Circulating small extracellular vesicle-based miRNA classifier for follicular thyroid carcinoma: a diagnostic study.

BACKGROUND: The diagnosis of follicular thyroid carcinoma (FTC) prior to surgery remains a major challenge in the clinic. METHODS: This multicentre diagnostic study involved 41 and 150 age- and sex-matched patients in the training cohort and validation cohort, respectively. The diagnostic properties of circulating small extracellular vesicle (sEV)-associated and cell-free RNAs were compared by RNA sequencing in the training cohort. Subsequently, using a quantitative real-time polymerase chain reaction (qRT‒PCR) assay, high-quality candidates were identified to construct an RNA classifier for FTC and verified in the validation cohort. The parallel expression, stability and influence of the RNA classifier on surgical strategy were also investigated. RESULTS: The diagnostic properties of sEV long RNAs, cell-free long RNAs and sEV microRNAs (miRNAs) were comparable and superior to those of cell-free miRNAs in RNA sequencing. Given the clinical application, the circulating sEV miRNA (CirsEV-miR) classifier was developed from five miRNAs based on qRT‒PCR data, which could well identify FTC patients (area under curve [AUC] of 0.924 in the training cohort and 0.844 in the multicentre validation cohort). Further tests revealed that the CirsEV-miR score was significantly correlated with the tumour burden, and the levels of sEV miRNAs were also higher in sEVs from the FTC cell line, organoid and tissue. Additionally, circulating sEV miRNAs remained constant after different treatments, and the addition of the CirsEV-miR classifier as a biomarker improves the current surgical strategy. CONCLUSIONS: The CirsEV-miR classifier could serve as a noninvasive, convenient, specific and stable auxiliary test to help diagnose FTC following ultrasonography.

Higher Potential Sensitization of Cow αS1-Casein over Goat αS1-Casein in a Mouse Model due to Enhanced Dendritic Cell Uptake and Activation.

Cow's milk allergy is a common food allergy, with the milk protein αS1-casein being a major allergen. This study aimed to investigate differences in sensitization between cow and goat αS1-CN. Cow and goat αS1-CN were labeled with fluorescent dyes and given to mice sensitized with cholera toxin adjuvant. Both proteins reached immune organs, suggesting no major difference in digestion. However, compared with goat αS1-CN, cow αS1-CN is more readily taken up by dendritic cells, inducing dendritic cell maturation. Furthermore, cow αS1-CN can more effectively induce the generation of Th2 cells, leading to a higher production of specific IgE. In a Caco-2/RBL-2H3 cell model, cow αS1-CN caused more mast cell degranulation and loss of epithelial barrier integrity than goat αS1-CN. In summary, this study found differences in immune responses between cow and goat milk αS1-CN. Cow αS1-CN elicited stronger dendritic cell and Th2 responses, leading to increased mast cell degranulation.

Exosome-mediated delivery of miR-519e-5p promotes malignant tumor phenotype and CD8+ T-cell exhaustion in metastatic PTC.

CONTEXT: Distant metastases are the primary cause of therapy failure and mortality in patients with papillary thyroid carcinomas (PTCs). However, the underlying mechanism responsible for the initiation of tumor cell dissemination and metastasis in PTCs has rarely been investigated. OBJECTIVE: The aim of this study was to investigate effects and underlying molecular mechanisms of circulating exosomal microRNAs (miRNAs) in distant metastatic PTCs. METHODS: The most relevant circulating exosomal miRNA to distant metastatic PTCs were verified between distant metastatic PTCs and nondistant metastatic PTCs by miRNA microarray, quantitative real-time polymerase chain reaction (qRT‒PCR) assays and receiver operating characteristic (ROC) curves. The parental and recipient cells of that circulating exosomal miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of circulating exosomal miRNAs that contribute to the development of distant metastases. RESULTS: We identified that PTC-derived exosomal miR-519e-5p was significantly upregulated in the circulatory system in distant metastatic PTCs. Further tests demonstrated that PTC cells can acquire a more malignant phenotype via hnRNPA2B1 mediated sorting of tumor suppressor miR-519e-5p into exosomes to activate Wnt signaling pathway via upregulating PLAGL2. Furthermore, miR-519e-5p included in PTC-derived exosomes can be transferred to recipient CD8+ T cells and aid in tumor immune escape in distant organs through inhibiting Notch signaling pathway by downregulating NOTCH2. CONCLUSION: Our findings highlighted the dual role of PTC-derived exosomal miR-519e-5p in distant metastasis, which may improve our understanding of exosome-mediated distant metastatic mechanisms.

