Youzhong Zhang

Distribution of Th17 cells and Foxp3-expressing T cells in tumor-infiltrating lymphocytes in patients with uterine cervical cancer

BACKGROUND Recent studies suggest a potential impact of Th17 cells on tumor. In the present study, we investigated the distribution of Th17 cells in relation to Foxp3-expressing T cells in the tumor-infiltrating lymphocytes (TILs) from patients with uterine cervical cancer (UCC), cervical tissues from patients with cervical intraepithelial neoplasia (CIN) and healthy cervical tissues. METHODS Th17 cells and Foxp3-expressing T cells were evaluated by immunohistochemical staining. IL-6, TGF-β, IL-17 and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). Immunohistochemical staining for microvessel density (MVD) was performed in order to assess the association of IL-17 expression with angiogenesis. RESULTS Compared with controls, patients with UCC or CIN had a higher proportion of Th17 cells and Foxp3-expressing T cells, when the ratio of Th17/Foxp3-expressing T cells in TILs was decreased in individual cases, it was more markedly decreased in TILs than normal cervical tissues. Meanwhile, the cytokine(IL-6, TGF-β and IL-10) concentrations were significantly higher in UCC patients than those in healthy controls. Interestingly, the levels of intratumoral Th17 cells were positively correlated with MVD in tumors. CONCLUSIONS The imbalance of Th17/Foxp3-expressing T cells may play critical roles in the development and progression of UCC and Th17 cells may promote tumor progression by fostering angiogenesis.

Genomic amplification patterns of human telomerase RNA gene and C-MYC in liquid-based cytological specimens used for the detection of high-grade cervical intraepithelial neoplasia

BackgroundThe amplification of oncogenes initiated by high-risk human papillomavirus (HPV) infection is an early event in cervical carcinogenesis and can be used for cervical lesion diagnosis. We measured the genomic amplification rates and the patterns of human telomerase RNA gene (TERC) and C-MYC in the liquid-based cytological specimens to evaluate the diagnostic characteristics for the detection of high-grade cervical lesions.MethodsTwo hundred and forty-three residual cytological specimens were obtained from outpatients aged 25 to 64 years at Qilu Hospital, Shandong University. The specimens were evaluated by fluorescence in situ hybridization (FISH) using chromosome probes to TERC (3q26) and C-MYC (8q24). All of the patients underwent colposcopic examination and histological evaluation. A Chi-square test was used for categorical data analysis.ResultsIn the normal, cervical intraepithelial neoplasia grade 1 (CIN1), grade 2 (CIN2), grade 3 (CIN3) and squamous cervical cancer (SCC) cases, the TERC positive rates were 9.2%, 17.2%, 76.2%, 100.0% and 100.0%, respectively; the C-MYC positive rates were 20.7%, 31.0%, 71.4%, 81.8% and 100.0%, respectively. The TERC and C-MYC positive rates were higher in the CIN2+ (CIN2, CIN3 and SCC) cases than in the normal and CIN1 cases (p < 0.01). Compared with cytological analysis, the TERC test showed higher sensitivity (90.0% vs. 84.0%) and higher specificity (89.6% vs. 64.3%). The C-MYC test showed lower sensitivity (80.0% vs. 84.0%) and higher specificity (77.7% vs. 64.3%). Using a cut-off value of 5% or more aberrant cells, the TERC test showed the highest combination of sensitivity and specificity. The CIN2+ group showed more high-level TERC gene copy number (GCN) cells than did the normal/CIN1 group (p < 0.05). For C-MYC, no significant difference between the two histological categories was detected (p > 0.05).ConclusionsThe TERC test is highly sensitive and is therefore suitable for cervical cancer screening. The C-MYC test is not suitable for cancer screening because of its lower sensitivity. The amplification patterns of TERC become more diverse and complex as the severity of cervical diseases increases, whereas for C-MYC, the amplification patterns are similar between the normal/CIN1 and CIN2+ groups.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1308004512669913.

