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Abstract Aim The aim of this study was to analyze prognostic factors of early-stage squamous cell carcinoma of the vulva. Methods A retrospective analysis was conducted on 35 patients who were treated for early-stage squamous cell carcinoma of the vulva at Sun Yat-sen University Cancer Center from January 1980 to December 2005. The Statistical Package for Social Science (SPSS) was used to compare the different strategies of operation and to analyze the prognostic factors. Results Thirty-five patients had early-stage squamous cell carcinoma of the vulva. Of these cases, 26 were well differentiated, seven were moderately differentiated, and two were poorly differentiated. The five-year survival rate was 77.1%. Five cases were in FIGO stage 1a and 30 cases were in stage 1b; median survival times were 182.3 months and 152.5 months, and the five-year survival rates were 100% and 81.5% (P >0.05), respectively. The five-year survival of the patients who underwent local excision; radical vulvectomy and en bloc resection of inguinofemoral lymphadenectomy; orradical vulvectomyen bloc resection of inguinofemoral lymphadenectomy, and pelvic lymph nodes was 50%, 81.8%, and 83.9%, respectively. For these cases, 74.3% of the tumors were medial while 25.7% were lateral, and the five-year survival rates of patients according to tumor location were 87.0% and 64.8% (P P Conclusions For patients with early-stage squamous cell carcinoma of the vulva, surgical operation is the primary, yet the best, treatment. The related prognostic factors were tumor location (lateral/medial), stage, gross morphology, and clinical state of the inguinal lymph node.

Abstract Background The correlation of S-phase kinase–associated protein 2 (Skp2) with metastasis and prognosis in esophageal squamous cell carcinoma (ESCC) is controversial. The purpose of this study was to explore whether there was a correlation between the expression of Skp2 evaluated by immunohistochemistry and the clinical outcome of patients with operable ESCC, and to further determine the possible mechanism of the impact of Skp2 on survival. Methods Tissue microarrays that included 157 surgically resected ESCC specimens was successfully generated for immunohistochemical evaluation. The clinical/prognostic significance of Skp2 expression was analyzed. Kaplan-Meier analysis was used to compare the postoperative survival between groups. The prognostic impact of clinicopathologic variables and Skp2 expression was evaluated using a Cox proportional hazards model. A cell proliferation assay and a colony formation assay were performed in ESCC cell lines to determine the function of Skp2 on the progression of ESCC in vitro. Results Skp2 expression correlated closely with the T category (p = 0.035) and the pathological tumor-node-metastasis (TNM) stage (p = 0.027). High expression of Skp2 was associated with poor overall survival in resectable ESCC (p = 0.01). The multivariate Cox regression analysis demonstrated that pathological T category, pathological N category, cell differentiation, and negative Skp2 expression were independent factors for better overall survival. In vitro assays of ESCC cell lines demonstrated that Skp2 promoted the proliferative and colony-forming capacity of ESCCs. Conclusions Negative Skp2 expression in primary resected ESCC is an independent factor for better survival. Skp2 may play a pro-proliferative role in ESCC cells.

