Transcriptional profile and immune infiltration in colorectal cancer reveal the significance of inducible T-cell costimulator as a crucial immune checkpoint molecule.

BACKGROUND: Emergence of novel immuno-therapeutics has shown promising improvement in the clinical outcome of colorectal cancer (CRC). OBJECTIVE: To identify robust immune checkpoints based on expression and immune infiltration profiles of clinical CRC samples. METHODS: One dataset from The Cancer Genome Atlas database and two from Gene Expression Omnibus were independently employed for the analysis. Genes associated with overall survival were identified, and distribution of each immune checkpoint with respect to different clinical features was determined to explore key immune checkpoints. Multiple staining methods were used to verify the correlation between key immune checkpoint ICOS and clinical pathological features. Differentially expressed mRNA and long non-coding RNA (lncRNA) were then detected for gene set enrichment analysis and gene set variation analysis to investigate the differentially enriched biological processes between low- and high-expression groups. Significant immune-related mRNAs and lncRNA were subjected to competing endogenous RNA (ceRNA) network analysis. Correlation of inducible T-cell costimulator (ICOS) and top 10 genes in ceRNA network were further considered for validation. RESULTS: ICOS was identified from 14 immune checkpoints as the most highly correlated gene with survival and clinical features in CRC. The expression of ICOS protein in the poorly differentiated group was lower than that in the moderately differentiated group, and the expression in different pathological stages was significant. In addition, the expressions of ICOS were negatively correlated with Ki67. A conspicuous number of immune-related pathways were enriched in differentially expressed genes in the ICOS high- and low-expression groups. Integration with immune infiltration data revealed a multitude of differentially expressed immune-related genes enriched for ceRNA network. Furthermore, expression of top 10 genes investigated from ceRNA network showed high correlation with ICOS. CONCLUSION: ICOS might serve as a robust immune checkpoint for prognosis with several genes being potential targets of ICOS-directed immunotherapy in CRC.

α-Hederin promotes ferroptosis and reverses cisplatin chemoresistance in non-small cell lung cancer.

BACKGROUND: Cisplatin is a core chemotherapy regimen in non-small cell lung cancer (NSCLC). However, chemoresistance to cisplatin leads to a poor prognosis in NSCLC. α-Hederin is a natural compound extracted from Nigella sativa. The study aims to explore the effects of α-Hederin on cisplatin resistance in NSCLC. METHODS: NSCLC cisplatin-resistant cell lines A549/DPP and PC-9 were cultured to evaluate the efficacy of α-Hederin in the treatment of NSCLC in vitro and in vivo. Metabolomics and RNA-seq analysis were used to determine the potential mechanisms of action of α-Hederin. RESULTS: The results showed that α-Hederin inhibited cisplatin-resistant NSCLC cells proliferation and metastasis. Mice xenograft, orthotopic, and metastatic A549/DPP cell models also showed the anti-tumor effects of α-Hederin. The metabolomics and RNA-seq analysis results showed that α-Hederin activated DDIT3/ATF3 pathway and ferroptosis via silencing SLC7A11 and GPX4. Furthermore, α-Hederin enhanced the nuclear expression of EGR1. Bioinformatics and luciferase experiments confirmed that EGR1 binds to the miR-96-5p promoter region, inhibiting transcription. In addition, miR-96-5p directly suppressed the levels of DDIT3. CONCLUSION: This study revealed that α-Hederin activated EGR1 nuclear translocation and directly repressed miR-96-5p. It also promoted DDIT3/ATF3-mediated ferroptosis and reversed cisplatin resistance in NSCLC.

Classification of Colorectal Cancer Subtypes Based on Endoplasmic Reticulum Stress.

