c-erbB-3 proto-oncogene expression in uterine cervical carcinoma

Over-expression of epidermal growth factor receptor (EGFR) and c-erb B-2, in uterine cervical carcinomas, is associated with a worsened prognosis. A third member of this proto-oncogene family, c-erb B-3, has now been identified and its over-expression has been described in a variety of carcinomas. In this immunohistochemical study we have shown that c-erb B-3 is widely expressed in cervical carcinomas, but we have found no association between its over-expression and lymph node status or clinical outcome. In a similar study examining the expression of EGFR and c-erb B-2 it was possible to demonstrate an association between over-expression and a worse prognosis. We conclude, therefore, that it is unlikely that demonstration of c-erb B-3 over-expression will be of any value as a prognostic indicator in carcinoma of the uterine cervix.     

血清胆固醇水平对宫颈癌患者预后的影响

目的:探讨治疗前血清胆固醇水平对宫颈癌患者预后的影响。方法:回顾分析2016年1月1日至2016年12月31日四川省肿瘤医院妇科肿瘤中心收治的277例宫颈癌患者的临床病理资料和随访记录。绘制ROC曲线,评价治疗前血清胆固醇对患者预后的预测效果。分析患者临床病理资料与血清胆固醇水平的关系。应用Kaplan-Meier法绘制生存曲线,建立Cox比例风险模型分析患者预后影响因素。结果:血清胆固醇水平预测DFS、OS的临界值分别为4.875mmol/L、4.605mmol/L。Cox比例风险模型单因素及多因素分析显示,治疗前血清胆固醇水平是影响宫颈癌患者DFS及OS的危险因素。结论:治疗前血清胆固醇水平可作为宫颈癌患者预后风险评价指标。     

人宫颈癌bcl-2基因表达与预后的关系

目的 探讨人宫颈中ｂｃｌ－２基因表达的改变与其临床意义。方法 对１４９例宫颈组织采用免疫组化ＡＢＣ法检测ｂｃｌ－２基因蛋白的表达,结合临床资料分析该基因改变的临床意义。结果 宫颈癌中ｂｃｌ－２基因蛋白表达（５５．２９％）显著高于宫颈下沉和炎症组织（１８．７５％）（ｐ〈０．０１）,其中０期（３／３）、Ⅰ期（８４．６２％）、Ⅱ期（７４．５１％）显著高于Ⅲ期（２８．５７％）（ｐ〈０．０１）。ｂｃｌ－２蛋     

C-erbB-2及VEGF基因蛋白在宫颈癌中的表达及临床意义

目的:探讨C-erbB-2及VEGF基因蛋白在宫颈癌的表达及临床意义。方法:用免疫组化SP法检测60例宫颈癌组织、20例宫颈CIN组织和10例正常宫颈组织中C-erbB-2及VEGF基因蛋白的表达。结果:在宫颈癌组织、宫颈CIN组织和正常宫颈组织中,C-erbB-2阳性表达率分别为61.7%、35.0%和10.0%,VEGF阳性表达率分别为70.0%、35.0%和20.0%,组间差异有统计学意义(均P<0.05)。宫颈癌组的不同临床分期、不同病理学分级、有无淋巴结转移及不同肿瘤体积组间比较,C-erbB-2和VEGF的阳性表达率均有显著性差异(均P<0.05),且二者表达强度呈显著正相关(P<0.05)。C-erbB-2及VEGF表达阳性者较C-erbB-2及VEGF表达阴性者5年生存期显著缩短(均P<0.05)结论:C-erbB-2和VEGF基因蛋白的异常表达与宫颈癌的发生、发展有关,二者联合检测可作为评估宫颈癌恶性程度、预后及指导治疗的重要参考指标。     

Prognostic factors in node-positive patients with stage IB-IIB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy.