Abstract Background It has been suggested that p300 participates in the regulation of a wide range of cell biological processes and mutation of p300 has been identified in certain types of human cancers. However, the expression dynamics of p300 in hepatocellular carcinoma (HCC) and its clinical/prognostic significance are unclear. Methods In this study, the methods of reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate protein/mRNA expression of p300 in HCCs. Receiver operating characteristic (ROC) curve analysis, spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. Results Up-regulated expression of p300 mRNA and protein was observed in the majority of HCCs by RT-PCR and Western blotting, when compared with their adjacent non-malignant liver tissues. According to the ROC curves, the cutoff score for p300 high expression was defined when more than 60% of the tumor cells were positively stained. High expression of p300 was examined in 60/123 (48.8%) of HCCs and in 8/123 (6.5%) of adjacent non-malignant liver tissues. High expression of p300 was correlated with higher AFP level, larger tumor size, multiplicity, poorer differentiation and later stage (P < 0.05). In univariate survival analysis, a significant association between overexpression of p300 and shortened patients' survival was found (P = 0.001). In different subsets of HCC patients, p300 expression was also a prognostic indicator in patients with stage II (P = 0.007) and stage III (P = 0.011). Importantly, p300 expression was evaluated as an independent prognostic factor in multivariate analysis (P = 0.021). Consequently, a new clinicopathologic prognostic model with three poor prognostic factors (p300 expression, AFP level and vascular invasion) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P < 0.0001). Conclusions Our findings provide a basis for the concept that high expression of p300 in HCC may be important in the acquisition of an aggressive phenotype, suggesting that p300 overexpression, as examined by IHC, is an independent biomarker for poor prognosis of patients with HCC. The combined clinicopathologic prognostic model may become a useful tool for identifying HCC patients with different clinical outcomes.

N 6 -methyladenosine (m 6 A) RNA methylation has emerged as an important factor in various biological processes by regulating gene expression. However, the dynamic profile, function and underlying molecular mechanism of m 6 A modification during skeletal myogenesis remain elusive. Here, we report that members of the m 6 A core methyltransferase complex, METTL3 and METTL14, are downregulated during skeletal muscle development. Overexpression of either METTL3 or METTL14 dramatically blocks myotubes formation. Correspondingly, knockdown of METTL3 or METTL14 accelerates the differentiation of skeletal muscle cells. Genome-wide transcriptome analysis suggests ERK/MAPK is the downstream signaling pathway that is regulated to the greatest extent by METTL3/METTL14. Indeed, METTL3/METTL14 expression facilitates ERK/MAPK signaling. Via MeRIP-seq, we found that MNK2, a critical regulator of ERK/MAPK signaling, is m 6 A modified and is a direct target of METTL3/METTL14. We further revealed that YTHDF1 is a potential reader of m 6 A on MNK2, regulating MNK2 protein levels without affecting mRNA levels. Furthermore, we discovered that METTL3/14-MNK2 axis was up-regulated notably after acute skeletal muscle injury. Collectively, our studies revealed that the m 6 A writers METTL3/METTL14 and the m 6 A reader YTHDF1 orchestrate MNK2 expression posttranscriptionally and thus control ERK signaling, which is required for the maintenance of muscle myogenesis and may contribute to regeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xie, Lei, Yang, Diao, Liao, He, Tao, Hu, Hou, Sun, Peng, Zhang and Xiao.)

Background: Cancer metastasis is the major reason for cancer-related deaths, but the mechanism of cancer metastasis still unclear. Adrenomedullin (ADM), a peptide hormone, functions as a local paracrine and autocrine mediator with multiple biological activities, such as angiogenesis, cell proliferation, and anti-inflammation. However, the expression and potential function of ADM in triple-negative breast cancer (TNBC) remain unclear., Methods: Real-time polymerase chain reaction and western blotting were performed to examine the expression of ADM in TNBC tissues and cell lines. A total of 458 TNBC tissue samples and adjacent nontumor tissue samples were detected by immunochemistry to determine the correlation between ADM expression and clinicopathological characteristics. We determined the role and mechanistic pathways of ADM in tumor metastasis in cell lines., Results: Our data showed that ADM expression was noticeably decreased in TNBC samples and cell lines. Low expression levels correlate with an increased risk of recurrence and metastasis. Furthermore, low ADM expression was associated with poor prognosis and was an independent marker for TNBC. In vitro, ADM may decrease cancer cell invasion, which is likely the result of its effect on the cancer cell epithelial-mesenchymal transition., Conclusions: Our findings suggest that ADM is a valuable biomarker for TNBC prognosis and an anti-metastasis candidate therapeutic target in triple-negative breast cancer., Competing Interests: None., (AJTR Copyright © 2020.)