INTRODUCTION: Endoplasmic reticulum stress (ERS) is associated with the occurrence and development of colorectal cancer (CRC). METHODS: One thousand nine CRC samples and 3 ERS gene sets from GEO database were used to screen and validate genes related to stage and prognosis of CRC. Twenty thousand five hundred thirty samples from the TCGA database validated the ERS genes related to prognosis. PPI network construction and coexpression analysis were used to investigate the correlation of genes. ConsensusClusterPlus analysis was used to classify CRC subtypes. Cox regression and the LASSO algorithm were used to screen ERS genes related to prognosis. HE staining, immunohistochemical staining, and RT-qPCR of 50 owner-central samples were used to verify the genes. The ERscore model was constructed based on the ERS genes related to prognosis. The nomogram model was used to verify that different subtypes of CRC patients have different prognosis. RESULTS: Fifty ERS differentially expressed genes related to CRC stage and 8 ERS model genes related to prognosis were screened. Three subtypes of CRC were classified based on the former 50 genes. The clinical characteristics were significantly different among the subtypes. The ERscore model was constructed based on the latter 8 genes, and its accuracy was verified by clinical samples. Finally, the nomogram was constructed based on ERscore, age, and CRC stage, and the accuracy of the nomogram prediction was verified. CONCLUSION: ERS-related genes can be used as classification criteria for CRC, and the related clinical characteristics of different CRC subtypes are different.

α-SMA+ cancer-associated fibroblasts increased tumor enhancement ratio on contrast-enhanced multidetector-row computed tomography in stages I-III colon cancer.

BACKGROUND AND AIM: Our prior research revealed that the tumor enhancement ratio (TER) on triphasic abdominal contrast-enhanced MDCT (CE-MDCT) scans was a prognostic factor for patients with stages I-III colon cancer. Building upon this finding, the present study aims to investigate the proteomic changes in colon cancer patients with varying TER values. METHODS: TER was analyzed on preoperative triphasic CE-MDCT scans of 160 stages I-III colon cancer patients. The survival outcomes of those in the low-TER and high-TER groups were compared. Proteomic analysis on colon cancer tissues was performed by mass spectrometry (MS) and verified by immune-histological chemistry (IHC) assays. In vivo, mouse xenograft models were employed to test the function of target proteins identified through the MS. CE-MDCT scans were conducted on mice xenografts, and the TER values were compared. RESULTS: Patients in the high-TER group had a significantly worse prognosis than those in the low-TER group. Proteomic analysis of colon cancer tissues revealed 153 differentially expressed proteins between the two groups. A correlation between TER and the abundance of α-SMA protein in tumor tissue was observed. IHC assays further confirmed that α-SMA protein expression was significantly increased in high-TER colon cancer, predominantly in cancer-associated fibroblasts (CAFs) within the cancer stroma. Moreover, CAFs promoted the growth of CRC xenografts in vivo and increased TER. CONCLUSIONS: Our study identified the distinct protein changes in colon cancer with low and high TER for the first time. The presence of CAFs may promote the growth of colon cancer and contribute to an increased TER.

Efficacy of continuous gastric artery infusion chemotherapy in relieving digestive obstruction in advanced gastric cancer.

BACKGROUND: Obstruction or fullness after feeding is common in gastric cancer (GC) patients, affecting their nutritional status and quality of life. Patients with digestive obstruction are generally in a more advanced stage. Existing methods, including palliative gastrectomy, gastrojejunostomy, endoluminal stent, jejunal nutrition tube and intravenous chemotherapy, have limitations in treating these symptoms. AIM: To analyze the efficacy of continuous gastric artery infusion chemotherapy (cGAIC) in relieving digestive obstruction in patients with advanced GC. METHODS: This study was a retrospective study. Twenty-nine patients with digestive obstruction of advanced GC who underwent at least one cycle of treatment were reviewed at The Second Affiliated Hospital of Zhejiang University School of Medicine. The oxaliplatin-based intra-arterial infusion regimen was applied in all patients. Mild systemic chemotherapy was used in combination with local treatment. The clinical response was evaluated by contrast-enhanced computed tomography using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Digestive tract symptoms and toxic effects were analyzed regularly. A comparison of the Karnofsky Performance Status (KPS) score and Stooler's Dysphagia Score before and after therapy was made. Univariate survival analysis and multivariate survival analysis were also performed to explore the key factors affecting patient survival. RESULTS: All patients finished cGAIC successfully without microcatheter displacement, as confirmed by arteriography. The median follow-up time was 24 mo (95%CI: 20.24-27.76 mo). The overall response rate was 89.7% after cGAIC according to the RECIST criteria. The postoperative Stooler's Dysphagia Score was significantly improved. Twenty-two (75.9%) of the 29 patients experienced relief of digestive obstruction after the first two cycles, and 13 (44.8%) initially unresectable patients were then considered radically resectable. The median overall survival time (mOS) was 16 mo (95%CI: 9.32-22.68 mo). Patients who received radical surgery had a significantly longer mOS than other patients (P value < 0.001). Multivariate Cox regression analysis indicated that radical resection after cGAIC, intravenous chemotherapy after cGAIC, and immunotherapy after cGAIC were independent predictors of mOS. None of the patients stopped treatment because of adverse events. CONCLUSION: cGAIC was effective and safe in relieving digestive obstruction in advanced GC, and it could improve surgical conversion possibility and survival time.

