Caveolin-1 Expression Together with VEGF can be a Predictor for Lung Metastasis and Poor Prognosis in Osteosarcoma Abstract Caveolin-1, the major protein component of caveolae, plays vital functions in tumorigenesis and metastasis. Previous evidence demonstrated the positive role of Caveolin-1 in the regulation of endothelial cell differentiation and the involvement of Caveolin-1 in vascular endothelial growth factor (VEGF) mediated angiogenesis. The correlation of Caveolin-1 expression and angiogenesis is not yet elucidated in osteosarcoma. This study aimed to investigate the expression levels of Caveolin-1 and VEGF in osteosarcoma and their associations with clinicopathological data. This study included 66 formalin-fixed and paraffin embedded osteosarcoma tissue samples. The expression levels of Caveolin-1 and VEGF were assessed by immunohistochemistry. Then associations with clinicopathological variables and the correlation between both markers were evaluated statistically. We also investigated the expression of Caveolin-1 and VEGF values in gene microarrays of osteosarcoma patients and cell lines by using GEO data sets on https://www.ncbi.nlm.nih.gov. Caveolin-1 and VEGF were expressed in 19.6% and 77.3%, respectively. Caveolin-1 expression was associated positively with osteoblastic histological subtype (P < 0.0001). VEGF expression showed positive association with patient age, histological grade and clinical stage (P = 0.031, P = 0.024 and P < 0.001; respectively). An inverse correlation between Caveolin-1 and VEGF expressions in osteosarcoma was found (r = 0.2 P = 0.04). In silico analysis of Caveolin-1 and VEGF expression supported our results. Our results suggest that Caveolin-1 may act as a tumor suppressor in osteosarcoma. Down-regulation of Caveolin-1 can be used as an indicator for poor prognosis in osteosarcoma patients. Meanwhile, overexpression of VEGF is a predictor of pulmonary metastasis and poor prognosis.

Neutrophil Extracellular Traps Associate with Clinical Stages in Breast Cancer Abstract Recently, neutrophil extracellular traps (NETs), three-dimensional structures formed of neutrophil enzymes such as neutrophil elastase (NE) and nuclear components (DNA), have been associated with progression in different types of cancer. However, data remain scarce in breast cancer. Thus, the aim of this study was to associate NETs with clinical stages of breast cancer. A prospective analysis was performed in 45 plasma samples of female patients with newly diagnosed breast cancer. NE-DNA complexes were evaluated by ELISA. Optical density was dichotomized at the median for comparisons (low and high levels of NE-DNA). The most frequent clinical stage was localized (n = 28, 62%) followed by regional (n = 13, 29%) and distant (n = 4, 9%). Higher levels of NE-DNA complexes were observed in regional and distant stages compared to localized disease (68% vs 32%, p = 0.034). No differences were observed when comparing other clinical characteristics between both groups. We demonstrated that the levels of NETs increase in proportion to the stage of the disease, observing higher levels of NE-DNA complexes in regional and metastatic disease, which coincides with the proposed mechanism by which cancer progression and metastasis might result from the formation of NETs.

Renal Cell Carcinoma with Clear Cell Papillary Features: Perspectives of a Differential Diagnosis Abstract Thirty-one cases of low-grade renal cell carcinoma (RCC) with clear cells and tubulopapillary/papillary architecture were analyzed retrospectively with immunohistochemical and genetic markers to gain more experience with the differential diagnosis of such cases. All samples coexpressed CK7 and CA9; the TFE3 or TFEB reactions were negative; the CD10 and the AMACR stainings were negative in 27 cases and 30 cases, respectively. The FISH assays for papillary RCC, available in 27 cases, and deletion of chromosome 3p, available in 29 cases, gave negative results. The results for 3p deletion, VHL gene mutation or VHL gene promoter region hypermethylation testing, along with the diffuse CD10-positivity in 2 cases confirmed 21 cases as clear cell papillary RCC (CCPRCC; CK7+, CA9+; no 3p loss, no VHL abnormality) and 10 cases as clear cell RCC (CCRCC; CK7+, CA9+; no 3p loss, VHL abnormality mutation/hypermethylation present). In CCPRCCs, the representative growth pattern was branching tubulo-acinar, commonly accompanied by cyst formation. The linear nuclear arrangement or cup-shaped staining of CA9 did not necessarily indicate CCPRCC, and the absence of these did not exclude the diagnosis of CCPPRC. One tumor infiltrated the renal sinus; the others exhibited pT1 stage; and metastatic outcome was not recorded. The CCRCC cases were in pT1 stage; 6 exhibited cup-shaped staining of CA9, and 1 displayed lymph node metastasis at the time of surgery. Distant metastatic disease was not observed. In summary, the VHL abnormalities distinguished the subset of CCRCC with diffuse CK7-positivity and no 3p loss from cases of CCPRCC.

