in validation cohort). Receiver operating characteristic curves were used to calculate diagnostic accuracy. Artificial intelligence (AI) method named gradient boosting machine (GBM) were applied for model construction to enhance diagnostic accuracy. RESULTS: Serum EFNA1 and MMP13 were identified, and showed significantly higher levels in ESCC patients compared to normal controls. An integrated Five-Biomarker Panel (iFBPanel) established by combining EFNA1, MMP13, carcino-embryonic antigen, Cyfra21-1 and squmaous cell carcinoma antigen had AUCs of 0.881 and 0.880 for ESCC in test and validation cohorts, respectively. Importantly, the iFBPanel also exhibited good performance in detecting early-stage ESCC patients (0.872 and 0.864). Furthermore, the iFBPanel was further empowered by AI technology which showed excellent diagnostic performance in early-stage ESCC (0.927 and 0.907). CONCLUSIONS: Our study suggested that serum EFNA1 and MMP13 could potentially assist ESCC detection, and provided an easy-to-use detection model that might help the diagnosis of early-stage ESCC.

Exosomal cargos-mediated metabolic reprogramming in tumor microenvironment.

Metabolic reprogramming is one of the hallmarks of cancer. As nutrients are scarce in the tumor microenvironment (TME), tumor cells adopt multiple metabolic adaptations to meet their growth requirements. Metabolic reprogramming is not only present in tumor cells, but exosomal cargos mediates intercellular communication between tumor cells and non-tumor cells in the TME, inducing metabolic remodeling to create an outpost of microvascular enrichment and immune escape. Here, we highlight the composition and characteristics of TME, meanwhile summarize the components of exosomal cargos and their corresponding sorting mode. Functionally, these exosomal cargos-mediated metabolic reprogramming improves the "soil" for tumor growth and metastasis. Moreover, we discuss the abnormal tumor metabolism targeted by exosomal cargos and its potential antitumor therapy. In conclusion, this review updates the current role of exosomal cargos in TME metabolic reprogramming and enriches the future application scenarios of exosomes.

The role of tripartite motif-containing 28 in cancer progression and its therapeutic potentials.

Tripartite motif-containing 28 (TRIM28) belongs to tripartite motif (TRIM) family. TRIM28 not only binds and degrades its downstream target, but also acts as a transcription co-factor to inhibit gene expression. More and more studies have shown that TRIM28 plays a vital role in tumor genesis and progression. Here, we reviewed the role of TRIM28 in tumor proliferation, migration, invasion and cell death. Moreover, we also summarized the important role of TRIM28 in tumor stemness sustainability and immune regulation. Because of the importance of TRIM28 in tumors, TIRM28 may be a candidate target for anti-tumor therapy and play an important role in tumor diagnosis and treatment in the future.

Exosomal miR-205-5p enhances angiogenesis and nasopharyngeal carcinoma metastasis by targeting desmocollin-2.

The aim of this study was to investigate whether and how exosomal miR-205-5p regulated angiogenesis and nasopharyngeal carcinoma (NPC) metastasis. We found that up-regulated serum exosomal miR-205-5p levels were associated with NPC progression and worse overall survival of NPC patients. miR-205-5p over-expression significantly increased tube formation, wound healing, migration and invasion of NPC cells, and lung metastasis of NPC tumors, whereas miR-205-5p inhibition had opposite effects. Exosomal miR-205-5p from NPC cells promoted the migration, tube formation, and microvessel density (MVD) of HUVECs in vitro and in vivo. Furthermore, bioinformatics-, luciferase reporter-, and biotinylated miR-205-5p-based pull-down assays indicated that miR-205-5p directly bound to the 3' UTR of desmocollin-2 (DSC2). Exosomal miR-205-5p targeted DSC2 to enhance the EGFR/ERK signaling and MMP2/MMP9 expression, promoting angiogenesis and NPC metastasis, which was abrogated by DSC2 over-expression. Finally, the levels of miR-205-5p transcripts were positively correlated with MVD but negatively with DSC2 expression in NPC tissues, and patients with miR-205high/DSC2low NPC had worse overall survival. In conclusion, exosomal miR-205-5p promotes angiogenesis and NPC metastasis by targeting DSC2 to enhance EGFR/ERK signaling and MMP expression. This exosomal/miR-205-5p/EGFR/ERK axis may be a new therapeutic target for intervention of NPC metastasis.

First-line or second-line PD-1 inhibition in advanced oesophageal squamous cell carcinoma: A prospective, multicentre, registry study.