OBJECTIVE: The purpose of the present study was to identify prognostic factors in surgically treated patients with stage IB-IIB cervical cancers, who also presented with positive pelvic nodes. METHOD: The patient population consisted of 68 individuals presenting with stage IB-IIB cervical cancers and with histologically proven pelvic lymph nodes. RESULT: We found no association between the type of adjuvant therapy and patient outcome. Multivariate analysis revealed that non-squamous histology was an independent prognostic factor for disease-free and overall survival rates. In squamous cell carcinomas, the bilateral nature of the positive nodes was found to be a significant factor for disease-free survival rates. In non-squamous cell carcinomas, positive nodes of more than 2 cm in size were found to be a significant factor for disease-free survival rates. CONCLUSION: Non-squamous histology was an independent prognostic factor and chemoradiotherapy did not improve the survival outcomes of the patients in this study population.     

The expression of c-erbB-2 (HER-2/neu) oncogene in invasive ovarian malignancies

The expression of c-erbB-2 oncogene has been studied in 74 formalin fixed paraffin embedded invasive epithelial ovarian malignancies using a monoclonal c-erbB-2 protein antibody. Only four (5.4%) tumors showed membrane immunostaining. FIGO stage, size of residual disease after primary surgery, histologic type and tumor grade, were identified by the log rank test as prognostic factors for survival. No difference in survival was observed between those with and without membrane staining (24 months probability of survival: 50% and 55.4% respectively). Our results did not show any adverse prognostic effect of c-erbB-2 protein expression in our patients.     

Relevance of gamma-glutamyltransferase--a marker for apoptotic balance--in predicting tumor stage and prognosis in cervical cancer

Introduction

Recent large epidemiologic population-based studies identified gamma-glutamyltransferase (GGT) as a marker for increased cervical cancer incidence. Furthermore, high levels of GGT seem to increase the risk of progression of high-grade cervical dysplasia to invasive carcinoma. Therefore, we evaluated the association between pre-therapeutic serum GGT levels, tumor stage and prognosis in patients with cervical cancer.

Materials and methods

In this multi-center trial, pre-therapeutic GGT levels were examined in 692 patients with cervical cancer. GGT levels were correlated with clinico-pathological parameters. Patients were assigned to previously described GGT risk groups and uni- and multivariable survival analyses were performed.

Results

GGT serum levels were associated with FIGO stage (p < 0.0001) and age (r = 0.2, p < 0.0001) but not with lymph node involvement (p = 0.85), and histological type (p = 0.98). High-risk GGT group affiliation (p = 0.01 and p < 0.0001) was associated with poor disease-free and overall survival in a univariate analysis, but not in a multivariable Cox-regression model (p = 0.59 and p = 0.171). We further investigated the association between prognosis and GGT and observed a linear correlation between GGT and prognosis. Therefore we were not able to identify a clear prognostic cut-off value for GGT in patients with cervical cancer.

Conclusions

High GGT - a marker for apoptosis and cervical cancer risk - is associated with advanced tumor stage in patients with cervical cancer.     

Downregulation of miR-599 predicts poor outcome in cervical cancer patients and promotes the progression of cervical cancer

ObjectiveCervical cancer remains a leading cause of gynecological cancer-related death. In this study, we aimed to investigate the expression pattern of miR-599 and its prognostic significance in cervical cancer.Materials and methodsThe RT-qPCR analysis was used to detect the expression levels of miR-599 in cervical cancer tissues and cell lines. The association between miR-599 expression and clinical characteristics of cervical cancer patients was analyzed using the χ² test. The Kaplan–Meier analysis and multivariate Cox proportional hazards model were used to explore the prognostic significance of miR-599. Then, CCK-8 assays, transwell migration, and invasion assays were used to assess the effects of miR-599 on tumor cell proliferation, migration, and invasion of cervical cancer cells, respectively.ResultsmiR-599 expression was significantly downregulated in cervical cancer tissues and cells compared with non-cancerous tissues and HaCaT cells, respectively. Statistical analysis revealed that miR-599 expression was associated with lymph node metastasis and FIGO stage. The miR-599 expression was an independent prognostic factor for overall survival. Functionally, overexpression of miR-599 suppressed cell proliferation, migration, and invasion of cervical cancer cells, while downregulation of miR-599 had opposite effects.ConclusionmiR-599 acts as a tumor suppressor in cervical cancer that inhibiting cell proliferation, migration, and invasion of cervical cancer cells, suggesting that miR-599 may be a potential prognostic biomarker and novel targeted strategy for cervical cancer.     