Review: Ewing Sarcoma Predisposition Abstract Ewing sarcoma is a rare tumor developed in bone and soft tissues of children and teenagers. This entity is biologically led by a chromosomal translocation, typically including EWS and FLI1 genes. Little is known about Ewing sarcoma predisposition, although the role of environmental factors, ethnicity and certain polymorphisms on Ewing sarcoma susceptibility has been studied during the last few years. Its prevalence among cancer predisposition syndromes has also been thoroughly examined. This review summarizes the available evidence on predisposing factors involved in Ewing sarcoma susceptibility. On the basis of these data, an integrated approach of the most influential factors on Ewing sarcoma predisposition is proposed.

Simultaneous endocrine expression and loss of melanoma markers in malignant melanoma metastases, a retrospective analysis Abstract Malignant melanoma metastases are chameleons of histopathology. In 4 primary malignant melanomas and 20 melanoma metastases expression of S-100, HMB-45 and melan-A as melanoma markers and CD56, synaptophysin and chromogranin-A as neuroendocrine markers was retrospectively analyzed. While all primary tumors expressed all 3 melanoma markers 7/20 of melanoma metastases had lost at least one melanoma marker, one had lost all three markers. Conversely about half of the samples stained for CD56, only 6/20 metastases were negative for all 3 neuroendocrine markers. None expressed chromogranin-A. Partial loss of melanoma markers and expression of neuroendocrine markers seems not to be infrequent. In patients with a history of malignant melanoma and suspected metastases, losing melanoma markers while expressing neuroendocrine markers is a potential diagnostic pitfall. Therefore all 3 melanoma markers should be performed as well as chromogranin-A staining. In doubt, metastases of the melanoma should be assumed.

LncRNA HEIH Enhances Paclitaxel-Tolerance of Endometrial Cancer Cells via Activation of MAPK Signaling Pathway Abstract This study aimed to investigate the function of lncRNA HEIH on promoting endometrial cancer cells’ tolerance of paclitaxel (PTX). LncRNA HEIH expression was measured by QRT-PCR in endometrial cancer tissues, human healthy tissues and cell lines. The PTX-resistant endometrial cancer cells (Ishikawa-RE and HHUA-RE) were intermittently exposed to increase concentrations of PTX and were constructed as evidenced by MTT assay. Besides, the specific siRNA of HEIH (siHEIH) and pcDNA3.1-HEIH plasmid transfection were utilized to alter the expression of HEIH in the cells and investigate the effects of HEIH on resistance to PTX in endometrial cancer cells. Moreover, MTT, colony formation and apoptosis analysis were taken advantage to evaluate cell viability and proliferation when treated with PTX. Then, differential genes in PTX-resistant and HEIH-knock-down PTX-resistant endometrial cancer cells were screened out by microarray analysis. Finally, gene-set enrichment analysis was used to predict the promising signaling pathway of HEIH and western blotting analysis were performed to verify the relevant genes expression of MAPK signaling pathway. LncRNA HEIH, the dysregulation of which involved in production of drug-resistance, was overexpressed in PTX-resistant endometrial cancer cells. Up-regulating HEIH would activate MAPK pathway, promote chemo-resistance of endometrial cancer cells and enhance cell proliferation and viability, whereas silencing HEIH depressed the MAPK signaling pathway, contributed to restoring chemo-sensitivity to PTX and repressed cell physiological process. Down-regulating lncRNA HEIH expression reversed the PTX-resistance of endometrial cancer cells through MAPK signaling pathway.

Development and Validation of a Model for Predicting Intravesical Recurrence in Organ-confined Upper Urinary Tract Urothelial Carcinoma Patients after Radical Nephroureterectomy: a Retrospective Study in One Center with Long-term Follow-up Abstract Although radical nephroureterectomy is the standard treatment method for upper urinary tract urothelial carcinoma, it is associated with a high risk of intravesical recurrence. There are no models for predicting IVR after RNU in patients with organ-confined UTUC. Therefore, we developed and validated a model for postoperative prediction of IVR after RNU. The development cohort consisted of 416 patients who underwent RNU with bladder cuff excision at our center between 1 January 2007 and 31 December 2015. Patient clinicopathologic data were recorded. Multivariate Cox proportional hazard ratio regression was used to build a predictive model with regression coefficients, backward step-wise selection was applied, and the likelihood ratio test with Akaike’s information criterion was used as the stopping rule. An independent cohort consisting of 152 consecutive patients from 1 January 2016 and 31 December 2017 was used for validation. The performance of this predictive model was assessed with respect to discrimination, calibration, and clinical usefulness. The predictors in this model included tumor stage, tumor diameter, tumor location, and tumor grade. In the validation cohort, the model showed good discrimination, with a concordance index of 0.689 (95% CI, 0.629 to 0.748) and good calibration. Decision curve analysis demonstrated that the model was also clinically useful. This study presents a good model that may facilitate individualized postoperative prediction of IVR after RNU in patients with organ-confined UTUC, and thus, may help improve postoperative strategies and facilitate treatment outcomes.