WHAT IS KNOWN AND OBJECTIVE: First-line and second-line immunotherapy with programmed death-1 (PD-1) inhibitors both improve overall survival in patients with advanced oesophageal squamous cell cancer (ESCC). This study explored survival differences between first-line and second-line PD-1 inhibition in advanced ESCC. METHODS: This registry study included 167 patients with advanced ESCC who were exposed to PD-1 inhibitors in either a first-line or a second-line setting between 15 January 2019 and 31 October 2020. The primary endpoint was overall survival, and secondary endpoints included overall tumour response, progression-free survival (PFS) and PFS2. A propensity score-matching (PSM) analysis was performed using the nearest-neighbour method. RESULTS AND DISCUSSION: Sixty-one patients started first-line treatment with chemotherapy and a PD-1 inhibitor (Group 1), while 106 started chemotherapy as the first-line choice and received a PD-1 inhibitor as the second-line choice (Group 2). The median PFS was 7.1 months in Group 1 and 4.1 months in Group 2 (log-rank p = 0.001). The median PFS2 was 7.1 months in Group 1 and 7.4 months in Group 2 (log-rank p = 0.4). Before PSM, the median overall survival was 13.5 months in Group 1 and 14.1 months in Group 2 (log-rank p = 0.9), and the sensitivity analysis showed consistent results (14.0 vs. 14.1 months). After PSM, the median overall survival rates for Group 1 (n = 61) and Group 2 (n = 61) were 13.5 and 13.1 months (log-rank p = 0.7) respectively. WHAT IS NEW AND CONCLUSION: In this study, patients with advanced ESCC who received first-line or second-line PD-1 inhibitors seemed to have comparable overall survival.

Thoracic para-aortic lymph node recurrence in patients with esophageal squamous cell carcinoma: A propensity score-matching analysis.

BACKGROUND: Thoracic para-aortic lymph node (TPLN) recurrence in esophageal squamous cell carcinoma (ESCC) is rare and its impact on survival is unknown. We studied survival in patients with ESCC who developed TPLN recurrence. AIM: To study the survival in patients with ESCC who developed TPLNs recurrence. METHODS: Data were collected retrospectively for 219 patients who had undergone curative surgery for ESCC during January 2012 to November 2017 and who developed recurrences (36.29% of 604 patients who had undergone curative surgeries for ESCC). The patients were classified into positive (+) and negative (-) TPLN metastasis subgroups. We also investigated TPLN recurrence in 223 patients with ESCC following definitive chemoradiotherapy during 2012-2013. Following propensity score matching (PSM) and survival estimation, factors predictive of overall survival (OS) were explored using a Cox proportional hazards model. RESULTS: Among the patients with confirmed recurrence, 18 were TPLN (+) and 13 developed synchronous distant metastases. Before PSM, TPLN (+) was associated with worse recurrence-free (P = 0.00049) and OS [vs TPLN (-); P = 0.0027], whereas only the intergroup difference in recurrence-free survival remained significant after PSM (P = 0.013). The Cox analysis yielded similar results. Among the patients who had received definitive chemoradiotherapy, 3 (1.35%) had preoperative TPLN enlargement and none had developed recurrences. CONCLUSION: TPLN metastasis is rare but may be associated with poor survival.

Circulating Levels of L1-cell Adhesion Molecule as a Serum Biomarker for Early Detection of Gastric Cancer and Esophagogastric Junction Adenocarcinoma.

Background: Low serum L1 cell adhesion molecule (L1CAM) has been found in several malignant tumors. Here, we aimed to evaluate the diagnostic potential for serum L1CAM in patients with gastric cancers (GC) and esophagogastric junction adenocarcinoma (EJA). Methods: Enzyme-linked immunosorbent assay (ELISA) was carried out to detect L1CAM level in sera of 148 GC patients, 59 EJA patients and 148 healthy controls. Receiver operating characteristics (ROC) was employed to evaluate diagnostic accuracy. Results: The concentrations of serum L1CAM were significantly lower in GC and EJA than those in healthy controls (P<0.001). Detection of L1CAM provided a sensitivity of 83.1%, a specificity of 62.2%, and an area under the curve (AUC) of 0.769 (95% CI: 0.715-0.823) in diagnosing GC, and a sensitivity of 66.1%, a specificity of 62.2%, and an AUC of 0.672 (95% CI: 0.590-0.755) in diagnosing EJA. Similar results were observed in the diagnosis of early-stage GC (0.681 (95%CI: 0.596-0.766)) and early-stage EJA (0.674 (95%CI: 0.528-0.820)). Analysis of clinical data showed that the levels of L1CAM were significantly associated with lymph node metastasis in GC (P<0.05). Conclusions: Our study showed that serum L1CAM might be a diagnostic biomarker for GC and EJA.

