RIT1 suppresses esophageal squamous cell carcinoma growth and metastasis and predicts good prognosis.

Ras-like without CAAX1 (RIT1) protein is a member of Ras family, which plays critical roles in signaling pathways and cellular process regulation. However, the role of RIT1 in esophageal squamous cell carcinoma (ESCC) is unclear. In this study, we found that the expression of RIT1 is downregulated in ESCC compared to corresponding non-tumor tissues. The low-level expression of RIT1 was correlated with poorer prognosis. Then we showed that RIT1 inhibited proliferation, invasion, and migration of ESCC cells, and silencing RIT1 by shRNA promoted tumorigenicity and metastasis in nude mice. We further demonstrated that RIT1 inhibited the malignant behaviors of ESCC through inhibiting the PI3K/AKT and MAPK pathway and epithelial-mesenchymal transition in ESCC cells. Our study also revealed that RIT1 increased drug sensitivity to cisplatin (CDDP), and this function could be carried out through downregulating stemness of ESCC. In conclusion, our study indicates for the first time that RIT1 displays tumor-suppressing functions in ESCC, and these functions were carried out by inhibiting MAPK and PI3K/AKT signaling pathway, inhibiting EMT, and downregulating cancer stemness of ESCC cells.

Genomic comparison of esophageal squamous cell carcinoma and its precursor lesions by multi-region whole-exome sequencing.

Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC); however, the genetic evolution from dysplasia to ESCC remains poorly understood. Here, we applied multi-region whole-exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported in ESCC. Moreover, dysplasia is polyclonal, and remarkable heterogeneity is often observed between tumors and their neighboring dysplasia samples. Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma. The sharp contrast in the prevalence of the 'two-hit' event on TP53 between the two cohorts suggests that the complete inactivation of TP53 is essential in promoting the development of ESCC.The pathogenesis of oesophageal squamous cell carcinoma is a multi-step process but the genetic determinants behind this progression are unknown. Here the authors use multi-region exome sequencing to comprehensively investigate the genetic evolution of precursor dysplastic lesions and untransformed oesophagus.

Expression of programmed cell death-ligand 1 and its correlation with clinical outcomes in gliomas.

Programmed cell death-ligand 1(PD-L1) was expressed in various malignancies, and interaction with its receptor programmed cell death 1 (PD-1) often contributed to immune evasion of tumor cells. In this study, we explored the expression of PD-L1 and its correlation with clinical outcomes in gliomas. Clinicopathological data of 229 patients with gliomas was collected. PD-L1 expression was assessed by tissue-microarray-based immunohistochemistry. Over 5% of tumor cells with cytoplasm or membrane staining was defined as PD-L1 positive expression. The associations of clinicopathological features with overall survival (OS) and disease-free survival (DFS) were analyzed by univariate analysis and multivariate analysis was further performed by Cox regression model. PD-L1 positive expression was observed in 51.1% gliomas patients and no significant association was verified between PD-L1 expression and pathological grade in 229 gliomas patients. However, PD-L1 expression rate was 49.2%, 53.7% and 68.8% for grade II, III and IV in 161 patients with those ≥ 12 months of OS, respectively. Although no significant discrepancies was displayed, there was a certain degree of differences between PD-L1 expression and pathological grade (49.2% vs. 53.7% vs. 68.8%, P = 0.327). Univariate analysis showed that PD-L1 expression was significantly associated with poor OS in the patients with long-time survival or follow up (OS ≥ 12 months) (P = 0.018), especially in patients with grade IV (P = 0.019). Multivariate analysis revealed that a strong tendency towards statistical significance was found between PD-L1 expression and poor OS (P = 0.081). In gliomas patients with long-time survival or follow up, PD-L1 positive expression could indicate the poor prognosis and it is possible that immunotherapy targeting PD-L1 pathway needed to be determined in the further study.

Cytoplasmic expression of BAP1 as an independent prognostic biomarker for patients with gliomas.