Tc17 cells in patients with uterine cervical cancer.

Background The existence of Tc17 cells was recently shown in several types of infectious and autoimmune diseases, but their distribution and functions in uterine cervical cancer (UCC) have not been fully elucidated. Methods The frequency of Tc17 cells in peripheral blood samples obtained from UCC patients, cervical intraepithelial neoplasia (CIN) patients and healthy controls was determined by flow cytometry. Besides, the prevalence of Tc17 cells and their relationships to Th17 cells and Foxp3-expressing T cells as well as microvessels in tissue samples of the patients were assessed by immunohistochemistry staining. Results Compared to controls, patients with UCC or CIN had a higher proportion of Tc17 cells in both peripheral blood and cervical tissues, but the level of Tc17 cells in UCC tissues was significantly higher than that in CIN tissues. Besides, the increased level of Tc17 in UCC patients was associated with the status of pelvic lymph node metastases and increased microvessel density. Finally, significant correlations of infiltration between Tc17 cells and Th17 cells or Foxp3-expressing T cells were observed in UCC and CIN tissues. Conclusions This study indicates that Tc17 cell infiltration in cervical cancers is associated with cancer progression accompanied by increased infiltrations of Th17 cells and regulatory T cells as well as promoted tumor vasculogenesis.

Positive Surgical Margin, HPV Persistence, and Expression of Both TPX2 and PD-L1 Are Associated with Persistence/Recurrence of Cervical Intraepithelial Neoplasia after Cervical Conization

Objective To determine the clinicopathologic and immunohistochemical predictors of the persistence/recurrence of cervical intraepithelial neoplasia (CIN) after cervical conization. Methods Medical records of 502 patients who received cervical conization treatment of CIN between 2005 and 2012 were reviewed. The clinicopathologic parameters were analyzed using Cox hazard regression. Fifty patients with CIN persistence/recurrence were matched to 50 cases without CIN persistence/recurrence. These 100 cervical specimens were assessed for expression of insulin-like growth factor II messenger RNA (mRNA)-binding protein 3 (IMP3), targeting protein for xenopus kinesin-like protein 2 (TPX2), and programmed cell death-1 ligand-1 (PD-L1) using immunohistochemical staining. Results Multivariate analysis found that the independent predictors of CIN persistence/recurrence were positive surgical margin (hazard ratio 5.777, 95% confidence interval 2.334–14.301, p < 0.001) and human papilloma virus persistence for 6 months (hazard ratio 20.685, 95% confidence interval 7.350–57.657, p < 0.001). Co-expression of TPX2 and PD-L1 was significantly higher in CIN persistence/recurrence group than the group without CIN persistence/recurrence (p = 0.013). The depth of glandular involvement (GI) was less than 3mm in about 86.8% (59/68) CIN2-3 lesions, However, No statistically significant associations between GI and persistence/recurrence were observed (P = 0.58). Conclusion Positive surgical margin, HPV persistence, and expression of both TPX2 and PD-L1 are associated with persistence/recurrence of cervical intraepithelial neoplasia after cervical conization.

Clinical and pathological factors related to the prognosis of chinese patients with stage Ib to IIb cervical cancer.