Serum IGFBP-1 as a potential biomarker for diagnosis of early-stage upper gastrointestinal tumour.

BACKGROUND: Early detection would improve upper gastrointestinal cancer prognosis. We aimed to identify serum protein biomarker for the detection of early-stage upper gastrointestinal cancer. METHODS: We performed a three-tiered study including 2028 participants from three medical centres. First, we applied two different antibody arrays to screen candidate serum proteins that increased in 20 patients with oesophageal squamous cell carcinoma (ESCC) compared with 20 normal controls. We then evaluated the selected protein by enzyme-linked immunosorbent assay in 1064 participants including 731 upper gastrointestinal cancer patients (287 ESCCs, 237 oesophagogastric junction adenocarcinomas (EJAs), and 207 stomach cancers) and 333 normal controls. The diagnostic value of the selected protein was finally validated in two independent cohorts of ESCC patients and controls (n=472 and 452, respectively). The receiver operating characteristic was used to calculate diagnostic accuracy. FINDINGS: Serum insulin-like growth factor binding protein-1 (IGFBP-1) identified in both antibody arrays showed significantly elevated levels in upper gastrointestinal cancers, compared with normal controls. Serum IGFBP-1 provided high diagnostic accuracy of early-stage ESCC, EJA, stomach and cancer (areas under the curve: 0·898, 0·936 and 0·864, respectively). This protein maintained diagnostic performance for early-stage ESCC in independent cohorts 1 and 2 (0·849 and 0·911, respectively). Additionally, serum levels of IGFBP-1 dropped significantly after surgical resection of primary tumours, compared with the corresponding pre-operative ESCC samples (p < 0·05). INTERPRETATION: Serum IGFBP-1 represents a promising diagnostic biomarker to detect early-stage upper gastrointestinal cancer.

The Diagnostic Value of Serum IGFBP7 in Patients with Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell cancer (ESCC) is one of the leading malignant cancer in the world and especially in China with high incidence and mortality. The exploration of novel serum biomarkers is required for early detection of ESCC. We investigated the diagnostic value of serum insulin like growth factor binding protein 7 (IGFBP7) in ESCC, evaluating its potential to improve the diagnosis of ESCC. The serum samples of 106 patients with ESCC and 107 normal controls were tested by enzyme-linked immunosorbent assay (ELISA). The levels of IGFBP7 in ESCC group were significantly higher than that in normal controls, compared by the Mann-Whitney U test (P<0.0001). Using receiver operating characteristic (ROC) curve, the diagnostic value of serum IGFBP7 was demonstrated. Versus normal group, the area under the ROC curve (AUC) of all ESCC was 0.794 (95%CI: 0.735-0.853) and early-stage ESCC was 0.725 (95%CI: 0.633-0.817). With optimized cutoff value of 2.993 ng/mL, IGFBP7 showed certain diagnostic value with specificity of 90.7%, sensitivities of 40.6% and 32.4% in ESCC and early-stage ESCC, respectively. Considering the correlation between clinical data and IGFBP7, no significant association was found (all P>0.05). Thus, we supposed that serum IGFBP7 might be a potential biomarker in the diagnosis of ESCC.

CDK4/6 inhibition versus mTOR blockade as second-line strategy in postmenopausal patients with hormone receptor-positive advanced breast cancer: A network meta-analysis.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib and abemaciclib) and mammalian target of rapamycin (mTOR) inhibitors (everolimus) are effective agents for restoring endocrine sensitivity in patients with advanced breast cancer progression on prior aromatase inhibitors. We conducted a network meta-analysis to compare these treatments in terms of progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). METHODS: The PubMed and Embase databases were searched for relevant publications between January 2000 and June 2018. Treatments were ranked based on a network meta-analysis. Ranking was determined by P-score. A random-effect model was used when heterogeneity was detected; otherwise, a fixed-effect model was used. RESULTS: Six trials comprising 4063 patients formed the comparison network. Compared with everolimus plus exemestane, the combinations of palbociclib or abemaciclib with fulvestrant showed similar efficacies in PFS and no differences in ORR. For the CBR, palbociclib demonstrated improvement, while abemaciclib did not. Incidences of severe adverse events did not significantly differ. A total of 29%, 15.9%, and 4% of patients discontinued everolimus, abemaciclib, and palbociclib, respectively, due to toxicity. CONCLUSION: These results suggest similar efficacies between CDK4/6 inhibition and mTOR blockade; however, CDK4/6 inhibitors were associated with favorable toxicity profiles.