BACKGROUND: BRCA1-associated protein-1 (BAP1) has been investigated the prognostic value for some carcinomas, including mammary carcinoma, pulmonary carcinoma and mesothelioma and so on. However, the status of BAP1 expression and the relationship of that with overall survival were not still estimated in patients with gliomas. Therefore, it was necessary to investigate the effect of BAP1 expression for the survival of patients with gliomas in this study. PATIENTS AND METHODS: Clinicopathological information of 229 patients with gliomas was used to perform the further analysis. We defined the nucleus expression of BAP1 score of median 0 and cytoplasmic expression of BAP1 score of median 100 as the rational cutoff value for survival analysis, respectively. These patients were categorized into the low cytoplasmic expression of BAP1 and the high expression of BAP1 group, presence of nucleus expression and absence of nucleus expression according to the corresponding cutoff point, respectively. The associations of clinicopathological characteristics with overall survival (OS) were investigated by univariate analysis in patients with gliomas. Multivariate analysis was further performed to find the independent prognostic indicator of OS by Cox regression model. RESULTS: Thirty-nine of 229 patients (17.0%) with gliomas had the nucleus expression of BAP1, 213 of 229 patients (93.0%) had the cytoplasmic expression of BAP1, and 28 patients (12.2%) with both cytoplasmic and nucleus expression, 5 cases (2.2%) without neither cytoplasmic nor nucleus expression. Univariate analysis demonstrated that high cytoplasmic expression of BAP1, tumor location, tumor relapse, advanced clinical stage were significant linkage with worse OS (P<0.05). Multivariate analysis revealed that high cytoplasmic expression of BAP1 was a significantly independent biomarker for adverse OS (hazard ratio: 1.516, 95% CI: 1.029-2.234, P=0.035). In stratified analysis, we found that the patients with high cytoplasmic expression of BAP1 had the shorter overall survival than these with low cytoplasmic expression of BAP1 in the 190 patients without nucleus expression of BAP1 (P=0.001). ROC curve analysis showed that cytoplasmic expression of BAP1 was superior to nucleus expression of BAP1 as a predictive factor in patients with gliomas (AUC=0.583, P=0.030 vs. AUC=0.516, P=0.679). CONCLUSIONS: This study suggested that cytoplasmic expression of BAP1 might be served as a valuable predictive biomarker of the prognosis in gliomas. High cytoplasmic expression of BAP1 might be benefit to identify patients who need to carry out further therapy.

Expression of ETV6/TEL is associated with prognosis in non-small cell lung cancer.

The ETV6/TEL gene is a member of the ETS family of transcription factors that has been mainly studied in hematological diseases. This study provides the first investigation of ETV6 expression in non-small cell lung cancer (NSCLC). In this study, ETV6 expression was immunohistochemically studied in 170 consecutive patients with NSCLC. The association between ETV6 expression and clinicopathological parameters was evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of ETV6 expression on survival. ETV6 expression was observed in 135 of the 170 (79.4%) patients. ETV6 expression was positive for nuclear staining. From the clinicopathological standpoint, the expression of ETV6 was significantly correlated with age (P=0.014). The overall survival was significantly enhanced in the group with a low expression of ETV6 compared with the group with a high expression of ETV6 (five-year survival rates, 56.53% versus 29.88%; P=0.002), and the same finding was obtained for disease-free survival (five-year survival rates, 52.24% versus 30.47%; P=0.001). Multivariable analysis confirmed that ETV6 expression increased the hazard of death after adjusting for other clinicopathological factors (hazard ratio, 2.002; 95% confidence interval, 1.303-3.074; P=0.002). Our study demonstrated that ETV6 was markedly involved in the development of NSCLC and could serve as a potential prognostic marker for this deadly disease.

Embryonal rhabdomyosarcoma of the paranasal sinuses: a case report and review of literature.

Embryonal rhabdomyosarcoma (ERMS) is a rare malignancy with a poor outcome. In this article, we describe a case of ERMS in the paranasal sinuses from a 60-year-old male patient. ERMS derived from the paranasal sinuses is extremely rare. The diagnosis of ERMS must be based on histological findings and immunohistochemical findings. In this case, microscopic observation showed tumor cells were arranged in flocked sheets, cord-like and acinar-like by hyperplastic fibrous tissue. And ERMS tissues were immunopositive for myogenin, desmin, MSA, CD56, vimentin, CD99, Syn and Ki-67 (40%+), and immunonegative for CK, EMA, LCA, GFAP, NSE, S-100, HMB-45 and Melan-A. Here, the patient was treated with multimodal therapy including endoscopic surgery, chemotherapy and radiation, but the patient's postoperative recovery is not too smooth.