The prognostic significance of vascular invasion (VI) in nonmetastatic gastric cancer (GC) remains a matter of controversy. The purpose of this study was to assess the impact of VI on survival in this group of GC patients. We enrolled 361 GC patients without metastasis who underwent curative gastrectomy between 1996 and 2009 in Sun Yat-sen University Cancer Center. A retrospective analysis of the clinicopathological data was performed, focusing on the impact of VI detected by routine H&E staining on disease-free survival (DFS) and cancer-specific survival (CSS). The presence of VI was detected in 13.9% of our cohort. The VI status was significantly correlated with the tumor size, infiltration depth, and TNM stage (P < 0.05). Patients with VI showed significantly lower DFS and CSS compared with patients without VI (P < 0.0001 for both). The subgroup analysis indicated that the presence of VI was a negative predictor of DFS in all TNM stages and a predictor of lower CSS only in stage I (P < 0.05 for all). A multivariate Cox proportional analysis identified VI as an independent predictor of CSS (P = 0.022). The presence of VI is a risk factor for recurrence and an independent predictor of poor survival in nonmetastatic GC after curative resection. The VI status should be considered to stratify with this group of GC patients for adjuvant treatment and more effective follow-up protocol.

Purpose: Currently, nasopharyngeal carcinoma (NPC) prognosis evaluation is based primarily on the TNM staging system. This study aims to identify prognostic markers for NPC., Patients and Methods: We detected expression of 18 biomarkers by immunohistochemistry in NPC tumors from 209 patients and evaluated the association between gene expression level and disease-specific survival (DSS). We used support vector machine (SVM)--based methods to develop a prognostic classifier for NPC (NPC-SVM classifier). Further validation of the NPC-SVM classifier was performed in an independent cohort of 1,059 patients., Results: The NPC-SVM classifier integrated patient sex and the protein expression level of seven genes, including Epstein-Barr virus latency membrane protein 1, CD147, caveolin-1, phospho-P70S6 kinase, matrix metalloproteinase 11, survivin, and secreted protein acidic and rich in cysteine. The NPC-SVM classifier distinguished patients with NPC into low- and high-risk groups with significant differences in 5-year DSS in the evaluated patients (87% v 37.7%; P < .001) in the validation cohort. In multivariate analysis adjusted for age, TNM stage, and histologic subtype, the NPC-SVM classifier was an independent predictor of 5-year DSS in the evaluated patients (hazard ratio, 4.9; 95% CI, 3.0 to 7.9) in the validation cohort., Conclusion: As a powerful predictor of 5-year DSS among patients with NPC, the newly developed NPC-SVM classifier based on tumor-associated biomarkers will facilitate patient counseling and individualize management of patients with NPC.

Objective: To investigate the expressions of epidermal growth factor receptor (EGFR) in primary nasopharygeal carcinoma (NPC) and lymph node metastases., Methods: Archived samples of primary NPC and paired lymph node metastases from 86 patients were examined immunohistochemically for the protein expression of EGFR., Results: EGFR expression positivity was detected in the primary NPC and lymph node metastases at the rate of 73.3% and 60.5%, respectively, and primary and metastatic foci showed significant difference in the expression levels (P=0.001). A discrepancy of EGFR expression between the primary and metastatic foci was found in 25 patients, with a discrepancy rate of 29.1% (25/86)., Conclusion: The difference in EGFR expression between the primary and lymph node metastastic foci of NPC needs to be evaluated when performing EGFR-targeted therapies especially in advanced NPC cases.