Th2 type inflammation promotes the gradual progression of HPV-infected cervical cells to cervical carcinoma

Objectives

To investigate the role of immunological parameters in tumorigenesis of cervical cancer in women infected with high risk human papillomavirus (hr-HPV), and determine whether key findings with human material can be recapitulated in the mouse TC1 carcinoma model which expresses hr-HPV epitopes.

Methods

Epithelial and lymphoid cells in cervical tissues were analyzed by immunohistochemistry and serum IL10 levels were determined by ELISA. Tumor draining lymph nodes were analyzed in the mouse TC1 model by flow cytometry.

Results

The mucosa was infiltrated by CD20 + and CD138 + cells already at cervical intraepithelial neoplasia 1 (CIN1) and infiltration increased in cervical intraepithelial neoplasia 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC), where it strongly correlated with infiltration by CD32B + and FoxP3 + lymphocytes. GATA3 + and T-bet + lymphoid cells were increased in ICC compared to normal, and expression in epithelial cells of the Th2 inflammation-promoting cytokine TSLP and of IDO1 was higher in CIN3/CIS and ICC. As a corollary, serum levels of IL10 were higher in women with CIN3/CIS or ICC than in normals. Finally we demonstrated in the mouse TC1 carcinoma, which expresses hr-HPV epitopes, an increase of cells expressing B cell or plasma cell markers or Fc receptors in tumor-draining than distal lymph nodes or spleen.

Conclusions

hr-HPV initiates a local Th2 inflammation at an early stage, involving antibody forming cells, and fosters an immunosuppressive microenvironment that aids tumor progression.     

Pretreatment leukocytosis is an indicator of poor prognosis in patients with cervical cancer

Objectives

The aim of this study was to investigate the prognostic value of pretreatment leukocytosis in patients with cervical cancer in relation to well-established conventional risk factors.

Methods

The baseline characteristics and outcome data from 536 patients treated for cervical cancer between 1996 April to 2007 March were collected and reviewed. Cox proportional hazards regression model was used to identify independent prognostic factors for overall survival. Subsequently, the prognostic significance of pretreatment WBC count was prospectively investigated in 156 patients newly diagnosed cervical cancer from 2007 April to 2010 March.

Results

In a retrospective analysis, patients with leukocytosis (WBC ≥ 10,000/μl) showed significantly higher treatment failure rate (P < 0.0001) and shorter OS (P < 0.0001) than the patients without leukocytosis. Tumors from patients with leukocytosis showed significantly stronger immunoreactivity for G-CSF than those obtained from patients without leukocytosis. Multivariate analyses revealed that clinical stage, tumor diameter, histology, and elevated WBC count (≥ 10,000/μl) were significant prognostic factors in terms of overall survival. In a prospective investigation, patients with leukocytosis showed significantly higher treatment failure rate (P < 0.0001), shorter PFS (P < 0.0001), and higher serum G-CSF concentrations (p = 0.001) than the patients without leukocytosis. Multivariate analyses revealed that clinical stage, tumor diameter, and elevated WBC count were significant prognostic factors in terms of PFS.

Conclusion

Pretreatment leukocytosis is an independent prognostic factor in patients with cervical cancer. Our finding can be used to identify patients with poor prognosis and to design future tailored clinical trials.     

Prevalence and clinical relevance of cyclooxygenase-1 and -2 expression in stage IIB cervical adenocarcinoma

Objective

The objective of this study was to determine the relationship between cyclooxygenase (COX)-1 and -2 and prognosis in patients diagnosed with FIGO stage IIB cervical adenocarcinoma who underwent concurrent chemoradiotherapy.

Study design

Twenty-three patients diagnosed with stage IIB cervical adenocarcinoma and treated with concurrent chemoradiotherapy between 1990 and 1995 were included in this study. COX-1 and -2 expression and clinicopathologic features were evaluated. COX-1 and -2 expression was determined by immunohistochemistry.