Retrospective Analysis of Cancer-Associated Myositis Patients over the Past 3 Decades in a Hungarian Myositis Cohort Abstract Association between cancer and myositis has been extensively reported and malignancy is a potentially life-threating complication in myositis. In this retrospective study authors give an overview of Hungarian cancer-associated myositis (CAM) patients treated at a single centre managing 450 myositis patients. All patients were diagnosed according to Bohan and Peter. Statistical analysis of disease onset, age, sex, muscle, skin and extramuscular symptoms, muscle enzymes, presence of antibodies, treatment and prognosis was performed. 43 patients could be considered as having CAM. 83.72% had cancer within one year of diagnosis of myositis. Most common localizations were ductal carcinoma of breast and adenocarcinoma of lung. Significant differences were observed between CAM and the non-CAM control patients: DM:PM ratio was 2.31:1 vs. 0.87:1, respectively (p = 0.029), age at diagnosis was 56.60 ± 12.79 vs. 38.88 ± 10.88 years, respectively (p < 0.001). Tumour-treatment was the following: surgical removal in 55.81%, chemotherapy in 51.1%, radiotherapy in 39.53%, hormone treatment in 18.6%, combination therapy in 51.16% of patients. Muscle enzyme levels of patients undergoing surgery were significantly reduced after intervention. 36 patients died (83.72%); 25 DM (83.33%) and 11 PM patients (84.62%); 5 years survival was 15.4% for PM and 27.5% for DM. This study demonstrates that DM, distal muscle weakness, asymmetric Raynaud’s phenomenon, older age, ANA-negativity are risk factors for developing malignancy and polymyositis patients have less chance of long-lasting survival. It is very important to think about cancer and follow every single myositis patient in the clinical routine because survival rate of CAM is very poor.

LncRNA CASC9 Suppressed the Apoptosis of Gastric Cancer Cells through Regulating BMI1 Abstract Long noncoding RNAs (lncRNAs) play important roles in regulating the apoptosis of gastric cancer (GC) cells. This study aims to investigate the underlying mechanism of lncRNA CASC9 in regulating the apoptosis of GC cells. The expressions of lncRNA and protein in GC tissues and cell lines were detected by qRT-PCR and western blot. GC cell apoptosis was detected by flow cytometry analysis. RNA pull-down and RNA immunoprecipitation (RIP) assays were conducted to verify the interaction between CASC9 and BMI1. LncRNA CASC9 was upregulated in GC tissue and GC cells, and high CASC9 expression was positively correlated with TNM stage and lymph node metastasis. Silencing CASC9 promoted the apoptosis of GC cells. LncRNA CASC9 could interact with BMI1 and positively regulate BMI1 expression. Silencing CASC9 promoted the ubiquitination of BMI1. In addition, lncRNA CASC9 regulated the apoptosis of GC cells through BMI1. Furthermore, interfering CASC9 inhibited the tumor growth of GC. LncRNA CASC9 could interact with BMI1 to regulate the degradation of BMI1, thus to affect the apoptosis of GC cells and suppressed tumor growth.

CDGSH Iron Sulfur Domain 2 Deficiency Inhibits Cell Proliferation and Induces Cell Differentiation of Neuroblastoma Abstract CDGSH iron sulfur domain 2 (CISD2) is reported to be highly expressed in several cancers, but the role of it in neuroblastoma has not been identified yet. Here, for the first time, we show that CISD2 is involved in neuroblastoma tumorigenesis and regulates neuroblastoma cell proliferation and differentiation. We found that high CISD2 expression correlated significantly with poor outcome of neuroblastoma patients, as well as advanced neuroblastoma tumor stages. Knockdown of CISD2 greatly repressed neuroblastoma cell proliferation and tumorigenesis both in vitro and in vivo. Further investigation showed that CISD2 deficiency resulted in cell cycle arrest in G1 phase and induced cell differentiation of neuroblastoma. Several Cyclins and Cyclin-Dependent Kinases (CDKs) were down-regulated by CISD2 knockdown, indicating that CISD2 probably regulates cell cycle through those genes. Together, we provide evidence that CISD2 is an indicator for neuroblastoma patients prognosis and is indispensable for neuroblastoma cell proliferation and tumorigenesis; CISD2 deficiency can induce neuroblastoma cell cycle arrest and differentiation. These findings suggest that CISD2 could work as a novel and potential therapeutic target for neuroblastoma treatment.