A novel intronic circular RNA circFGFR1int2 up-regulates FGFR1 by recruiting transcriptional activators P65/FUS and suppressing miR-4687-5p to promote prostate cancer progression.

Fibroblast growth factor receptor 1 (FGFR1) is a core component of the FGFs/FGFR pathway that activates multiple signalling pathways, including ERK1/2, PI3K/AKT, PLCγ, and NF-κB. Aberrant expression of FGFR1 due to gene amplification, chromosome rearrangement, point mutation, and epigenetic deregulations, have been reported in various cancers. FGFR1 overexpression has also been reported in prostate cancer (PCa), but the underlining mechanisms are not clear. Here we report a novel circular RNA, circFGFR1int2, derived from intron 2 of FGFR1 gene, which is overexpressed in PCa and associated with tumor progression. Importantly, we show that circFGFR1int2 facilitates FGFR1 transcription by recruiting transcription activators P65/FUS and by interacting with FGFR1 promoter. Moreover, we show that circFGFR1int2 suppresses post-transcriptional inhibitory effects of miR-4687-5p on FGFR1 mRNA. These mechanisms synergistically promote PCa cell growth, migration, and invasion. Overexpression of circFGFR1int2 is significantly correlated with higher tumor grade, Gleason score, and PSA level, and is a significant unfavorable prognosticator for CRPC-free survival (CFS) (RR = 3.277, 95% confidence interval: 1.192-9.009; P = 0.021). These findings unravelled novel mechanisms controlling FGFR1 gene expression by intronic circRNA and its potential clinicopathological utility as a diagnostic or therapeutic target.

Integration of hepatic lipidomics and transcriptomics reveals the effect of butter-derived ruminant trans fatty acids on lipid metabolism in C57BL/6J mice.

Dysregulation of lipid metabolism results in metabolism-related diseases. Our previous research indicated that 1.3% E and 4% E ruminant trans fatty acids (R-TFA) caused dyslipidemia and promoted atherosclerotic plaques in ApoE-/- mice, presenting detrimental effects. However, the effect of R-TFA on the lipid metabolism of normal mice remains unclear. Therefore, our current research aims to explore the effects of butter-derived R-TFAs on the lipid metabolism of C57BL/6J mice through the integration of lipidomics and transcriptomics. As a result, we found that 1.3% E butter-derived R-TFA promoted dyslipidemia and impaired hepatic function in C57BL/6J mice fed a high-fat diet, which was associated with an increase in DG (18:1/22:5), TG (18:1/18:2/22:4) and FA (24:5) as determined through lipidomics analysis, but had a less significant effect on C57BL/6J mice fed a low-fat diet. Through a combination analysis and verification of gene expression, we found that the arachidonic acid pathway might be involved in the disruption of lipid metabolism by butter-derived R-TFA. In addition, butter-derived R-TFA up-regulated the expression of unigene thromboxane-A synthase 1 (Tbxas1), arachidonate lipoxygenase 3 (Aloxe3), acyl-coenzyme A thioesterase 2 (Acot2), epoxide hydrolase 2 (Ephx2) and carbonyl reductase 3 (Cbr3) in C57BL/6J mice fed a high-fat diet. Herein, our research provides a new perspective for exploring the effects of butter-derived R-TFA on lipid metabolism and speculates on the possible mechanism of lipid metabolism disorder induced by butter-derived R-TFA in C57BL/6J mice fed a high-fat diet.

miR-142-3p encapsulated in T lymphocyte-derived tissue small extracellular vesicles induces Treg function defect and thyrocyte destruction in Hashimoto's thyroiditis.