Aging characteristics of colorectal cancer based on gut microbiota.

BACKGROUND: Aging is one of the factors leading to cancer. Gut microbiota is related to aging and colorectal cancer (CRC). METHODS: A total of 11 metagenomic data sets related to CRC were collected from the R package curated Metagenomic Data. After batch effect correction, healthy individuals and CRC samples were divided into three age groups. Ggplot2 and Microbiota Process packages were used for visual description of species composition and PCA in healthy individuals and CRC samples. LEfSe analysis was performed for species relative abundance data in healthy/CRC groups according to age. Spearman correlation coefficient of age-differentiated bacteria in healthy individuals and CRC samples was calculated separately. Finally, the age prediction model and CRC risk prediction model were constructed based on the age-differentiated bacteria. RESULTS: The structure and composition of the gut microbiota were significantly different among the three groups. For example, the abundance of Bacteroides vulgatus in the old group was lower than that in the other two groups, the abundance of Bacteroides fragilis increased with aging. In addition, seven species of bacteria whose abundance increases with aging were screened out. Furthermore, the abundance of pathogenic bacteria (Escherichia_coli, Butyricimonas_virosa, Ruminococcus_bicirculans, Bacteroides_fragilis and Streptococcus_vestibularis) increased with aging in CRCs. The abundance of probiotics (Eubacterium_eligens) decreased with aging in CRCs. The age prediction model for healthy individuals based on the 80 age-related differential bacteria and model of CRC patients based on the 58 age-related differential bacteria performed well, with AUC of 0.79 and 0.71, respectively. The AUC of CRC risk prediction model based on 45 disease differential bacteria was 0.83. After removing the intersection between the disease-differentiated bacteria and the age-differentiated bacteria from the healthy samples, the AUC of CRC risk prediction model based on remaining 31 bacteria was 0.8. CRC risk prediction models for each of the three age groups showed no significant difference in accuracy (young: AUC=0.82, middle: AUC=0.83, old: AUC=0.85). CONCLUSION: Age as a factor affecting microbial composition should be considered in the application of gut microbiota to predict the risk of CRC.

Tumor enhancement ratio on preoperative abdominal contrast-enhanced CT scan for predicting recurrence risk in stage II colon cancer.