OBJECTIVE The aim of this retrospective study is to analyze the clinical and pathological factors related to the prognosis of Chinese patients with stage Ib to IIb cervical cancer. METHODS AND RESULTS 13 clinical pathological factors in 255 patients with stage Ib to IIb cervical cancer undergoing radical hysterectomy and systematic lymphadenectomy were analyzed to screen for factors related to prognosis. The cumulative 5-year survival of the 255 patients was 75.7%. The result of the univariate analysis suggested that clinical stage, cell differentiation, depth of cervical stromal invasion, parametrial tissue involvement, and lymph node metastasis were prognostic factors for patients with stage Ib to IIb cervical cancer (P<0.05). Compared with cases with involvement of iliac nodes, obturator nodes, or inguinal lymph nodes, cases with metastasis to the common iliac lymph nodes had a poorer prognosis (P<0.05). Cases with involvement of four or more lymph nodes had a poorer prognosis than those with involvement of three or fewer lymph nodes (P<0.05). Using multivariate Cox proportional hazards model regression analysis, non-squamous histological type, poor differentiation, parametrial tissue involvement, and outer 1/3 stromal invasion were found to be independently related to patients poor prognosis (P<0.05). CONCLUSION Non-squamous histological type, poor cell differentiation, parametrial tissue involvement, and outer 1/3 stromal invasion are the independent poor prognostic factors for patients with stage Ib to IIb cervical cancer.

Is it necessary to perform routine appendectomy for mucinous ovarian neoplasms? A retrospective study and meta-analysis

OBJECTIVES To evaluate whether routine appendectomy is necessary in all patients with mucinous borderline ovarian tumor (mBOT) or mucinous ovarian cancer (MOC) who undergo gynecologic surgery. METHODS The database of Qilu Hospital was searched for women who underwent appendectomy in a primary surgery for an ovarian tumor between June 2005 and June 2015 and whose final diagnosis was mBOT, MOC or primary appendiceal tumor. A retrospective review was performed, as well as a meta-analysis of the literature to further validate the findings. RESULTS Seventy-one patients, 29 with mBOT and 42 with malignant mucinous tumors (including 40 with primary MOC and 2 with appendiceal mucinous adenocarcinoma), underwent appendectomy at the time of primary surgery. Among those with mBOT, two (6.9%) appendices were grossly abnormal and pathologically diagnosed with appendiceal implantation by mBOT. In the 42 patients with malignant disease, five (12%) appendices had a grossly abnormal appearance, one (2.4%) was diagnosed with an appendiceal metastasis from MOC and two (4.7%) were primary appendiceal adenocarcinoma. For grossly normal appendices, only one (2.4%) was confirmed to have microscopic metastasis from MOC. The meta-analysis included a total of 914 mBOT and MOC cases with appendectomies, including our current cases. The estimated rate of overall appendiceal pathology is 4.97%, and the pooled odds ratio (OR) showed statistical differences between MOC and mBOT (MOC vs. mBOT, OR=2.15, P<0.05). The estimated malignant pathology rate in macroscopically normal vs. abnormal appendices is 1.4% and 59%, respectively, with an estimated OR up to 97.5 (95% CI 28.1-338.5, P<0.05). CONCLUSION There is not sufficient evidence to support a routine appendectomy for patients with a grossly normal appendix in mBOT and MOC. A careful intra-operative exploration of the appendix is crucial, but appendectomy is only warranted when the appendix is abnormal.

Significance of Human Telomerase RNA Gene Amplification Detection for Cervical Cancer Screening

AIM Liquid-based cytology is the most often used method for cervical cancer screening, but it is relatively insensitive and frequently gives equivocal results. Used as a complementary procedure, the high-risk human papillomavirus (HPV) DNA test is highly sensitive but not very specific. The human telomerase RNA gene (TERC) is the most often amplified oncogene that is observed in cervical precancerous lesions. We assessed genomic amplification of TERC in liquid-based cytological specimens to explore the optimal strategy of using this for cervical cancer screening. METHODS Six hundred and seventy-one residual cytological specimens were obtained from outpatients aged 25 to 64 years. The specimens were evaluated by the Digene Hybrid Capture 2 (HC2) HPV DNA test and fluorescence in situ hybridization (FISH) with a chromosome probe to TERC (3q26). Colposcopic examination and histological evaluation were performed where indicated. RESULTS The TERC positive rate was higher in the CIN2+ (CIN2, CIN3 and SCC) group than in the normal and CIN 1 groups (90.0% vs. 10.4%, p<0.01). In comparison with the HC2 HPV DNA test, the TERC amplification test had lower sensitivity but higher specificity (90.0% vs. 100.0%, 89.6% vs. 44.0%, respectively). TERC amplification test used in conjunction with the HC2 HPV DNA test showed a combination of 90.0% sensitivity and 92.2% specificity. CONCLUSION The TERC amplification test can be used to diagnose cervical precancerous lesions. TERC and HPV DNA co-testing shows an optimal combination of sensitivity and specificity for cervical cancer screening.