Results

The prevalence of COX-1 and -2 expression was similar at 73.9%. Significant COX-1 and -2 expression was 47.8 and 60.9%, respectively. COX-2 expression was associated with poor response to treatment and cancer-related death (P = 0.043 and 0.012, respectively). Poor survival was identified in patients who showed high COX-2 expression (P = 0.016). There was no correlation between COX-1 expression and patient prognosis.

Conclusion

Only COX-2 was found to be a potent prognostic factor in patients treated with concurrent chemoradiotherapy for stage IIB cervical adenocarcinoma. However, further studies with more samples are needed to definitely demonstrate the relationship between COX expression and cervical adenocarcinoma.     

Association between cigarette smoking and prognosis in locally advanced cervical carcinoma treated with chemoradiation: a Gynecologic Oncology Group study

OBJECTIVE: To determine if smoking, a known risk factor for a number of cancers including cervical cancer, is associated with poor prognosis in patients with locally advanced cervical carcinoma treated with chemoradiation. METHODS: Patients with primary, previously untreated, histologically confirmed stage II-B, III-B or IV-A cervical carcinoma participated in a Gynecologic Oncology Group (GOG) phase III study (GOG 165) and were randomly allocated to receive radiation plus either cisplatin or 5-fluorouracil. Smoking behavior was ascertained using an administered questionnaire and by quantifying urine cotinine concentration. Disease progression was defined as a >or=50% increase in the cross product of the existing tumor compared with previous assessments. Patients were followed until death. RESULTS: Of 328 enrolled patients, 12 were ineligible, one was inevaluable for reported smoking status and 40 others were inevaluable for cotinine-derived smoking status. Among evaluable patients, 133 (42%) were reported smokers and 111 (40%) were cotinine-derived smokers. The kappa for agreement between the groups was 0.872 (P<0.01). Compared with non-smokers, median survival was 15 months shorter for reported smokers and 20 months shorter for cotinine-derived smokers (P<0.01). After adjusting for covariates, a significant increase in the risk of death (but not disease progression) was observed for reported smokers (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.01-2.27; P=0.04) and cotinine-derived smokers (HR: 1.57; 95% CI: 1.03-2.38; P=0.04). CONCLUSIONS: Smoking predicts worse overall survival in women with locally advanced cervical carcinoma treated with chemoradiation.     

Expression and genetic analysis of transporter associated with antigen processing in cervical carcinoma

OBJECTIVE: Transporter associated with antigen processing (TAP) loss causes human leukocyte antigen (HLA) class I downregulation which is frequently found in cervical carcinomas and their precursors. HLA class I molecules activate T-cells by antigen presentation and are therefore essential for immunological surveillance. To add to the hitherto limited knowledge of molecular mechanisms underlying TAP loss, we investigated TAP expression, loss of heterozygosity (LOH) and possible TAP mutations. METHODS: Twenty-three cervical carcinomas and adjacent precursor lesions were stained with HLA-A-, HLA-B/C-, beta2 -microglobulin-, TAP1- and TAP2- antibodies. In order to separate tumour and non-tumour cells, cervical carcinoma samples were sorted by flow-cytometry and were subsequently analysed for LOH with 3 markers in the TAP region on chromosome 6p21.3. Mutation analysis of the complete TAP1 gene was performed. RESULTS: Aberrant TAP1 expression was detected in 10/23 cervical carcinoma lesions and in 5/10 adjacent cervical intraepithelial neoplasia (CIN) lesions. All the lesions with low TAP expression also had reduced HLA class I expression. LOH was found in 7 out of 10 lesions with TAP loss. Mutation analysis detected no aberrations, but identified a polymorphism in the 5'-untranslated region (UTR) of the TAP1 gene in two lesions. CONCLUSIONS: This study shows that defective TAP expression in cervical carcinoma is often associated with LOH in the TAP region but not with mutations in the TAP1 gene.     