A case of mucoepidermoid carcinoma located in the left forearm of a middle-aged pregnant woman.

In this article, we described a mucoepidermoid carcinoma (MEC) located in the left forearm of a 39-year-old pregnant woman. Here, the patient had a superficial tip size apophysis nearly 3 years, which begin to sustained growth after pregnant in 2012, and stopped growth after childbirth. MEC is a rare malignant tumor. Previously reports showed it mainly arise from the salivary, bronchial, thyroid, breast, lacrimal gland and conjunctiva. Here, we reported a case of MEC arising from the forearm gland for the first time. Histological finding showed a cystic and solid tumor in fibrous tissue below the squamous epithelium, and some columnar or cuboidal mucous cells covering on the epidermal cells or mixed with epidermal cells included in the tumor tissues. Also, Focal hyperplasia epidermal cells with round or oval nucleus in center were distributed in small pieces but no keratosis. The tumor tissues were immunopositive for CEA, P63, ki-67 (10%), CK7 and CK5/6, and immunonegative for CK20 and GCDFP-15. This case is a low-grade MEC and the patient's postoperative recovery is smooth.

Nasopharyngeal adenoid cystic carcinoma: a case report and review of the literature.

ACC derived from nasopharyngeal epithelial cells is rare, usually benign. In this article, we reported a nasopharyngeal adenoid cystic carcinoma (NACC) in a 31-year-old woman with a symptom of hoarseness, headache, epistaxis slightly, diplopia, facial numbness and dysphagia near 3 months. A tumor on the right side of the nasopharynx was confirmed by laryngoscope check and MRI of the skull base. Histopathological findings showed that tumor cells were arranged in cord-like or acinar-like by atypical hyperplastic epithelial cells forming a cribriform and tubular pattern, and immunohistochemical findings showed that tumor tissues were immunopositive for p63 (+), CK7 (+), CK19 (+), CK8 (+), CK18 (+), SMA (+), CK (+), p53 (++), S-100 (+) and Ki-67 (5%+), and negative for CD34 (-), CK5/6 (-), CEA (-) and CD117 (-). Patient was treated by surgical operation and radiotherapy, and was followed-up near 10 months, no local recurrence and distant metastasis.

Malignant myoepithelioma of the breast: a case report and review of literature.

In this article, we described a malignant myoepithelioma of the breast (MMB) in a 69-year-old woman. Breast cancer derived from myoepithelial cells is very rare, usually benign. The diagnosis of MMB based on histological and immunohistochemical finding. In this case, the author diagnosed the tumor as MMB, because tumor tissues were immunopositive for 34ßE12, P63, SMA, S-100, CD10, E-Cad and Ki-67, and immunnegative for CK5/6, desmin, ER, PR and C-erbB-2, because tumor tissue showed invasive growth and local hemorrhage or necrosis, suggesting malignant, and also because there was a transition between the tumor cells and hyperplastic myoepithelium of non-tumorous ducts. The patient's postoperative recovery is smooth and regular following of patient is essential.

Reduced expression of ZDHHC2 is associated with lymph node metastasis and poor prognosis in gastric adenocarcinoma.