BACKGROUND: Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disease characterized by lymphocyte infiltration that destroys thyrocyte cells. The aim of the present study was to elucidate the role and mechanisms of tissue small extracellular vesicle (sEV) microRNAs (miRNAs) in the pathogenesis of HT. METHODS: Differentially expressed tissue sEV miRNAs were identified between HT tissue and normal tissue by RNA sequencing in the testing set (n = 20). Subsequently, using quantitative real-time polymerase chain reaction (qRT‒PCR) assays and logistic regression analysis in the validation set (n = 60), the most relevant tissue sEV miRNAs to HT were verified. The parental and recipient cells of that tissue sEV miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of sEV miRNAs that contribute to the development of HT. RESULTS: We identified that miR-142-3p encapsulated in T lymphocyte-derived tissue sEVs can induce Treg function defect and thyrocyte destruction through an intact response loop. Inactivation of miR-142-3p can effectively protect non-obese diabetic (NOD).H-2h4 mice from HT development display reduced lymphocyte infiltration, lower antibody titers, and higher Treg cells. Looking at the mechanisms underlying sEV action on thyrocyte destruction, we found that the strong deleterious effect mediated by tissue sEV miR-142-3p is due to its ability to block the activation of the ERK1/2 signaling pathway by downregulating RAC1. CONCLUSIONS: Our findings highlight the fact that tissue sEV-mediated miR-142-3p transfer can serve as a communication mode between T lymphocytes and thyrocyte cells in HT, favoring the progression of HT.

Quantitative Phosphoproteome of Infant Formula: New Insights into the Difference of Phosphorylation in Milk Proteins between Bovine and Goat Species.

Phosphorylation is a broad post-translational protein modification, and the level of phosphorylation of milk proteins is associated with lactation, coagulation properties, and digestibility. However, phosphoproteins in bovine milk-based and goat milk-based infant formula have not been systematically explored. Here, we have analyzed six bovine and six goat milk-based infant formula using a quantitative phosphoproteomics approach, from which we identified 200 phosphoproteins with 276 phosphorylation sites and 156 phosphorylation sites from 75 phosphoproteins, respectively. Of these, 99 phosphorylation sites from 26 shared phosphoproteins were differentially expressed between bovine and goat milk-based infant formula. Especially, CSN1S1 was the most phosphoprotein with 25 quantified phosphorylation sites. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the identified phosphoproteins not only provide nutrition to the infant but also have anti-inflammatory, antipathogenic, and other biological functions. Our results shed light on the composition, phosphorylation sites, and biological functions of phosphoproteins in bovine milk and goat milk-based infant formula, which provide new insights into the key role of protein modifications during infant development. It also helps us to better understand the differences in digestibility of infant formula from different animal milk sources and thus guides the choice of milk source for infant formula.

circEZH2E2 /E3 is a dual suppressor of miR363/miR708 to promote EZH2 expression and prostate cancer progression.

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is overexpressed in a variety of malignancies including prostate cancer (PCa) and may play important roles in tumor progression. Gene copy number gains, enhanced transcription, and a few circRNAs have been reported to upregulate EZH2. It was not known whether EZH2 itself generates circRNAs that promote its own expression. We here report the identification of circEZH2E2/E3 that is derived from exons 2 and 3 of the EZH2 gene and overexpressed in PCa. We show that circEZH2E2/E3 functions as a dual inhibitor for both miR363 and miR708 that target the EZH2 3'UTR and CDS, respectively, resulting in the upregulation of EZH2 expression and hence the downregulation of EZH2-repressed genes (e.g., CDH1 and DAB2IP), and enhancement of PCa cell proliferation, migration, invasion, and xenograft PCa growth. Overexpression of circEZH2E2/E3 is significantly correlated with higher tumor grade, tumor progression, and unfavorable progression-free and disease-specific survival in PCa patients. These findings show a novel autoenhancing EZH2-circEZH2E2/E3 -miR363/miR708-EZH2 regulatory loop, by which circEZH2E2/E3 plays important roles in PCa tumorigenesis and progression by upregulating EZH2, and may have potential diagnostic, prognostic, and therapeutic uses in PCa management.

Dietary Plant Protein Intake Can Reduce Maternal Insulin Resistance during Pregnancy.