Clinical outcome of patients with FIGO stage IA2 squamous cell carcinoma of the uterine cervix

Objective

The objective of this analysis was to present the clinical outcome of the patients with FIGO stage IA2 squamous cell cervical cancer treated at the Department of Obstetrics and Gynecology between 1973 and 2009, and to clarify the discrepancies in clinical guidelines regarding the radicality of treatment applied in patients with stage IA2 squamous cell cervical cancer.

Methods

In our study we enrolled 89 women, diagnosed with FIGO stage IA2 squamous cell microinvasive carcinoma (MIC) in the period 1973-2009. The analysis involved the following parameters women's age at operation, type of operation, cell type, mitotic activity, invasive growth pattern, host defense reaction, lymph-vascular space invasion and patient's survival. Additionally, using the Rainer′s scoring system, the prognostic score for each MIC was calculated.

Results

The mean women's age at operation was 41.48 ± 10.67 years. The mean depth of invasion was 3.09 ± 1.13 mm, and the mean area of carcinoma 4.05 ± 2.40 mm². In 66 (74.2%) women the suggested treatment was conization, according to the Rainer's scoring system and individualization of treatment based on decision of the tumor board. Three of the 89 patients diagnosed with MIC stage IA2 died; only in one patient the cause of death was cervical carcinoma. At the end of the observed period the survival rate was 98.0%.

Conclusion

We may conclude that conservative management of stage IA2 MIC is safe when exact evaluation of tumor extension and surgical margins of the cone are considered, and results in very low risk of recurrence, lymph node disease, and death caused by cancer. We believe that our experience will contribute to the achievement of the international consensus concerning the treatment of IA2 MIC.     

The value of preoperative platelet count in the prediction of cervical involvement and poor prognostic variables in patients with endometrial carcinoma

OBJECTIVE(S): To evaluate the relationship between preoperative platelet counts and prognostic factors extensively, among endometrial cancer patients, especially with respect to cervical involvement. METHODS: One-hundred fifty-five patients with endometrial carcinoma, who underwent surgery as the initial treatment consisting peritoneal cytology, total abdominal hysterectomy, bilateral salpingo-oophorectomy, systematic pelvic-paraaortic lymphadenectomy, and omentectomy were retrospectively analyzed. RESULTS: There were no differences with respect to age, histological type (endometrioid vs. non-endometrioid), depth of myometrial invasion, peritoneal cytology, LVSI, and lymphatic metastasis. However, advanced stage (stages III and IV), poorly differentiated tumor grade (grade 3), the presence of cervical and adnexal involvements were associated with significantly higher median preoperative platelet counts. Accepting 325.000/microl platelet count as a threshold value, multivariate analysis revealed cervical involvement (P=0.008; OR=1.84, 95% CI:1.17-2.89) and presence of high grade histology (P=0.014; OR=2.23, 95% CI:1.18-4.23, for grade 3 disease) to be significantly associated with higher platelet count. At a cut-off value of 326.000/microl, 42.3% sensitivity and 82.8% specificity for the prediction of cervical involvement was observed under receiver operator characteristic curve method. CONCLUSION(S): Higher preoperative platelet counts, even in conditions with normal range (150.000-400.000/microl), may reflect poor prognostic factors such as cervical involvement and high grade among patients with endometrial carcinoma. Also, the higher platelet count should be taken into consideration for the necessity of radical hysterectomy.     

Clinical aspects and prognosis of pelvic recurrence of cervical carcinoma.

OBJECTIVE: To identify which patients with locally recurrent cervical carcinoma are potentially curable. METHOD: A total of 664 stage IB-IVA patients were examined following surgery or radiotherapy. RESULT: Among the 664 patients, 193 (29%) developed recurrence. Sixty-seven (35%) of these recurrences were located in the pelvis alone. Among these 67 recurrences, 24 (35%) were central recurrences and the remaining 43 (65%) were pelvic side-wall recurrences. Of the 24 patients with central recurrences, 8 were salvaged. Of these 8 patients, 3 underwent pelvic exenteration, and 5 received optimal radiotherapy. The recurrent tumor in these 5 survivors who received radiotherapy had consisted of a small (<2 cm) tumor. All 43 patients with pelvic wall recurrence developed progressive disease. CONCLUSION: The following patients are potentially curable: patients with a resectable, centrally located tumor who are candidates for pelvic exenteration, and patients with a small central recurrence for whom complete radiation therapy is feasible.     