B7-H3 is related to tumor progression in ovarian cancer

B7-H3, a co-stimulatory molecule, has been found expressed in ovarian cancer, but its role and mechanism is not clear. In this study, we further verified the expression of B7-H3 in ovarian carcinoma and normal epithelial ovarian tissues. Three ovarian cancer cell lines, A2780, SKOV3 and HO8910 were selected to explore the effects of B7-H3 on proliferation, apoptosis, migration and invasion. We found that B7-H3 was mainly located in the cytoplasm of ovarian cancer cells as determined by immunofluorescence staining. The ability of cell invasion, migration, proliferation decreased after silencing B7-H3 whereas the apoptosis increased, which was related to the upregulation of Bax, caspase-8, cleaved caspase-8 and the downregulation of Bcl-2, Bcl-xl, matrix metalloproteinase-2 (MMP2) by western blotting. In addition, B7-H3 enhanced the H08910 cell capacities in invasion, migration and proliferation. Expression of the phosphorylation signal transducer and activator of transcription 3 (pStat3) molecules and their upstream molecules phosphorylation Janus kinase 2 (pJak2) were significantly increased. In order to investigate whether B7-H3 plays a role in this pathway, we treated the overexpressed HO8910 cells with AG490 (inhibitors of Jak2). Our findings revealed that B7-H3 affect ovarian cancer progression through the Jak2/Stat3 pathway, indicating that B7-H3 has the potential to be a useful prognostic marker.

Effective treatment of a patient with stage IV ovarian cancer: A case report

The present case report describes a patient with stage IV ovarian cancer who survived for 9 years without achieving a complete remission since the first relapse. The patients long-term survival may be ascribed to the slow growth of the cancer cells, limited metastasis and favorable responses to the treatments received. The patient manifested initially with malignant pleural effusion and was not able to tolerate surgical treatment. However, the disease was well-controlled using various treatments, including neoadjuvant chemotherapy, interval cytoreductive surgery and post-operative long-term chemotherapy. Management of ovarian cancer is most effective when tailored to the individual needs of the patient, maximizing its efficacy and prolonging the patients survival rate. The present case may offer useful insight into the clinical management of stage IV ovarian cancer.

Significance of the Factors Associated With Parametrial Involvement in Stage IB to IIA Cervical Cancer.

Objective The aim was to explore the factors associated with parametrial involvement (PI) in patients with stage IB to IIA cervical cancer. Materials and Methods Medical records of 507 patients were reviewed. Nine factors were analyzed by univariate analysis using χ2 test and multivariate analysis using logistic regression analysis to screen for factors associated with PI. Results There were 46 patients with PI. Result of univariate analysis suggested depth of stromal invasion, lymphovascular space invasion (LVSI), and lymph node metastasis, and uterine involvement was associated with PI (P < 0.05 for all). The multivariate analysis model included factors that could be diagnosed by a cone biopsy, and the result suggested nonsquamous histological type and LVSI was the independent factor of PI. The incidence of PI in the patients with no LVSI and squamous cancer was 6.97%. When the patients with inner 1/3 stromal invasion were stratified into those with squamous cancer and no LVSI, the incidence of PI was 1.17%. The incidence of PI in the patients with LVSI and nonsquamous cancer was 33.33%. Conclusions The patients with inner 1/3 stromal invasion, no LVSI, and squamous histological type may be considered for less radical surgery. The patients with nonsquamous histological type and LVSI may be considered for radical hysterectomy including a complete resection of parametrium.