Background & Objective: Cervical adenosquamous carcinoma is a special histological type of cervical carcinoma. Its clinic-pathologic characteristics and prognostic factors have seldom been reported. This study was to explore the clinic-pathologic characteristics and prognostic factors of cervical adenosquamous carcinoma., Methods: Clinical data of 83 pathologically confirmed adenosquamous cervical carcinoma patients in Sun Yat-sen University Cancer Center from Nov. 1982 to May 2006 were analyzed., Results: The median overall survival (OS) of 83 patients was 47 months and the median disease-free survival was 43 months. The 5-year survival rate was 74.0%, and the recurrence rate (DFS) was 30.1% (25/83). The median OS and DFS were 58 months and 54 months versus 37 months and 21 months in patients with or without lymph node metastasis (P=0.005, P<0.001). The median DFS was 47 months and 16 months for patients with the tumor diameter >4 or < or =4 cm (P=0.015), respectively. Lymph node metastasis was correlated to FIGO stage, tumor diameter and invasion depth. The recurrence rate of patients with ovarian preservation was 33.3% (3/9)., Conclusions: Lymph node metastasis is an independent risk factor for prognosis in cervical adenosquamous carcinoma. Adjunctive postoperative irradiation would improve the OS and DFS. Tumor diameter greater than 4cm is an independent prognostic risk of DFS. The impact of ovarian preservation on prognosis is unclear.

Objective: To investigate the impact of visceral pleural invasion (VPI) on prognosis and staging in patients with stage Ib non-small cell lung cancer (NSCLC)., Methods: Clinical data of 232 patients with stage Ib NSCLC surgically treated by curative resection between January 1994 and December 2003 was retrospectively reviewed. Histopathological diagnosis was reviewed by an experienced pathologist. According to the tumor size and status of VPI, patients were stratified into three group: group A: tumor > 3 cm and VPI(-); group B: tumor < or = 3 cm and VPI (+); group C: tumor > 3 cm and VPI(+). There were 45 patients in group A, 96 in group B and 91 in group C. Kaplan-Meier method was used for survival analysis. Cox proportional hazards model was used for multivariate analysis., Results: 187 (80.6%) patients had visceral plural invasion, while 45 (19.4%) had no. The 5-and 10-year survival rates of patients with VPI were 59.3% and 42.6%, while it was 70.1% and 56.7% for the patients without (P = 0.035), respectively. The 5-year survival rates of patients in group A, B and C were 70.1%, 61.9% and 56.2%; and 10-years survival rates were 56.7%, 50.6% and 35.9%, respectively (P = 0.018). VPI with large size of tumor was revealed by Cox multivariate analysis as an independent prognostic factor (RR = 1.530, 95% CI: 1.132-2.067, P = 0.006)., Conclusion: A significant difference in survival exists among the stage Ib NSCLC patients who have different T status, the patient with > 3 cm tumor and visceral plural invasion may have the worst prognosis. Further studies are still needed to assess whether it is necessary or not to modify the T2 statue of tumor > 3 cm with visceral plural invasion.

Objective: To investigate the effect of membrane type-1 matrix metalloproteinase (MTI-MMP) on the invasive potential of breast cancer cell and analyze its mechanisms., Methods: After treatment of breast cancer MDA-MB-453 cell line with concanavalin A ( ConA, 20 microg/ml) for 24 h, MT1-MMP protein was detected in cancer cells by Western analysis and immunocytochemistry. MDA-MB-453 cells were cultured with exogenous latent proMMP-2 and MMP-2 activity was analyzed by gelatin zymography. The invasive potential of the tumor cells was measured with a membrane invasion culture system. Cancer cells of the cell line were divided into four groups: the control group treated by neither reagent, group ConA was only treated by ConA, group MMP-2 was treated only by MMP-2, and group ConA + MMP-2 was treated by both ConA and MMP-2. RESULTS The expression of MTI-MMP protein could be detected in groups ConA and ConA + MMP-2, but nothing was detected in control and group MMP-2. There was only 72 000 precursor form of MMP-2 in group MMP-2 and there were both 72 000 precursor form and 64 000 active enzyme form of MMP-2 in group ConA + MMP-2, but there was no forms of MMP-2 in the other two groups detected by gelatin zymography. The largest amount of cells penetrated through Matrigel was observed in group ConA + MMP-2 than in the other three groups., Conclusion: MTI-MMP can remarkably promote the invasive potential of breast cancer cells mainly through its ability of activating latent proMMP-2 to degrade