PURPOSE: The identification of high recurrence risk stage II colon cancer patients was critical to adjuvant chemotherapy decision. However, current definition of high-risk features remains inadequate. This study aimed to construct a model for predicting recurrence risk based on tumor enhancement ratio (TER) on abdominal contrast-enhanced CT scan. METHOD: 282 stage II colon cancer patients were included and randomly divided into training and validation sets in the ratio of 7:3. TER was calculated using maximum tumor attenuation value in contrast-enhanced CT scan divided by the minimum. Kaplan-Meier survival analyses were adopted to evaluate the prognostic value of variables. A model based on TER was built to predict recurrence risk through the LASSO Cox model. The recurrence risk score of patients was calculated based on this model. RESULTS: The optimal cut-off value of TER was 1.83 derived from the time-dependent ROC (tdROC) curve. Patients with high-TER showed increasingly poorer disease-free survival (DFS) in both training (p < 0.001) and validation (p < 0.001) sets. A model was built based on TER demonstrated satisfactory performance to recurrence risk prediction (C-index: 0.784 in the training set and 0.725 in the validation set). Patients were regrouped into modified high-risk and non-high risk according to recurrence risk score (cut-off value: 1.75) and a significant DFS difference was observed (training set: p < 0.001; validation set: p < 0.001). CONCLUSION: TER can serve as a high-risk feature of stage II colon cancer. And a model based on TER provided a new approach to assess recurrence risk of stage II disease.

Procalcitonin Levels in Post TACE Infection.

PURPOSE: This study aimed to evaluate the value of serum procalcitonin (PCT) levels in the diagnosis of abscess and sepsis following transarterial chemoembolization (TACE) therapy among patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: In this study, a retrospective review of patient charts was performed in 2221 patients who suffered from hepatocellular carcinoma and had undergone 8656 TACE procedures from January 2012 to January 2018. According to the diagnosis of infection and abscess after TACE, these participants were divided into infection group (group A, n=48) and abscess group (group B, n=35). Group B included subgroup B1 (suffered from liver abscess but no sepsis, n=16) and subgroup B2 (suffered from liver abscess and sepsis, n=19). The main observational indexes included sociodemographic characteristics and laboratory and clinical parameters. RESULTS: The results showed that the mean PCT and C-reactive protein (CRP) levels were higher in group B, but receiver-operating characteristic (ROC) analysis showed low sensitivity and specificity. Only the mean PCT level was higher in subgroup B2 than in subgroup B1 (P<0.001); the ROC analysis had high sensitivity and specificity. However, all other data such as NEUT (neutrophil count) and NEUTP (neutrophil percentage) showed no significant differences. CONCLUSION: Serum PCT level was a promising inexpensive marker for the diagnosis of liver abscess and sepsis following TACE therapy among patients with primary liver cancer. A cutoff level of 5.1 ng/mL for PCT had high sensitivity and specificity in predicting liver abscess with sepsis.

Catastrophic vertebral artery and subclavian artery pseudoaneurysms caused by a fishbone: A case report.

BACKGROUND: Fishbone is the most common esophageal foreign body and tends to migrate after piercing the esophagus to nearby structures. Vascular injury around the esophagus is a serious complication and has a high mortality rate, especially in the case of multiple vascular injuries. CASE SUMMARY: We report an extremely rare case of successive vertebral artery and subclavian artery pseudoaneurysms caused by swallowing a fishbone in a previously healthy 29-year-old female. She was transferred to the emergency department of our hospital because of hemorrhagic shock due to a vertebral artery pseudoaneurysm. We successfully managed the vertebral artery pseudoaneurysm with endovascular stent implantation and the patient's vital signs as well as hemodynamics once became stable. However, the patient died of the second subclavian artery pseudoaneurysm occurring within a short time, which was thought be related to the obvious displacement of the fishbone in the mediastinum. CONCLUSION: Surgery and endovascular stent implantation may be the best choice for treating such complications. Early removal of the fishbone is of great significance in improving the survival of such patients.

Extent of enhancement on multiphase contrast-enhanced CT images is a potential prognostic factor of stage I-III colon cancer.