Serum Autoantibodies against STIP1 as a Potential Biomarker in the Diagnosis of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) remains one of the leading causes of cancer-related mortality around the world. The identification of novel serum biomarkers is required for early detection of ESCC. This study was designed to elucidate whether autoantibodies against STIP1 could be a diagnostic biomarker in ESCC. An enzyme-linked immunosorbent assay was performed to detect serum levels of STIP1 autoantibodies in a training cohort (148 ESCC patients and 111 controls) and a validation cohort (60 ESCC patients and 40 controls). Mann-Whitney's U test showed that ESCC patients in two cohorts have higher levels of autoantibodies against STIP1 when compared to controls (P < 0.001). According to receiver operating characteristic analysis, the sensitivity, specificity, and area under the curve (AUC) of autoantibodies against STIP1 in ESCC were 41.9%, 90.1%, and 0.682 in the training cohort and 40.0%, 92.5%, and 0.710 in the validation cohort, respectively. Moreover, detection of autoantibodies against STIP1 could discriminate early-stage ESCC patients from controls, with sensitivity, specificity, and AUC of 35.7%, 90.1%, and 0.684 in the training cohort and 38.5%, 92.5%, and 0.756 in the validation cohort, respectively. Our findings indicated that autoantibodies against STIP1 might be a useful biomarker for early-stage ESCC detection.

Serum proteomic-based analysis identifying autoantibodies against PRDX2 and PRDX3 as potential diagnostic biomarkers in nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a major head and neck cancer with high occurrence in Southeast Asia and southern China. We aimed to identify autoantibodies that may contribute to early detection of NPC. METHODS: We used serological proteome analysis to identify candidate autoantibodies against tumor-associated antigens. Levels of autoantibodies and Epstein-Barr virus capsid antigen-IgA (VCA-IgA) were measured by ELISA in 129 patients with NPC and 100 normal controls. We employed receiver operating characteristics to calculate diagnostic accuracy. RESULTS: Sera from patients with NPC yielded multiple spots, two of which were identified as PRDX2 and PRDX3. Levels of serum autoantibodies against PRDX2 and PRDX3 were significantly higher for patients with NPC than for normal controls (P < 0.01), respectively. Combined detection of autoantibodies against PRDX2 and PRDX3 and VCA-IgA provided a high diagnostic accuracy in NPC (an area under the curve (AUC) of 0.811 (95% CI 0.753-0.869), 66.7% sensitivity, and 95.0% specificity). This combination maintained diagnostic performance for early NPC with AUC value of 0.754 (95% CI 0.652-0.857), 50.0% sensitivity, and 95.0% specificity. CONCLUSIONS: This study reports autoantibodies against PRDX2 and PRDX3 identified by a proteomic approach in sera from NPC patients. Our findings suggest that autoantibodies against PRDX2 and PRDX3 may serve as supplementary biomarkers to VCA-IgA for the screening and diagnosis of NPC.

The Effects of Upper Limb Exercise Through Yoga on Limb Swelling in Chinese Breast Cancer Survivors - A Pilot Study.

PURPOSE: Breast cancer is the most common female cancer. The aim of this study was to assess the impact of yoga on lymphedema in breast cancer survivors. DESIGN: Repeated measures before and after the intervention. We enrolled 15 women with breast cancer who had not previously worn elastic clothing to treat lymphedema. METHODS: The program was led by a certified trainer and consisted of 60-minute sessions, three times a week for 12 weeks. The volumes of the affected and normal limbs were measured. A self-assessed edema score was also recorded. FINDINGS: Fifteen patients completed the program, none of whom suffered from complications related to exercise. There was no significant edema after exercise. No significant differences were noted in subgroup analysis by age or the affected arm. CONCLUSIONS: Yoga does not induce lymphedema. CLINICAL RELEVANCE: Lymphedema is usually treated with uncomfortable elastic clothing, and high-resistance exercise may induce edema. Yoga may be suitable for these patients.

Tumor-associated autoantibodies against Fascin as a novel diagnostic biomarker for esophageal squamous cell carcinoma.