Evidence suggests that the source of dietary protein may have an impact on insulin resistance, but no studies have explored it in pregnant populations. In this study, we combined a population study and an animal experiment to explore this effect. The population study was conducted with data from NHANES. Multiple linear regression was used to observe the association of protein intake with outcomes, including fasting glucose (GLU), insulin (INS), and HOMA-IR. In the animal experiment, 36 pregnant SD rats in three groups were orally administered 100% animal protein, 50% animal protein and 50% plant protein, or 100% plant protein, respectively. The intervention continued throughout the whole pregnancy. On day 19.5, maternal plasma was collected after overnight fasting, and metabolomics was performed using UPLC-MS. We found plant protein intake was negatively correlated with INS and HOMA-IR in the whole population. During the third trimester, a similar correlation was also observed. The animal experiment also presented the same result. In metabolomic analysis, changes in various metabolites and related pathways including FoxO and mTOR signaling pathways were observed. In conclusion, we found a negative association between dietary plant protein intake and maternal insulin resistance during pregnancy. Changes in some active substances and related metabolic pathways may play an important role.

Butter-Derived Ruminant Trans Fatty Acids Do Not Alleviate Atherosclerotic Lesions in High-Fat Diet-Fed ApoE-/- Mice.

Atherosclerosis (AS) is the most common cardiovascular disease (CVD). Currently, it is widely believed that R-TFA and I-TFA may cause different biological effects. In the present study, we aim to elucidate the effect of mixed R-TFA derived from butter on the development of AS in high-fat diet-fed ApoE-/- mice and find the possible mechanism. It was shown that butter-derived R-TFA promoted dyslipidemia, reduced thoracic and abdominal aorta diameters, and induced aortic lipid deposition and atherosclerotic lesions in high-fat diet-fed ApoE-/- mice. Meanwhile, butter-derived R-TFA affected the serum lipid profile of high-fat diet-fed ApoE-/- mice and the lipid metabolism of human umbilical vein endothelial cells (HUVECs). Through lipidomic techniques, we found that butter-derived R-TFA had a significant effect on the glycerophospholipid metabolic pathway. In conclusion, our results demonstrated that butter-derived R-TFA does not alleviate but promotes atherosclerotic lesions in high-fat diet-fed ApoE-/- mice and that the glycerophospholipid metabolic pathway plays a major role in this pro-atherosclerotic effect.

Phosphoproteomics reveals that camel and goat milk improve glucose homeostasis in HDF/STZ-induced diabetic rats through activation of hepatic AMPK and GSK3-GYS axis.

Diabetes is a serious public health problem with global implications. Among many diabetes management therapies, non-pharmacological therapies such as those that focus on diet and exercise are gradually becoming more acceptable to patients. Within dietary management options, dairy products such as camel and goat milk are valued for their specific health benefits. The aim of this study was therefore to investigate the effect of camel and goat milk consumption on glucose homeostasis in high-fat diet and streptozotocin (HFD/STZ) induced diabetic rats. HFD/STZ-induced diabetic rats were fed with different milk for 35 days. Parameters related to glucose homeostasis, as well as hepatic proteome and phosphoproteome were investigated. The results of which showed that camel and goat milk consumption improved fasting glucose levels, glucose tolerance, and indicators related to lipid metabolism, while bovine and sheep milk consumption did not work. In addition, the hepatic phosphoproteome suggests that the ameliorative effect of both camel and goat milk was associated with the activation of AMPK. However, camel milk consumption further elevated the phosphorylation level of hepatic ACC, while goat milk consumption activated GSK3-GYS axis-related proteins. The present study investigated the possible mechanisms by which camel and goat milk consumption improves glucose homeostasis in HFD/STZ-induced diabetic rats and revealed their differences in the mechanism of antidiabetic effect.

Cow's milk αS1-casein is more sensitizing than goat's milk αS1-casein in a mouse model.

The aim of this study was to compare the sensitization of αS1-CN in cow and goat's milk in a mouse model. Fifty mice were divided into control group, adjuvant control group, cow's milk αS1-CN sensitized group, goat's milk αS1-CN sensitized group and cross sensitized group. Cow's and goat's milk αS1-CN were used to establish a mouse sensitization model. The results showed that cow's milk αS1-CN had higher allergenicity than goat's milk αS1-CN, as can be seen in significantly increased s-IgE and Th2 cell-related inflammatory factors, the proportion of Th2, and the expression of Th2 cell-related transcription factors. Furthermore, the sensitization of cow's milk αS1-CN damaged the intestinal barrier of mice, caused the leakage of LPS, activated the TLR4-NFκB pathway, and thus resulted in the increase of IFN-γ. In addition, mice allergic to cow's milk αS1-CN were less sensitized to goat's milk αS1-CN.