Changes in cervical neutrophil elastase levels during the menstrual cycle

Purpose  

Cervical mucus plays an important role in host defense mechanisms and is involved in the ascendance of sperm. To determine the change of neutrophil mediators contained in cervical mucus, we measured total neutrophil elastase (NE) levels throughout the menstrual cycle.     

Expression of epidermal growth factor receptor and c-erbB-2 oncoprotein in trophoblast populations of placenta accreta

OBJECTIVE: The purpose of this study was to investigate the expression of epidermal growth factor receptor and c-erbB-2 oncoprotein in trophoblast populations of placenta accreta. STUDY DESIGN: Paraffin sections of 43 placental specimens with (cases) and 43 without (controls) placenta accreta were studied immunohistochemically for epidermal growth factor receptor and c-erbB-2 expression in the syncytiotrophoblast, villous cytotrophoblast, and extravillous cytotrophoblast. Epidermal growth factor receptor and c-erbB-2 protein levels were also performed by Western blot analysis. Controls were matched for gestational age in this case-control study. RESULTS: The percentage of strong/intermediate immunoreactivity of epidermal growth factor receptor in the syncytiotrophoblast was significantly higher in cases (98%) than controls (79%; odds ratio,11.1; 95% CI, 1.3-92.0; P = .03), although strong/intermediate immunoreactivity of c-erbB-2 in the syncytiotrophoblast was significantly lower in cases (35%) than controls (81%; odds ratio, 0.1; 95% CI, 0.1-0.3; P < .001). Epidermal growth factor receptor and c-erbB-2 expression in the villous and extravillous cytotrophoblastic cells were not significantly different between controls and cases ( P > .05). Most immunoreactive bands on Western blots were consistent with the trends of immunohistochemical findings. CONCLUSION: The development of placenta accreta is related closely to the differential expression of epidermal growth factor receptor and c-erbB-2 in the syncytiotrophoblast.     

血清SCCAg及CA125在诊断宫颈鳞癌及评价预后中作用的研究

目的:探讨血清SCCAg及CA125用于宫颈鳞癌诊断、手术治疗及预后的价值。方法:选取ⅠA2～ⅡA期宫颈鳞状细胞癌为研究组,20例CIN及20例慢性宫颈炎分别为对照组1和对照组2。采用固相夹心法酶联免疫吸附实验(ELISA)检测血清SCCAg的数值,采用化学发光免疫分析法(CLIA)检测血清CA125数值。比较分析血清SCCAg及CA125与宫颈鳞癌临床病理特征、手术疗效及预后的关系。结果:宫颈鳞癌组术前血清SCCAg及CA125水平均高于慢性宫颈炎组,差异均具有统计学意义(P<0.01)。宫颈鳞癌组术前SCCAg水平高于CIN组,差异有统计学意义(P<0.001);宫颈鳞癌组术前CA125水平与CIN组的差异无统计学意义(P=0.049,P>0.0167)。血清SCCAg、CA125诊断宫颈鳞癌的临界值分别为1.03ng/ml、8.16U/ml。血清SCCAg、CA125及两项联合诊断宫颈癌的ROC曲线下面积分别为0.954、0.718、0.960,两项联合后诊断性能无明显增加。宫颈鳞癌术前血清SCCAg随临床分期增加具有线性增加的趋势。脉管有否癌栓、盆腔淋巴结有否转移也与术前血清SCCA水平有关,差异有统计学意义(P=0.011,P=0.043)。宫颈鳞癌组手术治疗后的血清SCCAg及CA125水平均有逐渐降低趋势,差异有统计学意义(P均<0.001)。结论:血清SCCAg对宫颈鳞癌有较高的诊断价值,可考虑作为诊断及手术疗效评估指标之一,有助于初步判断脉管及盆腔淋巴结转移。血清CA125对于宫颈鳞癌诊断、手术评估及随访的价值均低于SCCAg,与SCCAg联合不能增加诊断的敏感度和特异度。