BACKGROUND: Zinc finger, DHHC-type containing 2 (ZDHHC2), originally named as reduced expression associated with metastasis protein (REAM), has been proposed as a putative tumor/metastasis suppressor gene and is often aberrantly decreased in human cancers. However ZDHHC2 expression pattern and its clinical significance have not yet been investigated in gastric adenocarcinoma. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative Real-Time PCR (qRT-PCR) and immunostaining were performed to detect ZDHHC2 expression in gastric adenocarcinoma, and then the correlation between ZDHHC2 expression and clinicpathologic parameters, and patient survival was analyzed. Compared to the adjacent normal tissues, ZDHHC2 expression was significantly reduced in gastric tumor tissues as shown by qRT-PCR and immunostaining. Low expression of ZDHHC2 was observed in 44.7% (211/472) of gastric adenocarcinoma patients, and was associated significantly with lymph node metastasis (p<0.001) and histological grade (p<0.001). Multivariate Cox regression analysis indicated that ZDHHC2 expression had a significant, independent predictive value for survival of gastric cancer patients (HR = 0.627, p = 0.001). CONCLUSIONS/SIGNIFICANCE: Our data suggest that reduced ZDHHC2 expression is associated with lymph node metastasis and independently predicts an unfavorable prognosis in gastric adenocarcinoma patients.

The "stone-like" pattern of LC3A expression and its clinicopathologic significance in hepatocellular carcinoma.

Autophagy is an evolutionarily conserved process that involves lysosomal degradations of cellular organelles. Microtubule-associated protein 1 light chain 3A (LC3A), an autophagic gene, is differentially expressed in human cancers. However, the relationship between LC3A expression and hepatocellular carcinoma (HCC) has not been investigated. Tissue microarray-based immunohistochemistry was used to examine the expression patterns of LC3A in HCC. The resulting data were analyzed using receiver operating characteristic curves, Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression modeling. Two distinct patterns of LC3A expression were observed in HCC: "stone-like" structuring and diffuse cytoplasmic expression. High levels of LC3A expression were more frequently observed in HCC tissues compared to the adjacent non-tumorous tissue. Correlation analyses indicated that high expression of the "stone-like" LC3A was correlated with greater levels of serum AFP, poorer tumor differentiation and the presence of vascular invasion. Kaplan-Meier survival analysis showed a significant association between high expression of the "stone-like" LC3A and unfavorable prognosis (P<0.001). Importantly, multivariate analysis (P<0.05) identified the "stone-like" expression of LC3A in HCC as an independent prognostic factor. Collectively, our data provide compelling evidence that "stone-like" expression of LC3A plays an important role in HCC progression and may act as a biomarker of prognosis for patients with HCC.

Clinicopathological characteristics and outcome of primary sarcomatoid carcinoma and carcinosarcoma of the liver.

BACKGROUND: Primary sarcomatoid carcinoma (SC) and carcinosarcoma (CS) of the liver are rare tumors. PATIENTS AND METHODS: From November 1999 to June 2011, clinicopathological features and outcome of 10 SC and 14 CS patients were retrospectively studied. RESULTS: In the SC group, six patients had hepatocellular carcinoma and four had cholangiocellular carcinoma, while in the CS group, it was nine and five patients, respectively. All cases of the sarcomatous components were vimentin-positive. Pan-cytokeratin were stained in sarcomatous components of the SC group, but not in the CS group. The sarcomatous component in the SC group was negative for desmin, myoglobin, HHF35, SMA, CD68, Mac387, AAT, CD34, and S100. In the CS group, the sarcomatous components in six cases were malignant fibrous histiocytomas, six were fibrosarcomas, and two were rhabdomyosarcomas. Median survival times were 9.6 and 4.8 months for the SC and CS groups, respectively (P = 0.483). In univariate analysis, favorable predictors of overall survival were asymptomatic, Child-Pugh class A, no distant metastasis, and radical resection. CONCLUSIONS: SC and CS were highly aggressive malignancies with similar poor survival regardless of the histological and immunohistochemical findings. Early detection through regular physical examination and treatment with radical resection may improve the outcome of those patients.

Prognostic relevance of Id-1 expression in patients with resectable esophageal squamous cell carcinoma.