A novel promoter-associated non-coding small RNA paGLI1 recruits FUS/P65 to transactivate GLI1 gene expression and promotes infiltrating glioma progression.

Glioma-associated oncogene homolog 1 (GLI1) is a core component of the Hedgehog (HH) signalling pathway and is a transcription activator of numerous oncogenes, such as SOX9, VEGFA, BCL2, and CDK2. The complex regulation of GLI1 involves numerous pathways and molecules, including HH-dependent and independent, epigenetic and post-transcriptional mechanisms. Here, we report the discovery, characterization and function of a novel sense promoter-associated ncRNA, paGLI1 that is overexpressed in infiltrating glioma. We show that paGLI1 promotes GLI1 gene transcription through binding to and recruitment of the transcription factor complex FUS/P65 by interacting with paGLI1 DNA sequence. This interaction facilitates FUS/P65 binding to the GLI1 promoter to activate GLI1 transcription and hence its downstream oncogenes, which results in enhancement of glioma cell proliferation and invasiveness. Importantly, over-expression of paGLI1 is a significant unfavorable prognosticator for both disease-specific and progression-free survival in glioma patients, with relative risks being 2.932 (95% confidence interval: 1.280 to 6.713) (P < 0.05) and 2.284 (95% confidence interval: 1.051 to 4.966) (P < 0.05), respectively. The novel paGLI1/FUS/P65 regulatory mechanisms play important roles in infiltrating glioma progression and may serve as potential targets for future therapeutics.

Response to transarterial chemoembolization may serve as selection criteria for hepatocellular carcinoma liver transplantation.

AIMS: This study sought to extend the inclusion criteria for hepatocellular carcinoma (HCC) liver transplantation (LT), particularly addressing the safety and effectiveness of pre-LT transarterial chemoembolization (TACE). MATERIALS AND METHODS: Our study included 115 patients with HCC who underwent LT after TACE. The response measured after each TACE session was based on the mRECIST criteria: complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). We defined CR and PR patients as responders (64 cases) and SD and PD patients as non-responders (51 cases). RESULTS: The majority of responders could be identified after the first or second TACE sessions (57 cases, 89.1%). Overall survival rates at 1, 3 and 5 years were 95.3%, 89.1% and 75.0%, respectively, in the responder group, and these rates were much higher than those in the non-responder group (86.3%, 66.7% and 54.9%, P=0.016). In addition, the tumor-free survival rate in the responder group was also higher than in the non-responder group (P=0.009). In the responder group, a statistically improved long-term outcome was observed in patients whose HCC did not satisfy the Milan criteria (P<0.05). Univariate and multivariate Cox analyses showed that achieving CR or PR was the best predictor of survival and tumor-free survival following TACE. CONCLUSION: The response to TACE, particularly following the first two sessions, primarily and robustly predicted overall and tumor-free survival in HCC patients, particularly those whose HCC did not satisfy the Milan criteria.

Downregulation of miR-199a-5p promotes prostate adeno-carcinoma progression through loss of its inhibition of HIF-1α.

Hypoxia-inducible factor-1 alpha (HIF-1α) plays key roles in cell survival under both hypoxia and normoxia conditions. Regulation of HIF-1α is complex and involves numerous molecules and pathways, including post-transcriptional regulation by microRNAs (miRNAs). Although upregulation of HIF-1α has been shown to promote prostate adenocarcinoma (PCa) progression, the mechanism by which miRNAs modulate HIF-1α in prostate cancer has not been clarified. Here, we show that miR-199a-5p is underexpressed in prostate adenocarcinoma. Artificial overexpression of miR-199a-5p decreased cell proliferation, motility, and tumor angiogenesis and increased apoptosis in PCa cell liness PC-3 and DU145 by directly targeting the 3'-untranslated region (UTR) of HIF-1α mRNA, which reduced HIF-1α levels as well as downstream genes transactivated by HIF-1α (such as VEGF, CXCR4, BNIP3 and BCL-xL). Abnormalities of miR-199a-HIF regulation may contribute significantly to PCa pathogenesis and progression.

Skip lateral lymph node metastasis leaping over the central neck compartment in papillary thyroid carcinoma.