Objective: To investigate the effects of citrus reticulata blanco extract on the proliferation and collagen metabolism of fibroblasts from human hypertrophic scar., Methods: Human hypertrophic scar fibroblasts from two burn patients obtained from plastic surgery were cultured in vitro and divided into experimental group (n = 12, with basic culture medium and 2.5, 5.0, 10.0,25.0 mg/L citrus reticulata blanco extract, respectively, 3 bottles for each concentration of citrus reticulata blanco extract ), control group 1 (n = 3, with basic culture medium) , and control group 2 ( n = 3, with basic culture medium and 5% ethyl alcohol). The cell proliferation in each group was observed with MTT method, then the inhibition rate was calculated. Apoptosis and its index ( AI) in each group were determined after TUNEL staining . The changes in the content of ICTP and PINP in each group were observed by radioimmunity., Results: The inhibition rate in the experimental group with the citrus reticulata blanco extract in concentration of 2. 5, 5.0, 10.0, 25. 0 microg/ ml were (7. 100+/-0.038)% , (8. 100+/- 0. 048)% , (10. 900+/-0. 055)%, (15.900+/-0. 097) %, respectively, which were significantly higher than those in other two groups ( P <0.05 ). The Al (69. 7% , 71.7%, 86.4% , 95.2% ), ICTP [(17.2+/-0.6), (18.3+/-0.6), (19.8+/-0.5), (23.2+/-0.6) microg/L] and PINP [ (101.7+/-1.4) , (107. 8+/-1. 1) , (111.6+/-1.2) , (124. 6+/-1.3) microg/L] in experimental group with the citrus reticulata blanco extract in concentration of 2.5, 5.0, 10.0 , 25.0 mg/L were also obviously higher than other two control groups( P <0.05) ,but these indices in control 1 group were similar to those in control 2 group( P >0. 05)., Conclusion: The citrus reticulata blanco extract might be beneficial for the management of hypertrophic scar through inhibition of the proliferation of fibroblasts in hypertrophic scar, by promoting apoptosis and collagen degradation.

Background & Objective: The World Health Organization (WHO) histological classification of thymoma was published in 1999. This study was to investigate the correlations of WHO histological classification of thymoma to its clinical characteristics and prognosis., Methods: Records of 82 thymoma patients treated with surgery were reviewed retrospectively. Histological diagnosis based on WHO classification system was made by an experienced pathologist. The correlations of WHO histological classification of thymoma to its clinical characteristics and prognosis were analyzed., Results: Of the 82 cases, 5 (6.1%) were type A, 21 (25.6%) were type AB, 14 (17.1%) were type B1, 12 (14.6%) were type B2, 14 (17.1%) were type B3, and 16 (19.5%) were type C; according to Masaoka clinical staging system, 29 (35.4%) were in stage I, 13 (15.8%) in stage II , 32 (39%) in stage III , and 8 (9.8%) in stage IVa. The histological subtype of thymoma was significantly correlated with clinical stage (chi2 = 47.29, P < 0.001) and tumor invasive degree (chi2 = 30.78, P < 0.001). Complete resection rate was significantly higher in patients with type A, AB, B1 or B2 tumors than in patients with type B3 or C tumors (84.6% vs. 50.0%, chi2 = 11.29, P = 0.002). The 5-year survival rates of patients with stage I, II, III , and IVa were 100%, 100%, 69.5%, and 37.5%, respectively; the 10-57.1%, year survival rates were 88.1%, 47.5, and 0, respectively. The difference of survival rates among different clinical stages (log-rank = 40.31, P < 0.001) and histological subtypes (log-rank = 16.0, P = 0.007) were significant., Conclusion: To some extent, the WHO histological classification reflects the biological behavior and clinical characteristics of thymoma, and may be helpful in diagnosing and treating thymoma.