BACKGROUND: Inhibitor of differentiation or DNA binding 1 (Id-1) is a transcriptional regulator that is associated with enhanced malignant potential and unfavorable survival in many cancers. However, its role and clinical significance in resectable esophageal squamous cell carcinoma (ESCC) has not been elucidated adequately. The purpose of this study was to explore the pattern of Id-1 expression and analyze its correlation with clinical outcomes of patients with resectable ESCC. METHODS: Primary tumors from 407 surgically resected ESCC specimens assembled on tissue microarrays were evaluated with immunohistochemical analysis for Id-1. The effect of Id-1 expression on survival outcome was analyzed by the Kaplan-Meier method. RESULTS: The expression of Id-1 correlated closely with pT category (p<0.001), pathologic staging (p<0.001), and pN category (p<0.001). The sensitivity, specificity, and accuracy of predicting lymph node metastasis by Id-1 expression were 93.3%, 94.7%, and 94.1%, respectively. Disease-specific survival was significantly favorable in patients with low-level Id-1 expression (p<0.001). Overexpression of Id-1 was also effective to predict unfavorable survival in subgroups of patients with poor differentiation (p<0.001) or with advanced T staging (p<0.001). Multivariate analysis showed that the level of Id-1 expression was an independent prognostic factor in ESCC (p<0.001; relative risk, 1.578). CONCLUSIONS: Expression of Id-1 can be used as a complement for predicting lymph node metastasis in pretreatment workup. High level of Id-1 expression suggested unfavorable prognosis for patients with resectable ESCC.

Primary nasopharyngeal adenocarcinoma: a review.

Primary nasopharyngeal adenocarcinoma (NAC) accounts for approximately 0.5% of all nasopharyngeal cancer. The diagnosis, staging and treatment of NAC has not been well described. This article presents a literature review on NAC and identifies its characteristics and management. The NAC group of diseases contains various pathological types and has a series of specific clinical characteristics, including slow progression, a low incidence of neck masses and frequent cranial neuropathy. The Epstein-Barr virus may not play an important role in NAC carcinogenesis. The rarity of the disease makes the staging classification and treatment strategies of NAC parallel to those recommended for nasopharyngeal squamous carcinoma. Some patients might benefit from surgery, and radiotherapy using precise techniques might achieve good control for treating NAC, but the roles of chemotherapy and target therapy are not clear. The proper staging system and optimal treatment strategies need to be established in NAC.

Long-term molecular changes in WHO grade II astrocytomas following radiotherapy.

Monitoring the long-term radiotherapy-associated molecular changes in low-grade gliomas (LGGs) facilitates the understanding of LGG response to radiotherapy. In this study, we used immunohistochemistry to analyze the expression of Ki-67, tumor protein P53 (TP53), P21, and P27 in 8 paired WHO grade II astrocytoma samples. The interval between radiotherapy (RT) and the second surgery was more than 3 months in all cases. The average Ki-67 labeling index (LI) was 5.3% in pre-RT samples and 11.54% in post-RT samples. Ki-67 LI was higher in the primary tumors that underwent malignant transformation observed at the second surgery after radiation. Post-RT Ki-67 LI decreased in 2 cases with an interval of less than 12 months between RT and the second surgery. TP53 expression was found in 3 out of 4 pre-RT samples with malignant transformation and in 1 out of 4 pre-RT samples without malignant transformation. Post-RT TP53 increased in 2 cases in which increased expression of P21 or P27 was also observed. Our study suggests that radiotherapy can inhibit WHO grade II astrocytoma proliferation as reflected by Ki-67 LI, but the effect attenuates with time. In addition, there is a tendency of malignant transformation for WHO grade II astrocytomas with a high Ki-67 level or TP53 expression in initial samples.

Clinicopathological investigation of four cases of desmoplastic small round cell tumor.