OBJECTIVE: This study was performed to investigate the frequency and pattern as well as the predictive factors of skip metastasis (lateral cervical lymph node metastasis without central lymph node metastasis) in papillary thyroid carcinoma (PTC). METHODS: 450 PTC patients who received total thyroidectomy with central neck dissection(CND) combined with modified radical lateral neck dissection(LND) were divided into two groups: with or without skip metastases. The clinicopathological characteristics were statistically compared and analyzed, and univariate and multivariate analyses were performed to detect the risk factors of skip metastasis. RESULTS: The skip metastasis rate was 8.7% (39/450), and patients with skip metastases had fewer lateral lymph node metastases but were more likely to have single-level lateral metastasis, which are considered Level II(P<0.05). Skip metastasis was significantly associated with the primary tumor location in the upper portion (OR=18.495, 95% CI 6.612-51.731), a primary tumor size ≤10mm (OR=32.492, 95% CI 11.973-88.174) and Capsule invasion (OR=5.822, 95% CI 1.954-17.343) as demonstrated by our prospective study of 10 patients who received an injection of 0.1 ml carbon nanoparticles under ultrasonography in the upper portion of the lobe: 7(70%) had lateral compartment lymph node black staining without ipsilateral center compartment lymph node staining. However, skip metastasis did not affect the PTC patients' long-term tumor-free survival rate (P=0.432). CONCLUSION: Skip metastases can be common, and the primary tumor location in the upper portion, a primary tumor size ≤10 mm, and capsular invasion are closely linked to skip metastasis. The lateral compartment should be carefully evaluated.

Synchronous papillary thyroid carcinoma and breast ductal carcinoma: A rare case report and literature review.

BACKGROUND: The incidences of both thyroid cancer and breast cancer have been rising in recent years; however, it is very rare to find a single person with both of these cancers. Only a few cases of synchronous thyroid and breast cancer have been published, and even fewer cases have been reported in older patients (>60 years). CASE SUMMARY: The current study presents a case of synchronous papillary thyroid carcinoma and breast ductal carcinoma in an elderly patient. The patient first underwent a mastectomy and axillary lymphadenectomy in our department, followed by a total thyroidectomy and lymphadenectomy of the left lateral region of the neck 1 month later. Postoperative pathological examination identified invasive ductal carcinoma of the breast and papillary carcinoma of the thyroid. Over almost half a year of follow-up, the patient has exhibited no evidence of recurrence or metastasis, as demonstrated by careful ultrasound examinations. Herein, we not only report this case but also present a systematic review of the causes, diagnosis, and treatment of synchronous breast and thyroid cancer. CONCLUSION: Although synchronous primary tumors of the thyroid and breast are very rare, they remain a possibility; therefore, more attention should be paid to these cases.

IDH1/2 gene hotspot mutations in central nervous system tumours: analysis of 922 Chinese patients.

Mutations of isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes have been identified as early molecular events in the development of astrocytomas and oligodendrogliomas. Data regarding the status and prevalence of IDH1/2 mutations in Chinese patients are limited. Herein we report our data from West China Hospital, a major Chinese medical centre. IDH1(R132H) mutation was analysed by immunohistochemistry with the mutation-specific IDH1(R132H) antibody in 1011 patients, including 922 central nervous system (CNS) tumours and 89 non-neoplastic CNS lesions, and PCR-based direct sequencing of IDH1/2 gene mutation in 570 of these samples. Correlation with clinicopathological features and immunohistochemical expression of p53, EGFR, PTEN and Ki-67 was examined. Our data showed that IDH1/2 mutation was present in oligodendrogliomas, anaplastic oligodendrogliomas, diffuse or anaplastic astrocytomas, and glioblastomas, with decreasing frequency, but not in other types of CNS tumours or non-neoplastic lesions examined. IDH1(R132) mutation was most frequent in oligodendrogliomas (57/62, 91.9%), with IDH1(R132H) mutation as the most frequent mutation form. Only one case for each of the rare mutations (R132C, R132G, R132L, and R132S) was identified in the 570 samples analysed by sequencing. Younger age, low expression of p53 and low Ki-67 index were significantly correlated with IDH1 mutation status (p=0.000). All tumours with IDH1(R132) mutations were supratentorial, with frontal lobe as the most frequent site for IDH-mutated gliomas. Only three IDH2(R172) mutation cases were detected in this series. Univariate survival analysis in 459 glioma patients with diffusely infiltrating gliomas showed that IDH1 mutations as well as the more classical prognosticators (age, WHO grade, p53 and Ki-67 index) were of prognostic significance. Multivariate analysis by Cox proportional hazard regression model demonstrated that lack of IDH1 mutation was an independent prognostic factor for both progression-free survival [relative risk (RR)=2.450, 95% confidence interval (CI)=1.351-4.444] and disease-specific survival (RR=2.489, 95%CI=1.155-5.363).