OBJECTIVE: By evaluating extent of tumour enhancement on preoperative contrast-enhanced MDCT, we aimed to establish an imaging-based model to predict cancer-specific survival in stage I-III colon cancer. METHODS: A total of 548 stage I-III colon cancer patients who underwent curative resection from 2007 to 2013 were retrospectively included and divided into primary cohort and validation cohort according to admission time. The attenuation coefficient of each colon cancer was measured on the workstation by drawing the ROI in CT images. The enhancement ratio was calculated using maximum tumour attenuation value in triphasic MDCT scanning divided by the minimum. Patients were divided into low/high-enhancement groups according to the optimal cut-off value derived from time-dependent ROC curve. Kaplan-Meier method and COX regression analysis were adopted to evaluate prognostic value of variables. A nomogram for prognosis was conducted on the basis of a multivariate Cox proportional hazard model. RESULTS: No significant differences were observed in age, sex, pTNM stage, perioperative chemoradiotherapy, serum CEA, tumour size, tumour localisation and histologic type between low- and high-enhancement groups. The high-enhancement group had a significantly shorter cancer-specific survival rate (69.5%) than the low-enhancement group (85.9%) (p < 0.001). Subgroup analysis indicated that high-enhancement state was closely associated with increased risk of colon cancer mortality in stage I (p = 0.033), stage II (p = 0.002) and stage III (p = 0.014). Cox regression analysis indicated the extent of enhancement was an independent prognostic factor (HR 2.258, 95% CI 1.476-3.455; p < 0.001). CONCLUSIONS: The extent of tumour enhancement on MDCT can serve as a potential risk factor for stage I-III colon cancer. KEY POINTS: • Survival rates of stage I-III colon cancer vary widely even within the same stage. • Prognostic value of the extent of tumour enhancement on MDCT was assessed. • The high-enhancement group had a significantly shorter cancer-specific survival rate.

Contrast-enhanced multiple-phase imaging features of intrahepatic mass-forming cholangiocarcinoma and hepatocellular carcinoma with cirrhosis: A comparative study.

The intrahepatic mass-forming cholangiocarcinoma (IMCC) is frequently misdiagnosed as hepatocellular carcinoma (HCC) in patients with cirrhosis, by numerous radiologists and clinical doctors, which results in the incorrect therapeutic treatment. A retrospective case-control study was conducted, and the contrast-enhanced multiple-phase (CEMP) computed tomography (CT) and magnetic resonance imaging (MRI) findings of 22 pathologically confirmed IMCC patients and 22 HCC controls with underlying liver cirrhosis were analyzed at the present hospital, from January 2010 to December 2015. In addition, serum tests were conducted and clinical symptoms of patients evaluated. A statistical analysis revealed that the enhancement pattern, signal on MRI delayed phase (P<0.001), maximum diameter, capsule retraction, portal vein invasion, bile duct dilation and abdominal lymphadenectasis characteristics were different between IMCC and HCC patients with cirrhosis. On CEMP CT and MRI analysis, the most frequently occurring enhancement patterns of IMCC were progressive patterns (P=0.001 or P<0.001). Conversely, the most frequently occurring enhancement patterns present in HCC were the washout patterns (P<0.001). Therefore, the diagnosis of IMCC in cirrhotic patients should be verified with CEMP CT and MRI analysis for the future, to determine presence or absence of progressive and/or peripheral rim-like enhancement, a hyperintensive delayed phase with capsule retraction, portal vein invasion, bile duct dilation, abdominal lymphadenectasis and increased levels of CA199.

Multiple-phase spiral CT findings of pancreatic vasoactive intestinal peptide-secreting tumor: A case report.

The present study reports a case of pancreatic vasoactive intestinal peptide-secreting tumor (VIPoma), of 2.2 cm in diameter, arising from the region of the uncus of the pancreas with liver metastases in a 50-year-old patient, which demonstrated unusual multiple-phase spiral computed tomography (MPSCT) results. The pancreatic lesion was isodense compared with the pancreatic parenchyma. During the hepatic artery phase and portal venous phase, the mass was hypodense compared with the enhanced pancreas, with the mean CT attenuation (HU) values being 56 HU and 66 HU, respectively. During the hepatic parenchymal phase, the mass became hyperdense with the mean CT attenuation values being 74 HU. The process of contrast-enhanced MPSCT demonstrated progressive strengthening. Pancreaticoduodenectomy and wedge resection of a number of the liver metastases was performed. There are only a limited number of studies reporting CT findings of pancreatic VIPoma and no MPSCT findings have been described previously.