The purpose of this study was to perform clinicopathological and immunohistochemical analysis and to investigate the Ewing sarcoma gene (EWS)-Wilms' tumor suppressor gene (WT1) fusion within desmoplastic small round cell tumors (DSRCTs). Histology slides and clinical data were reviewed for four patients with DSRCT. A variety of immunohistochemical staining was performed. Fluorescence in situ hybridization (FISH) was performed to detect the EWS-WT1 fusion transcripts resulting from the chromosomal translocation t(11;22)(p13;q12). The patients consisted of four males aged from 26 to 52 years old (mean, 33.5). In three of these patients, the tumors were situated in the abdominal cavity and the tumor from the other patient was located in the pelvic cavity. The tumors were 8-15 cm in diameter (mean tumor diameter, 13), solid and gray-white, with an appearance of nodosity or sublobes, and hemorrhage or necrosis was observed. Microscopically, the tumors consisted of small round cell nests of unequal size. Hyperplastic and thick fibrous connective tissue surrounding the neoplastic cell nests was present in all cases. The tumor nuclei were hyperchromatic and contained inconspicuous nucleoli with a high level of karyokinesis. Immunohistochemical staining revealed diffuse and strong staining for CK, vimentin, desmin and CAM5.2 in all cases. Certain cases also expressed WT-1, EMA, NSE, CD56, CD99 and CK5/6. Staining was negative for myogenin, MyoD1, calretinin, CD117, CD34, HMB45 and CEA. EWS-WT1 fusion transcripts were detected in 3 out of 4 cases, but not in any other tumor types studied as controls using paraffin-embedded tissue by FISH. DSRCT is a highly maligant tumor occuring predominantly in the abdominal or pelvic cavity of young males with multiphenotypic differentiation. Basic morphological features, clinical manifestations and the detection of the EWS-WT1 fusion transcript within the tumor aid the recognition and diagnosis of the tumor.

A clinicopathological aspect of primary small-cell carcinoma of the uterine cervix: a single-centre study of 25 cases.

AIMS: Small-cell carcinoma is a variant of poorly differentiated neuroendocrine carcinoma. Primary small-cell carcinoma of the cervix (SCCC) is recognised as a rare and aggressive malignant tumour with poor prognosis. In this study, the authors report 25 Chinese cases of SCCC, with a particular focus on their clinical and pathological characteristics. MATERIAL AND METHODS: The records of 25 patients from 4075 Chinese patients with cervical cancer were collected and reviewed, including the patients' age, initial symptoms, cervical tumour size, International Federation of Gynaecology and Obstetrics clinical stage, lymph-node metastasis, treatments and follow-up results. Immunohistochemical detection was performed for cytokeratin, epithelial membrane antigen, neuron-specific enolase (NSE), synaptophysin (Syn), chromogranin A (CgA), neuronal cell adhesion molecules (CD56), thyroid transcriptional factor-1 and S100 protein (S100). RESULTS: The median age of 25 patients with SCCC was 43.7 years. The most common symptom was abnormal vaginal bleeding. Histologically, there were 19 'homogenous' SCCC samples and six samples of SCCC mixed with adenocarcinoma. The proportion of SCCC samples with positive immunoreactivity were 100.0% for NSE, 96.0% for Syn, 68.0% for CD56, 76.0% for CgA, 40.0% for thyroid transcriptional factor-1, 84.0% for epithelial membrane antigen, 68.0% for cytokeratin and 8.0% for S100, respectively. Every patient received one to three types of treatments, including surgery, chemotherapy and radiotherapy. The median survival time of patients was 20.9 months after diagnosis. CONCLUSION: The higher proportion of positive labelling of Syn, CD56, CgA, and NSE in SCCC implicated that they are valuably applied in a differential diagnosis of the malignancy. The patients with SCCC receive one to three types of therapies, including surgery, chemotherapy and radiotherapy, and have a poor prognosis.

miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer.

The microRNA miR-125b is dysregulated in various human cancers but its underlying mechanisms of action are poorly understood. Here, we report that miR-125b is downregulated in invasive breast cancers where it predicts poor patient survival. Hypermethylation of the miR-125b promoter partially accounted for reduction of miR-125b expression in human breast cancer. Ectopic restoration of miR-125b expression in breast cancer cells suppressed proliferation, induced G(1) cell-cycle arrest in vitro, and inhibited tumorigenesis in vivo. We identified the ETS1 gene as a novel direct target of miR-125b. siRNA-mediated ETS1 knockdown phenocopied the effect of miR-125b in breast cell lines and ETS1 overexpression in invasive breast cancer tissues also correlated with poor patient prognosis. Taken together, our findings point to an important role for miR-125b in the molecular etiology of invasive breast cancer, and they suggest miR-125b as a potential theranostic tool in this disease.