Hepatocellular carcinoma cases with high levels of c-Raf-1 expression may benefit from postoperative adjuvant sorafenib after hepatic resection even with high risk of recurrence.

BACKGROUND AND AIMS: Liver resection combined with postoperative sorafenib to prevent recurrence remains a controversial approach for cases of hepatocellular carcinoma (HCC), especially cases with a high risk of recurrence. This study aimed to investigate the efficacy and safety of liver resection combined with sorafenib for HCC with a high risk of recurrence. RESULTS: Most of the cases of HCC were caused by hepatitis B virus (HBV) infection (23 cases, 92%). Most of these tumors (21 cases, 84%) were stage III according to the TNM staging system (12 cases with IIIa, 9 cases with IIIb). In the months after hepatic resection, 19 of the 25 cases (76%) were diagnosed with HCC recurrence or metastasis. Based on the tumor histological biomarker grading system, the group with higher expression levels of c-Raf-1 showed significantly longer overall survival than the group with lower expression of c-Raf-1 (P = 0.012). However, the long-term tumor-free survival advantage disappeared (P = 0.061). Univariate and multivariate analyses indicated that higher expression of c-Raf-1 was significantly associated with better overall survival (hazard ratio [HR]: 1.842; 95% confidence interval [CI]: 1.211-2.542; P = 0.031) and tumor-free survival (HR: 1.319; 95% CI: 1.017-1.543; P = 0.046) in HCC patients who underwent radical hepatic resection. PATIENTS AND METHODS: We retrospectively collected 25 HCC cases with a high risk of recurrence who underwent radical liver resection and who took sorafenib postoperatively from Jan 2010 to Dec 2012. Factors that might contribute to tumor recurrence and treatment failure such as clinical factors, tumor features, and molecular biomarkers were included in our analysis. CONCLUSIONS: HCC patients with a high risk of post-hepatic resection recurrence may benefit from postoperative sorafenib administered as an adjuvant therapy, especially in cases with high levels of c-Raf-1 expression on histological examination.

Peripheral primitive neuroectodermal tumor of the kidney in a 51-year-old female following breast cancer: A case report and review of the literature.

Peripheral primitive neuroectodermal tumor/Ewing's sarcoma (pPNET/EWS) is an aggressive type of sarcoma that is rarely observed in the kidney. pPNET of the kidney principally occurs in young patients (<50 years old) and is very rare in older patients (≥50 years old). Additionally, only six cases of pPNET of the kidney have been reported in the literature in older patients (≥50 years old), and pPNET as a secondary primary tumor has rarely been reported. The current study presents a case of renal pPNET in a 51-year-old female who had been surgically treated for breast carcinoma and administered with adjuvant chemotherapy five years prior to hospitalization for pPNET. A computed tomography scan identified a tumor in the lower pole of the right kidney, which was treated by nephrectomy. Immunohistochemistry demonstrated diffuse, strong membranous positivity for cluster of differentiation (CD)99, positive nuclear staining for friend leukemia integration 1, and negative staining for Wilms' tumor 1 and other markers. Fluorescence in situ hybridization (FISH) analysis of the EWS breakpoint region 1 (EWSR1) demonstrated the characteristic EWSR1 translocation. The patient declined chemotherapy or radiotherapy but accepted traditional Chinese medicine. No evidence of recurrence was observed eight months after diagnosis. Only two cases of renal pPNET with a history of an earlier or synchronous primary cancer were reported in the literature from the USA and Germany, respectively. To the best of our knowledge, the present case is the first FISH-confirmed renal pPNET in an older patient following breast adenocarcinoma.