Differentiation between Graves' disease and painless thyroiditis by diffusion-weighted imaging, thyroid iodine uptake, thyroid scintigraphy and serum parameters.

The aim of the present study was to assess the apparent diffusion coefficient (ADC) in diffusion-weighted imaging (DWI), thyroid radioactive iodine uptake (RAIU), thyroid scintigraphy and thyrotropin receptor antibody (TRAb) levels in the differential diagnosis between Graves' disease (GD) and painless thyroiditis (PT). A total of 102 patients with GD and 37 patients with PT were enrolled in the study. DWI was obtained with a 3.0-T magnetic resonance scanner, and ADC values were calculated. RAIU and thyroid scintigraphy were performed. Tissue samples were obtained from patients with GD (6 cases) following thyroidectomy, and from patients with PT (2 cases) following biopsy. Receiver operating characteristic (ROC) curves were drawn, optimal cut-off values were selected, and the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were assessed. It was found that the ADC, TRAb and RAIU were significantly higher in GD than in PT (P<0.05). ROC curves showed areas under the curves for RAIU, ADC and TRAb that were >0.900. RAIU was the reference method. Sensitivity, specificity, accuracy, PPV and NPV were 96.078, 91.892, 95.000, 97.059 and 89.474% for ADC, and 88.235, 75.676, 84.892, 90.909 and 70.000% for TRAb, after the optimal thresholds of 1.837×10-3 mm2/sec and 1.350 IU/ml were determined respectively. Histopathology showed that tissue cellularity in PT was much higher than in GD due to massive lymphocytic infiltration. The results of the present study indicate that RAIU, ADC and TRAb are of diagnostic value for differentiating between GD and PT. DWI has great potential for thyroid pathophysiological imaging because it reflects differences in tissue cellularity between GD and PT.

Eosinophilic gastroenteritis associated with eosinophilic cystitis: Computed tomography and magnetic resonance imaging findings.

Eosinophilic gastroenteritis (EG) is a rare, distinct clinical entity, and EG associated with eosinophilic cystitis (EC) is extremely rare and has not been well documented. Here, we report two cases of EG and coexistent EC along with findings from computed tomography (CT) and magnetic resonance imaging (MRI). An 18-year-old male with a history of hematuria, urgency and occasional urodynia for two weeks and a 34-year-old male with a history of abdominal distention for one week were admitted to our hospital. Abdominal contrast-enhanced CT in both patients revealed wall thickening in different parts of the gastrointestinal tract with inhomogeneous reinforcement, coexistent with local or diffuse bladder wall thickening with progressive enhancement, and also showed that the bladder mucosal lining was nondestructive. Pelvic MRI showed that the local or diffuse thickened bladder wall was iso-intense on T1-weighted images, hypo-intense on T2-weighted images, and slightly restricted on diffusion weighted imaging (DWI) in one case. After therapy, the thickened wall of the gastrointestinal tract and urinary bladder had improved markedly in the two cases. To the best of our knowledge, this is the first report on the radiological imaging of EG and coexistent EC by both CT and MRI and the first with DWI findings.

Desmoplastic small round cell tumor: A case report of a rare differential diagnosis of solid tumors of the pleura.

Desmoplastic small round cell tumor (DSRCT) presents as a rare separate clinical pathological entity, and pleural DSRCT is very rare. Following review of the English literatures it was revealed that, to date, <15 cases of primary DSRCT of the pleura have been reported worldwide. Among these, there are few computed tomography (CT) findings of pleural DSRCT which have previously been described in detail. The present study reports a pathologically proven case of pleural DSRCT, with varying contrast CT findings in a 72-year-old female, which appeared as a large (12.0×10.0×6.5 cm), smooth, oval mass in the left lower thorax with slight-moderate uniform enhancement on contrast-enhanced CT. To the best of our knowledge, the present report is the first to describe the large solid-tumor pattern and the patient is the eldest reported case of pleural DSRCT.