BACKGROUND AND OBJECTIVE: Autoantibodies against tumor-associated antigens (TAAs) have been found in many kinds of cancers, and might serve as biomarkers for early cancer diagnosis. The present study was carried out to test if there is any relation between autoantibodies against Fascin and esophageal squamous cell carcinoma (ESCC). METHODS: One hundred and forty-nine patients with ESCC and 98 control subjects were recruited in the study. The levels of circulating autoantibodies against Fascin were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) was used to calculate diagnostic accuracy. RESULT: The levels of autoantibodies against Fascin in patients with ESCC were significantly higher than in control subjects (P<0.001). Measurement of autoantibodies against Fascin provided an area under the curve (AUC) of 0.636, [95% confidence interval (CI): 0.568-0.704] 24.8% sensitivity (95% CI: 18.3%-37.2%) and 99.0% specificity (95% CI: 93.6%-99.9%). Moreover, serum level of autoantibodies against Fascin in early-stage ESCC was significantly higher than that of normal controls (P<0.05). The positive rates of autoantibodies against Fascin were correlated with age (P<0.05), but not with gender, tumor size, tumor site, histological grade, T stage, N stage or TNM stage (P>0.05). CONCLUSIONS: Our results suggest that Fascin autoantibody may be a potential biomarker for the early detection of ESCC.

Combined detection of serum Dickkopf-1 and its autoantibodies to diagnose esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) can be treated effectively if diagnosed at an early stage. We evaluated whether measurement of Dickkopf-1 (DKK-1) in combination of DKK-1 autoantibodies in serum may benefit early diagnosis of ESCC. Serum DKK-1 and DKK-1 autoantibodies were measured by enzyme-linked immunosorbent assay in a training cohort (185 ESCC samples vs. 97 normal controls) and validated in a validation cohort (104 ESCC samples vs. 53 normal controls). Receiver operating characteristic (ROC) was applied to calculate diagnostic accuracy. Testing of DKK-1 and DKK-1 autoantibodies together could differentiate ESCC from normal controls (area under the ROC curve [AUC] 0.769, 95% confidence interval (CI), 0.715-0.823, 50.3% sensitivity, and 90.7% specificity in the training cohort; AUC 0.752, 95% CI, 0.675-0.829, 50.0% sensitivity, and 84.9% specificity in the validation cohort). Importantly, the diagnostic performance of the combination of DKK-1 and DKK-1 autoantibodies persisted in early ESCC patients (AUC 0.780, 95% CI, 0.699-0.862, 50.0% sensitivity, and 90.7% specificity in the training cohort; AUC 0.745, 95% CI, 0.626-0.865, 53.8% sensitivity, and 84.9% specificity in the validation cohort). Furthermore, the levels of serum DKK-1 or DKK-1 autoantibody after surgical resection were lower, respectively, compared with the corresponding preoperative samples (P < 0.05). Our results suggest that measurement of DKK-1 combined with DKK-1 autoantibodies is a potentially valuable tool for the early detection of ESCC.

Autoantibody Signatures Combined with Epstein-Barr Virus Capsid Antigen-IgA as a Biomarker Panel for the Detection of Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is prevalent in Southern China and Southeast Asia, and autoantibody signatures may improve early detection of NPC. In this study, serum levels of autoantibodies against a panel of six tumor-associated antigens (p53, NY-ESO-1, MMP-7, Hsp70, Prx VI, and Bmi-1) and Epstein-Barr virus capsid antigen-IgA (VCA-IgA) were tested by enzyme-linked immunosorbent assay in a training set (220 NPC patients and 150 controls) and validated in a validation set (90 NPC patients and 68 controls). We used receiver-operating characteristics (ROC) to calculate diagnostic accuracy. ROC curves showed that use of these 6 autoantibody assays provided an area under curve (AUC) of 0.855 [95% confidence interval (CI), 0.818-0.892], 68.2% sensitivity, and 90.0% specificity in the training set and an AUC of 0.873 (95% CI, 0.821-0.925), 62.2% sensitivity, and 91.2% specificity in the validation set. Moreover, the autoantibody panel maintained diagnostic accuracy for VCA-IgA-negative NPC patients [0.854 (0.809-0.899), 67.8%, and 90.0% in the training set; 0.879 (0.815-0.942), 67.4%, and 91.2% in the validation set]. Importantly, combination of the autoantibody panel and VCA-IgA improved diagnostic accuracy for NPC versus controls compared with the autoantibody panel alone [0.911 (0.881-0.940), 81.4%, and 90.0% in the training set; 0.919 (0.878-0.959), 78.9%, and 91.2% in the validation set), as well as for early-stage NPC (0.944 (0.894-0.994), 87.9%, and 94.0% in the training set; 0.922 (0.808-1.000), 80.0%, and 92.6% in the validation set]. These results reveal autoantibody signatures in an optimized panel that could improve the identification of VCA-IgA-negative NPC patients, may aid screening and diagnosis of NPC, especially when combined with VCA-IgA.