EZH2 protein: a promising immunomarker for the detection of hepatocellular carcinomas in liver needle biopsies.

BACKGROUND AND AIMS: A previous study of ours indicated that enhancer of zeste homologue 2 (EZH2) plays an important role in hepatocellular carcinoma (HCC) tumorigenesis. The aim of the present study was to investigate the potential diagnostic utility of EZH2 in HCC. METHODS: Immunohistochemistry was performed to examine the expression dynamics of EZH2 in two independent surgical cohorts of HCC and non-malignant liver tissues to develop a diagnostic yield of EZH2, HSP70 and GPC3 for HCC detection. The diagnostic performances of EZH2 and a three-marker panel in HCC were re-evaluated by using an additional biopsy cohort. RESULTS: Immunohistochemistry analysis demonstrated that the sensitivity and specificity of EZH2 for HCC detection was 95.8% and 97.8% in the testing cohort. Similar results were confirmed in the validation cohort. For diagnosis of well-differentiated HCCs, the sensitivity and specificity were 68.9% and 91.5% for EZH2, 62.5% and 98.5% for HSP70, 50.0% and 92.1% for GPC3, and 75.0% and 100% for a three-marker panel. In biopsies, positive cases for at least one marker increased from large regenerative nodule and hepatocellular adenoma (0/12) to focal nodular hyperplasia (2/20), dysplastic nodule (7/25), well-differentiated HCC (16/18) and moderately and poorly differentiated HCC (54/54). When at least two positive markers were considered, regardless of their identity, the positive cases were detected in 0/12 large regenerative nodules and hepatocellular adenomas, 0/20 focal nodular hyperplasias, 0/25 dysplastic nodules, 11/18 well-differentiated HCCs, 32/37 moderately differentiated HCCs and 15/17 poorly differentiated HCCs. CONCLUSION: Our findings suggest that EZH2 protein, as examined by immunohistochemistry, may serve as a promising diagnostic biomarker of HCCs, and the use of a three-marker panel (EZH2, HSP70 and GPC3) can improve the rate of detection of HCCs in liver biopsy tissues.

A new alternative for bony chest wall reconstruction using biomaterial artificial rib and pleura: animal experiment and clinical application.

OBJECTIVE: To evaluate a new method for chest wall reconstruction using porcine-derived artificial rib and pleura in an animal experiment. Further, the clinical application was performed in five patients with large defects in the chest wall as a preliminary observation. METHODS: In animal experiments, a full-thickness chest wall defect of 7 cm × 8 cm was created in 12 adult mongrel dogs. Six dogs underwent reconstruction with porcine-derived artificial ribs and pleura (test group), and six with methylmethacrylate and double polyester mesh in the form of traditional Marlex sandwich technique (control group). At follow-up of each for 3, 6, and 12 months postoperatively, a general performance assessment and thoracic radiography were performed. Gross and histopathological examinations were carried out following humane euthanasia at the time of last follow-up. In clinical application, five patients with wide tumor resection in the chest wall underwent reconstruction with porcine-derived artificial ribs and pleura as well. RESULTS: In animal experiment, no perioperative death or hyperpyrexia occurred and no difference in either infection or dyspnea was noted between the two groups. Postoperative radiography revealed good thoracic integrity with no evidence of collapse, deformation, or abnormal movement in the test group. In the control group, similar results were observed, except that two dogs had abnormal movement in the chest wall associated with respiration. Severe adhesions between the 'sandwich' complex and the host tissues were identified in the control group, but by contrast, only mild adhesions were noted in the test group. The non-degradable polyester mesh induced fibrous proliferation and rejection, whereas the artificial pleura was absorbed with mild fibrous hyperplasia after 12 months. In clinical application, no thoracic deformity, chronic pain, or respiratory discomfort were observed at 1 or 12 postoperative months. CONCLUSIONS: Porcine-derived ribs and pleura can be employed safely to create an artificial chest wall to repair bony chest defects. The clinical results corresponded well with those of animal experiments, and thus confirmed the safety and feasibility of this new alternative of chest wall reconstruction. However, a long-term study in a large number is needed due to the small number of animals in this study.